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Foreword
I am honoured to be asked to write the Foreword for this comprehensive textbook. It is a compilation of the writings of more than 100 distinguished TB experts from all over the world. They cover almost every aspect of the disease. I am impressed at the concerted effort being made by scientists and health staff working at different levels, through programmes and in hospitals and clinics, to save lives and prevent morbidity. I applaud and commend them for their efforts to find solutions to curtail the devastating effects of a relentless pandemic. Tuberculosis is a very old disease which we are still unable to contain. Since early biblical times the two main mycobacterial diseases, tuberculosis (consumption) and leprosy have caused great suffering and death. Although leprosy is now largely controlled, TB continues its rampant course throughout the world. Despite the fact that the cause of TB was discovered nearly 120 years ago it continues to kill 1.8 million people every year and is responsible for 1 in 4 preventable deaths. Tuberculosis has escalated to the point where millions of people a year develop the disease and die. This pandemic is further complicated by the additional burden of drug-resistant TB, HIV and poor health services in many countries that experience the highest number of TB infections. Tuberculosis is primarily a disease of poverty—patients are often victims of their circumstances rather than being responsible for the problem themselves. The resurgence of TB reflects the failure of global, political and economic institutions to improve the lives of poor people. This textbook with excellent illustrations and photographs will assist the professional and lay reader to understand TB from a variety of perspectives. It provides the latest updates on progress in tackling the disease such as finding solutions for rapidly diagnosing TB, newer drugs and shorter treatment regimens, and more effective
vaccines. The chapters ominously illustrate the enormity of the problem: nearly two million deaths each year, the emerging problems of drug-resistant TB and the serious hindrances in diagnosing and managing the disease caused by coinfection with HIV. While the overall picture for achieving TB control is still gloomy and advance in TB scientific research is slow, there remains room for optimism. Current data from WHO shows that the number of cases of TB reported last year is levelling out in several countries. This surely can be repeated elsewhere. In the short term, TB is likely to continue killing millions each year in poorly resourced countries; sadly the international donor community’s response has been disappointing. This is a disease that can be overcome and I challenge donors to support the work of thousands of dedicated healthcare workers, volunteers, scientists and doctors who are doing their best at the coalface. I am encouraged that this book contains substantial contributions from authors from Africa, particularly South Africa, where TB is taking its toll. By uniting African authors with their colleagues in Europe, Asia and the USA the editors have demonstrated that the way forward in the fight against TB is to move forward together. A vast amount of knowledge has been generated on the subject of TB in the past decade. This book gives a very helpful overview of this material in a readable form. Its publication is timely. I remind the donor community of the urgent need to work towards controlling TB worldwide. We can do it— together. Archbishop Emeritus Desmond Tutu
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Preface
On March 24, 1882, Dr. Robert Koch announced the discovery of Mycobacterium tuberculosis, the bacterium causing tuberculosis (TB). Koch’s achievement was the first step towards developing tools to control TB. Despite initial success with the discovery of anti-tuberculosis chemotherapy 60 years ago, the tubercle bacillus has been a tenacious human enemy, hard to conquer, and today TB disease still kills 5,000 people daily; that is one person every 20 seconds. More than 80 percent of TB cases arise in only 22 countries, most of which are under-resourced. One-third of the world’s population is infected with M. tuberculosis, and 5 to 10 percent of infected people are likely to develop active TB; for those infected with human immunodeficiency virus (HIV) and very young children, the likelihood of developing and dying from TB is much higher. In 2005, an estimated 1.8 million people died of TB; 195,000 were HIV co-infected. Today, fuelled by the HIV epidemic, TB disproportionately affects young adults in their most productive years. It is pushing medical research to its limits with synergic efforts, interdisciplinary approaches, and translational research using the latest technology. M. tuberculosis and HIV co-infection produces a deadly partnership making both infections more destructive together than alone. This is most apparent in Africa where, according to World Health Organization (WHO), TB cases increase 10 percent annually in the wake of increasing levels of HIV infection and, directly and indirectly, involve increasing numbers of children. TB control programmes worldwide are increasingly faced with multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) unresponsive to treatment that may return control programmes to the pre-antibiotic era, unless care is taken of currently existing drugs and new classes of anti-tuberculosis drugs are developed. The huge mortality caused by the TB epidemic underscores the importance of continuing clinical, basic science and operational research to better understand how M. tuberculosis interacts with the host. Research findings translated into health care interventions could improve the diagnosis, treatment and prevention of TB. This textbook was developed from the understanding that advances in infectious disease research should be translated into applied clinical and management practice using newer guidelines. Over the past decade there has been an explosion of research into all aspects of TB (conventional and molecular epidemiology, organism and host interactions, clinical management schedules for TB and HIV co-infected individuals, new diagnostics, newer therapeutic regimens, newer vaccines, operational and implementation research). The revolution has generated new data that is influencing clinical practice in HIV-infected and uninfected adults and children. Research and funding agendas are better coordinated and serious moves to link funding of TB research and development
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work are emerging between a conglomerate of official and nongovernmental agencies. The WHO STOP TB Partnership has established a ‘research movement’ to assist in operational and implementation research. With so much activity in the TB field and growing knowledge being translated into clinical terms, a need to update the literature exists. Currently there are several TB textbooks available, but they are focused either exclusively on research developments or clinical management guidelines. Furthermore most textbooks focus on adult TB and ignore the growing problem of childhood TB as this was not considered important to public health a decade ago. An enormous amount of new data has now accumulated changing our understanding of transmission dynamics, epidemiology, clinical presentation in HIV-infected adults and children, diagnostics, management and infection control. These data need condensation in a practical clinical textbook incorporating management of the HIVinfected patient with active TB. It is apparent on reading several existing TB textbooks that these have been written by authors with limited experience of clinical practice in developing countries, where the majority of TB cases occur. Existing textbooks lack representation of authors from developing countries, particularly Africa. Currently new information on TB generated from clinical and basic science research is published in scientific and medical journals, not readily accessible health workers in poor countries where the brunt of the TB epidemic is borne. The practical management of TB in these countries is based on guidelines formulated several years ago. Most of the practitioners are too busy to catch up with, or do not have access to, the latest developments in the field. Three years ago an urgent need was recognized for an up-todate, affordable, comprehensive textbook on the clinical management of TB in adults and children, preferably by experts from all over the world, but particularly from TB and HIV/AIDS endemic areas. The challenge was taken up by Professor Alimuddin Zumla (editor of Manson’s Tropical Diseases 21st and 22nd editions; himself a survivor of near fatal TB meningitis as a junior doctor); extensive international work on TB and TB advocacy activities led him to pursue this task with Elsevier Publishing convincing them of the need for a new clinical TB textbook. A strong editorial team was assembled to assist with the challenging task. To balance the book between adult and childhood TB, Professor Zumla (an adult physician) chose Professor Simon Schaaf, a distinguished and very experienced paediatrician from the Department of Paediatrics & Child Health, Stellenbosch University, Cape Town, South Africa, as co-editor. For the book to be truly globally representative, Professors Zumla and Schaaf enlisted six international leading TB authorities as associate editors: Professor John M Grange (UK and Europe), Dr. Mario C Raviglione (WHO, Geneva), Dr. Wing
PREFACE
Wai Yew (Asia), Professor Jeffrey R Starke (USA), Professor Madhukar Pai (Canada), and Professor Peter Donald (Africa). This editorial team invited 158 eminent authors from several continents (53 authors from Africa, 32 from USA and Canada, 56 from Europe and 17 from Asia and Australia) to write 107 chapters and 4 appendices to create ‘Tuberculosis: A Comprehensive Clinical Reference’ – an up-to-date, globally relevant TB treatise. The chapters present state-of-the-art on nearly every aspect of clinical TB relevant to clinical practice bringing readers up to date with scientific developments. Most chapters are amply illustrated with figures, graphs, tables and a diversity of clinical, pathological and radiological pictures. The chapters are clearly written with a healthy overlap between some chapters. A wide range of approaches is presented, reviewing current knowledge and indicating gaps and challenges; focused on practical information, a thorough overview of the latest topics places a strong emphasis on clinical practice. This textbook arises from the world-wide need for a comprehensive clinical text with the latest developments in TB research incorporated into advice on day to day clinical practice. Current TB clinical dogma and changing clinical practice due to the ominous consequences of co-infection with HIV and TB are highlighted and the collective experience of 158 authors ensures a unique and practical approach with global appeal. There is information and knowledge for clinical practitioners from major city hospitals to the rural health worker in the TB clinic. Knowledge is provided in clear practical terms to aid a variety of audiences, from general physicians, pulmonologists, TB and HIV clinic staff, medical assistants, nurse practitioners, TB programme staff, medical students, postgraduates, technical staff, clinician scientists (as a clinical guide for scientists), policy makers, politicians and donor agencies.
The bulk of the book is on clinical presentation, diagnosis and management and principles are demonstrated by system based case histories of adults and children. Tuberculosis-a comprehensive reference contains eleven sections. As an introduction to clinical TB, the first three sections provide a brief history, background updates on new knowledge of epidemiology and transmission dynamics, basic science (immunology, pathogenesis of TB and HIV, development of new TB vaccines and pathology and pathogenesis of TB) and natural history of TB. The main clinical thrust is manifested in sections 4 to 8. In these sections clinical presentation and diagnosis of pulmonary and extrapulmonary TB in adults and children are discussed. Complicated tuberculosis such as HIV/TB co-infection, MDR and XDR-TB and TB in pregnancy is also covered. Wellillustrated chapters on diagnostics and imaging are included. Clinical management (treatment and drug doses) of TB follow on the clinical presentation. Illustrative case histories emphasize day to day problems of clinical practice. Section 9 presents clinical cases of TB in nearly all organ systems and convey the considerable experience of the authors. Section 10 covers Social Science and structural issues in TB and TB/HIV which are always important in the overall study of TB. The epilogue introduces perspective and emphasises that current advances allow room for optimism to achieve control, but not total eradication. Professor Alimuddin I Zumla and Professor H Simon Schaaf Chief Editors February, 2009
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Contributors
Miriam Adhikari MBChB, FCP (Paeds) Professor and Head Paediatrics Department of Paediatrics Nelson R Mandela School of Medicine University of KwaZulu Natal Durban, South Africa
SA, MD (Univ
of Natal)
Vineet Ahuja Department of Gastroenterology All India Institute of Medical Sciences New Delhi, India Savvas Andronikou MBBCh, Radiologist Diagnostic Working Group Medicins Sans Frontiers Amsterdam, The Netherlands
FC Rad (Diag), FRCR (Lond) PhD
Phillip S Barie MD, MBA, FCCM, FACS Professor of Surgery and Public Health Department of Surgery New York-Presbyterian Hospital and Weill Medical College of Cornell University New York, NY, USA DCH, MD(UCT)
David W Beatty MBChB, MD Emeritus Professor of Paediatrics Red Cross Children’s Hospital and the School of Child and Adolescent Health University of Cape Town Rondebosch, South Africa Marcel A Behr MD, MSc Associate Professor of Medicine McGill University Montreal, QC, Canada
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Nulda Beyers MBChB, FCP (SA), MSc (Med), PhD Professor of Paediatrics and Child Health Faculty of Health Sciences Desmond Tutu TB Centre and Department of Paediatrics and Child Health Stellenbosch University Tygerberg, South Africa Juanita Bezuidenhout MBChB, MMed, PhD Professor of Anatomical Pathology Department of Anatomical Pathology Stellenbosch University Tygerberg, Cape Town, South Africa
Ludwig Apers MD, MPH, PhD Clinician and Public Health Specialist Institute of Tropical Medicine Antwerpen, Belgium
Eric D Bateman MBChB (UCT), FRCP, Professor of Respiratory Medicine Division of Pulmonology University of Cape Town Cape Town, South Africa
Linda-Gail Bekker MBChB, DTMH, DCH, FCP (SA), PhD Associate Professor Deputy Director of the Desmond Tutu HIV Centre Institute of Infectious Diseases and Molecular Medicine University of Cape Town Cape Town, South Africa
Leopold Blanc MD, MPH Coordinator Tuberculosis Strategy and Operations Stop TB Department, HIV/AIDS, TB and Malaria Cluster World Health Organisation Geneva, Switzerland Bj rn Blomberg MD, PhD Consultant Physician Department of Medicine Haukeland University Hospital and Institute of Medicine Bergen, Norway Franc¸ois GE Bonnici MD Associate Director Global Health Initiative, World Economic Forum Cologny, Geneva, Switzerland Matthys H Botha MBChB, FCOG, MMed Senior Specialist, Obstetrics and Gynaecology Department of Obstetrics and Gynaecology Stellenbosch University and Tygerberg Academic Hospital Tygerberg, South Africa
CONTRIBUTORS
Guillaume Breton MD Department of Internal Medicine Pitie´-Salpe´trie´re Hospital Groupe Hospitalier Pitie´-Salpeˆtrie`re Paris, France
Catherine M Corbishley FRCPath Consultant Histopathologist Department of Cellular Pathology St George’s Hospital London, UK
Daniel Brodie MD Assistant Professor of Clinical Medicine Columbia University College of Physicians and Surgeons New York, NY, USA
Charles L Daley MD Head of Division of Mycobacterial and Respiratory Infections Professor of Medicine National Jewish Medicine and Research Center Denver, CO, USA
Ertan Bulbuloglu MD Associate Professor Department of Surgery and Pathology Kahramanmaras Sutcuimam University Kahramanmars, Republic of Turkey
Thomas M Daniel MD Professor Emeritus of Medicine and International Health Center for Global Health and Diseases Case Western Reserve University Cleveland, OH, USA
William J Burman MD Associate Professor of Medicine Infectious Diseases Clinic Denver Public Health Denver, CO, USA
Rodney Dawson MBChB, FCP (SA) Cert Pulm Consultant Pulmonologist and Head Centre for Tuberculosis Research Innovation University of Cape Town Lung Institute and Division of Pulmonary Medicine Mowbray, Groote Schuur, South Africa
Jose´ A Caminero MD Pneumology Department Hospital General de Gran Canaria Las Palmas, Spain
Adelard I De Backer MD, PhD Head Department of Radiology General Hospital Sint-Lucas Ghent, Belgium
Mete C ¸ ek MD Associate Professor of Urology Department of Urology Osmanaga Mah Istanbul, Turkey
Ashwin S Dharmadhikari MD Department of Medicine Division of Pulmonary and Critical Care Medicine Brigham and Women’s Hospital Boston, MA, USA
Jeremiah M Chakaya MD Chief Research Officer Kenya Medical Research Institute Nairobi, Kenya Lakhbir S Chauhan MD Deputy Director General of Health Services Ministry of Health and Family Welfare Government of India New Delhi, India Chiang Chen-Yuan MD, MPH Director Department of Lung Health International Union against Tuberculosis and Lung Disease Taipei, Taiwan Gavin J Churchyard MB BCh, FCP (SA), Chief Executive Aurum Institute for Health Research Marshalltown, South Africa Harun Ciralik MD Assistant Professor Department of Pathology Kahramanmaras Sutcuimam University Kahramanmaras, Republic of Turkey
MMed, PhD
Keertan Dheda MBBCh, FCP(SA), FCCP, PhD (Lond) Consultant Physician in Respiratory and General Internal Medicine Honorary Senior Lecturer Division of Infection and Immunity University College London London, UK T Mark Doherty MD Coordinator Research and Strategy, Infectious Disease Immunology Statens Serum Institute Copenhagen, Denmark Peter R Donald MBChB (Stellenbosch), DCH (Glasgow), DTM&H (London), FCP(SA), FRCP (Edin) MD (Stellenbosch) Emeritus Professor of Paediatrics and Child Health Department of Paediatrics and Child Health Stellenbosch University and Tygerberg Children’s Hospital Western Cape, South Africa
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CONTRIBUTORS
Francis Drobniewski MB BS, MA, MSc, PhD, Head, Clinical TB and HIV Group CID Institute of Molecular Sciences London, UK
DTM&H, FRCPath
Christopher Dye DPhil Scientist Stop Tuberculosis Department HIV/AIDS, TB and Malaria Cluster World Health Organisation Geneva, Switzerland Soumitra R Eachempati MD, FACS New York-Presbyterian Hospital New York, NY, USA John B Eastwood MD, FRCP Professor of Medicine Department of Renal Medicine St. George’s Hospital London, UK Mary E Edginton MB BCH, FFCH, PhD, MSc, DPH, DOH, DTM&H, DHSM Associate Professor School of Public Health University of the Witwatersrand Johannesburg, South Africa Asma I ElSony MD, PhD Director Epidemiological Laboratory (Epi-Lab) Khartoum Epidemiological Laboratory (Epi-Lab) for Public Health/Implementation Research Khartoum, Sudan
Adem Fazlioglu MD Department of Urology Taksim Teaching Hospital Istanbul Medical School Istanbul, Turkey Katherine Floyd Economist Tuberculosis Monitoring and Evaluation Team Stop TB Department World Health Organization Geneva, Switzerland Gerald Friedland MD Professor of Medicine Yale University School of Medicine Connecticut, USA Mathew Gandy BA, PhD Professor of Geography University College London London, UK Neel R Gandhi MD Assistant Professor of Medicine and Epidemiology Division of General Internal Medicine Montefiore Medical Center and Albert Einstein College of Medicine New York Deliana Garcia MA Director of International Research and Development Migrant Clinicians Network Inc Austin, Texas, USA
Brian S Eley MBChB, FCPaed(SA), BSc(Hons) Head of Paediatric Infectious Diseases Red Cross Children’s Hospital School of Child and Adolescent Health University of Cape Town Rondebosch, Cape Town, South Africa
Claudia Garcia-Moreno MD, MSc Coordinator Gender, HIV/AIDS and Violence Department of Reproductive Health and Research World Health Organization Geneva, Switzerland
Donald A Enarson MD Senior Advisor International Union Against Tuberculosis and Lung Disease (IUATLD) Paris, France
Giuliano Gargioni MD Medical Officer Stop TB Department World Health Organization Geneva, Switzerland
Marcos Espinal MD, PhD, MPH Executive Secretary Stop TB Partnership Secretariat Stop TB Department, HIV/AIDS, TB and Malaria Cluster World Health Organisation Geneva, Switzerland
Haileyesus Getahun MPh, PhD Stop TB Department; HIV/AIDS, TB and Malaria Cluster World Health Organization Switzerland
Elizabeth L Fair PhD Assistant Professor Division of Pulmonary and Critical Care Medicine San Francisco General Hospital University of California San Francisco, CA, USA
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Robert P Gie MMed (Paed), FCP (SA) Department of Paediatrics and Child Health Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa
CONTRIBUTORS
Ishwarprasad Gilada MBBS, DVD Consultant in HIV/AIDS Medicine Unison Medicare and Research Centre Mumbai, India Michael Gotway MD Clinical Associate Professor Professor of Radiology and Pulmonary Critical Care Medicine UCSF; Consulating Staff, Scottsdale Medical Imaging (an Affiliate of Southwest Diagnostic Imaging) Scottsdale, AZ, USA Pierre Goussard MBChB, Mmed(paed) Pediatric Pulmonologist Tygerberg Children’s Hospital Department of Paediatrics and Child Health Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa Stephen M Graham MB BS, FRACP, DTCH Associate Professor in International Child Health University of Melbourne Department of Paediatrics Royal Children’s Hospital Australia John M Grange MBBS(Lond), MSc(Lond), MD(Lond) Visiting Professor Centre for Infectious Diseases and International Health Windeyer Institute London, UK Malgorzata Grzemska MD, PhD Medical Officer Stop TB Department HIV/AIDS, TB and Malaria Cluster World Health Organization Geneva, Switzerland
Tony Hawkridge MSc, FCPHM (SA) Clinical Director South African TB Vaccine Initiative Institute of Infectious Disease and Molecular Medicine University of Cape Town Cape Town, South Africa Leonid Heifets MD, PhD Director, Microbiology Laboratory National Jewish Medical and Research Center Denver, CO, USA Anneke C Hesseling MD, MSc Senior Researcher Department of Paediatrics and Child Health Desmond Tutu TB Centre Stellenbosch University Tygerberg, South Africa Christopher J Hoffmann MD, MPH, Fellow Division of Infectious Diseases John Hopkins School of Medicine Baltimore, MD, USA
MSc
Philip C Hopewell MD Professor and Associate Dean Division of Pulmonary and Critical Care Medicine San Francisco General Hospital University of California, San Francisco San Francisco, CA, USA S Mehran Hosseini MD Epidemiologist Stop TB Department HIV/AIDS, TB and Malaria Cluster World Health Organization Geneva, Switzerland
Phillipe Guerin MD, MPH, PhD Scientific Director of Epicentre Me´decins Sans Frontie`res Paris, France
Gregory D Hussey MBChB, DTM&H, MSc, MMed, FFCH Director South African TB vaccine Initiative Institute of Infectious Diseases and Molecular Medicine Cape Town, South Africa
Willem A Hanekom MBChB, DCH(SA), FCPaed(SA) Laboratory Director South African Tuberculosis Vaccine Initiative Institute for Infectious Disease and Molecular Medicine University of Cape Town Cape Town, South Africa
Elvis Irusen MD Stellenbosch University Tygerberg Hospital Tygerberg, South Africa
Anthony D Harries MA, MD, FRCP, DTM&H Technical Advisor in HIV Care and Support Ministry of Health Malawi Country Office Lilongwe, Malawi
Ernesto Jaramillo MD, PhD Medical Officer Stop TB Department World Heath Organisation Geneva, Switzerland
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CONTRIBUTORS
Prakash M Jeena MD Department of Paediatrics and Child Health University of Kwazuku-Natal Durban, South Africa
Christian Lienhardt MD, DTM, MSc, PhD Head, Clinical Trial Division International Union Against Tuberculosis and Lung Diseases Paris, France
John L Johnson MD Project Investigator Department of Medicine Case Western Reserve University and University Hospitals Case Medical Center Cleveland, OH, USA
Knut Lo¨nnroth MD, MSc (Clinical Epidemiology), PhD (Social Medicine) Medical Officer TB Strategy and Health Systems Stop TB Department World Health Organisation Geneva, Switzerland
Nico E Jonas MBChB, FRCS (Glas), FCORL Consultant Division of Otolaryngology University of Cape Town Medical School Cape Town, South Africa
Gary Maartens MBChB, MMed, FCP(SA), Professor of Clinical Pharmacology Division of Clinical Pharmacology UCT Health Sciences Faculty Cape Town, South Africa
DTM&H
H Francois Jordaan MBChB MMed Associate Professor and Head Division of Dermatology Department of Medicine Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa
Dermot Maher MA, BM BCh, DM, MRCGP, FRCP, Senior Clinical Epidemiologist MRC/UVRI Uganda Research Unit on AIDS Entebbe, Uganda
Shaloo P Kamble MBBS, India Program Manager Global Health Initiative World Economic Forum Geneva, Switzerland
Ben J Marais MBChB, MRCP (Paed UK), FCP (Paed MMed, PhD Associate Professor of Paediatrics and Child Health Department of Paediatrics and Child Health Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa
DTCD
Priya Khanna Clinical TB and HIV Group CID Institute of Molecular Sciences London, UK Sharon Kling MMed (Cape Town) FC Paed (SA) Senior Specialist Department of Paediatrics and Child Health Stellenbosch University Tygerberg, South Africa Fatih O Kurtulus MD Department of Urology Taksim Teaching Hospital Istanbul Medical School Istanbul, Turkey Stephen D Lawn MD The Desmond Tutu HIV Centre Institute for Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Cape Town, South Africa Jonathan Levin PhD Statistician MRC/UVRI Uganda Research Unit on AIDS Uganda Research Unit on AIDS Entebbe, Uganda
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Bongani M Mayosi Dphil, Professor and Head Department of Medicine University of Cape Town Groote Schuur Hospital Cape Town, South Africa
FFPH
SA),
FCP (SA), FESC, MASSAf
Christopher RE McEvoy BSc (Hons), PhD Postdoctoral Research Fellow DST/NRF Centre of Excellence in Biomedical TB Research Department of Medical Biochemistry Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa Helen McIlleron MBChB, PhD Senior Medical Researcher Pharamcokinetic Research Unit Division of Clinical Pharmacology, UCT Groote Schuur Hospital Cape Town, South Africa Salil Mehta MS, DNB Consultant Ophthalmologist Department of Opthalmology Lilavati Hospital and Research Centre Mumbai, India
CONTRIBUTORS
Graeme Meintjes MD Department of Medicine Institute of Infectious Diseases and Molecular medicine University of Cape Town Cape Town, South Africa Dick Menzies MD, MSc Professor of Respirology and Epidemiology Director Respiratory Division of the MUHC Montreal Chest Institute Montreal, Canada Anthony P Moll BSc, MBChB Chief Medical Officer Church of Scotland Hospital Tugela Ferry, South Africa Joia Mukherjee MD Assistant Professor Division of Social Medicine and Health Inequalities Brigham and Women’s Hospital Harvard Medical School Boston, MA, USA W Mulwafu MBChB Senior Registrar, Division of Otolarygology University of Cape Town Medical School Groote Schuur Hospital Cape Town, South Africa Jean B Nachega MD, PhD Professor of Medicine and Epidemiology Director Centre for Infectious Diseases Stellenbosch University Cape Town, South Africa Nani Nair MD Regional Advisor - Tuberculosis Regional Office for South-East Asia World Health Organisation New Delhi, India Edward A Nardell MD Associate Professor FXB Centre for Health and Human Rights Harvard School of Public Health Boston, MA, USA Lisa J Nelson MD Country Director, Mozambique, Global AIDS Program Centers for Disease Control and Prevention (CDC) Maputo, Mozambique Andrew Nunn MSc Associate Director MRC-Clinical Trials Unit London, UK
Paul Nunn MD, FRCP Coordinator TB/HIV and Drug Resistance Stop TB Department HIV/AIDS, TB and Malaria Cluster World Health Organization Geneva, Switzerland Philip C Onyebujoh MD, PhD, FRCP (Lond) Medical Officer and TB/HIV Research Officer Implementation Research and Methods UNICEF/UNDP/ World Bank/WHO Special Programme for Research and Training in Tropic Geneva, Switzerland Madhukar Pai MD, PhD Assistant Professor of Epidemiology Department of Epidemiology, Biostatics and Occupational Health, McGill University Montreal, Canada Mark D Perkins MD Chief Scientific Officer Foundation for Innovative New Diagnostics (FIND) Cointrin, Switzerland Robert J Pratt BA, MSc, RN, RNT, DN(Lond) Director Richard Wells Research Centre Institute for Research in Health and Human Sciences Thames Valley University London, UK Chris AJ Prescott MBChB, MMed, FCS(SA) Professor Division of Otolaryngology University of Cape Town Medical School Cape Town, South Africa Mario C Raviglione MD Director Stop TB Department (STB) HIV/AIDS, TB and Malaria Cluster World Health Organisation Geneva, Switzerland Helmuth Reuter MBChB, FCP (SA), MMed (Int), FRCP (Edinb) PhD Professor of Internal Medicine Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa Etienne de la Rey Nel MBChB, MMed Consultant Department of Paediatrics and Child Health University of Stellenbosch Cape Town, South Africa
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CONTRIBUTORS
John C Ridderhof PhD, HCLD (ABB) Associate Director of Health Sciences National Center for Preparedness Detection and Control of Infectious Diseases CCID Centers for Disease Control and Prevention Atlanta, GA, USA Colebunders Robert MD Head, HIV/STD unit Department of Clinical Science Institute of Tropical Medicine Antwerp, Belgium Graham AW Rook BA, MB, BChair, MD Professor of Microbiology Centre for Infectious Diseases and International Health Windeyer Institute of Medical Sciences London, UK
Kevin Schwartzman MD, Assistant Professor Department of Medicine McGill University Montreal, QC, Canada
MPH, FRCPC
N Sarita Shah MD, MPH Assistant Professor of Medicine and Epidimiology Division of General Internal Medicine Montefiore Medical Center and Albert Einstein College of Medicine New York Mahesh P Sharma MD, DM, FACG, FAMS Head of Department of Gastroenterology Department of Gastroenterology Rockland Hospital New Delhi, India
ID Rusen MD, MSc Director Department of Tuberculosis Control and Prevention International Union Against Tuberculosis and Lung Disease Paris, France
Om P Sharma MD, FRCP Professor of Medicine Department of Pulmonology and Critical Care Medicine LAC and USC Medical Center Los Angeles, CA, USA
Fabio Scano MD Stop TB Department HIV/AIDS, TB and Malaria Cluster World Health Organisation Geneva, Switzerland
Surendra K Sharma MD, PhD Chief Division of Pulmonary and Critical Care Medicine All India Institute of Medical Sciences New Delhi, India
H Simon Schaaf MBChB (Stell), MMed Paed (Stell), DCM (Stell), MD Paed (Stell) Professor of Paediatrics, sub-specialist Infectious Diseases, Department of Paediatrics and Child Health and Desmond Tutu Tuberculosis Centre, Faculty of Health Sciences, Stellenbosch University; Consultant, Tygerberg Children’s Hospital and Brooklyn Hospital for Chest Diseases, Cape Town, South Africa
Hari S Shukla MS, PhD, FRCSEd Professor and Head Department of Surgical Oncology Institute of Medical Sciences Banaras Hindu University Lanka, Varanasi, India
Neil W Schluger MD Professor of Medicine, Epidemiology, and Environmental Health Sciences Chief Division of Pulmonary, Allergy, and Critical Care Medicine Columbia University College of Physicians and Surgeons New York, NY, USA Johann W Schneider MBChB, MMed (Anat Path) Professor of Anatomical Pathology Department of Pathology Faculty of Health Sciences University of Stellenbosch Cape Town, South Africa Johan F Schoeman MBChB, MMed (Paeds), Professor of Paediatrics Department of Paediatrics and Child Health Faculty of Health Sciences Stellenbosch University Tygerberg, South Africa
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S Bertel Squire BSc, MBChir, MD, FRCP Senior Lecturer in Clinical Tropical Medicine Consultant Physician Liverpool School of Tropical Medicine Liverpool, UK Jeffrey R Starke MD Professor and Vice-Chairman Department of Pediatrics Baylor College of Medicine Texas Children’s Hospital Houston, TX, USA Martin Storm BSC, MBChB, FCS(Orth), Consultant Orthopaedic Surgeon Vredenburg, South Africa
FCP (Paeds) SA, MD
Willem A Sturm MD, PhD Professor of Medical Microbiology Department of Medical Microbiology Nelson R Mandela School of Medicine Congella, South Africa
MMed(Orth)
CONTRIBUTORS
Mallika Tewari MS, MRCSEd Senior Resident Department of Surgical Oncology Institute of Medical Science Banaras Hindu University Varanasi, Uttar Pradesh, India Rachael Thomson Co-ordinator EQUS-TB Project Liverpool School of Tropical Medicine Liverpool, UK Anna Thorson MD, PhD Division of International Health (IHCAR) Department of Public Health Services Karolinska Institute Stockholm, Sweden Guy E Thwaites MD, MBBS, MRCP, MRCPath, PhD Wellcome Trust Clinical Research Fellow Centre for Molecular Microbiology and Immunity Imperial College London, UK Jacqueline P Tulsky MD Professor of Clinical Medicine Department of Medicine, Positive Health Program University of California, San Francisco San Francisco, CA, USA Mukund W Uplekar MD Medical Officer Stop TB Department, HIV/AIDS, TB & Malaria Cluster World Health Organization Geneva, Switzerland Mahnaz Vahedi MBBS, MIPH Medical Officer Implementation and Research methods UNICEF/UNDP/World Bank/WHO Special program for Research and Training in Tropical Diseases (TDR) World Health Organisation Geneva, Switzerland Armand Van Deun MD Research Assistant & Bacteriology Consultant The Union Mycobacteriology Unit Institute of Tropical Medicine Antwerp, Belgium Paul van den Brande MD Pulmonologist Department of Pulmonology University Hospital Gasthuisberg Catholic University of Belgium Leuven, Belgium
Frederick H Van der Merwe MBChB, MMed (O&G), FCOG Specialist Obstetrician and Gynaecologist Department of Obstetrics and Gynaecology Tygerberg Academic Hospital and Stellenbosch University Tygerberg, South Africa Paul D van Helden PhD Director DST/NRF Centre of Excellence in Biomedical Tuberculosis Research Division of Molecular Biology and Human Genetics Department of Biomedical Sciences Faculty of Health Sciences University of Stellenbosch Tygerberg, South Africa Jan van den Hombergh Country Director PharmAccess Foundation Dar-Es-Salaam, Tanzania
MD, MSc, MPH
Filip M Vanhoenacker MD, PhD Medical Faculty Department of Radiology University Hospital Antwerp Edegem, Belgium Johan van Wijgerden RGN, BSc, Public Health Manager Ealing Primary Health Care Trust Southall, Middlesex, UK
MSc
Gert J Vlok MBChB (Stell), MMed (Orth) Stell, Professor and Head Department of Orthopaedic Surgery Faculty of Health Sciences University of Stellenbosch Tygerberg, South Africa
FC Orth (SA)
Robert S Wallis MD Medical Director Pharmaceutical Product Developments Inc. Washington DC, USA Fraser Wares MBChB, DTM&H, MPH Medical Officer (Tuberculosis) Office of the WHO Representative to India New Delhi, India Robin M Warren PhD DST/NRF Centre of Excellence in Biomedical Tuberculosis Research Division of Molecular Biology and Human Genetics Department of Biomedical Sciences Faculty of Health Sciences University of Stellenbosch Tygerberg, South Africa
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CONTRIBUTORS
Catherine J Watt DPhil Epidemiologist Stop TB Department, HIV/AIDS, TB and Malaria Cluster World Health Organization Geneva, Switzerland Diana EC Weil MD Senior policy Advisor Stop TB Department, HIV/AIDS, TB and Malaria Cluster World Health Organization Geneva, Switzerland Mary C White RN, MPH, PhD Professor Community Health Systems University of California, San Francisco San Francisco, CA, USA Andrew C Whitelaw MBBch, MSc, FCPath (Micro) SA Senior Specialist, National Health Laboratory Service Senior Lecturer, University of Cape Town Groote Schuur Hospital Cape Town, South Africa Nicky Wieselthaler MBChB, FCRad(DiagSA) Consultant Department of Radiology University of Cape Town Red Cross War Memorial Children’s Hospital Cape Town, South Africa Brian G Williams PhD Epidemiologist Tuberculosis Monitoring and Evaluation Stop TB Department, HIV/AIDS, TB AND Malaria Cluster World Health Organisation Geneva, Switzerland Robin Wood BSc, BM, BCH, FCP (SA) Professor of Medicine Desmond Tutu HIV Research Centre Institute of Infectious Disease and Molecular Medicine University of Cape Town Medical School Cape Town, South Africa
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Colleen A Wright MD Professor and Head of Discipline Department of Anatomical Pathology Faculty of Health Sciences NHLS Tygerberg Hospital Tygerberg, South Africa Alimuddin I Zumla BSc, MBChB, MSc (Lond), PhD (Lond), FRCP(Lond), FRCP(Edin) Professor of Infectious Diseases and International Health, University College London Medical School; Director, Centre for Infectious Diseases and International Health, Windeyer Institute of Medical Sciences, University College London, UK; Honorary consultant infectious diseases physician, University College London Hospitals NHS Foundation Trust, London, UK; Honorary Professor, Liverpool School of Tropical Medicine, University of Liverpool, UK; Visiting Professor, Department of Medicine, University of Cape Town, South Africa; Honorary Professor, University of Zambia School of Medicine, Lusaka, Zambia; Vice President, Royal Society of Tropical Medicine and Hygiene (2004-2006); Member of the Court of Governors, London School of Hygiene & Tropical Medicine, London, UK; Member of the Steering Technical Advisory Group, WHO STOP TB Partnership, Geneva, Switzerland; Member TB Alert; and formerly Associate Professor, Centre for Infectious Diseases, University of Texas Health Science Centre at Houston, School of Medicine and Public Health, Houston, Texas, USA. Edward Zuroweste MD Chief Medical Officer Migrant Clinicians Network Austin, TX, USA
Dedication
This textbook is dedicated to: all those selfless, committed individuals and institutions who are engaged in the fight against the killer disease Tuberculosis; the millions of people who suffer from the disease each year; and those who have succumbed to it.
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Acknowledgements
At the start of this project we were aware of the massive undertaking that we had taken on board. We were strongly encouraged by many members of the global TB fraternity who saw a great need for this textbook and unflinchingly supported us during the entire period of book development. The end result has been absolutely superb. We are very grateful to many individuals who assisted us in this formidable task. Our gratitude goes to our six associate editors, Professor John M Grange, Dr. Mario C Raviglione, Dr. Wing Wai Yew, Professor Jeffrey R Starke, Professor Madhukar Pai, and Professor Peter R Donald who were always willing to assist and review chapters in their areas of expertise. This high powered combination of TB leaders enabled us to easily attract the 158 willing authors who enthusiastically contributed chapters of the highest quality. Their excellent contributions will go a long way to furthering knowledge on TB and will help in the management of millions of adults and children with TB in the world.
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The staff at the publishers Elsevier Science were very cooperative and sincere thanks to Ms Sarah Penny, Ms Louise Cook, Ms Shereen Jameel for the efficient way they handled the production schedule and liaised with us. To our wives and families a special thank you for their support, patience and encouragement. We are indebted to Professor John M Grange for his generous and voluntary contributions to editorial activities. To our research and clinical teams at University College London and Stellenbosch University, we are indebted for their support received during the time we spent on editing the text. It’s been a pleasure editing this volume and we hope that the hard work of the editorial team and authors will be of major benefit to the readers world wide, and help in the battle against TB worldwide. Chief Editors Professors Alimuddin I Zumla and H Simon Schaaf
Abbreviations
AAFB AAP ABC ACH ACSM ACTH ADA AE AFB Ag AIDS AII AMTD APC ARDS APHA ARI ART ARV ATS AUC BAE BAL BCG BM BMI BOF bp BSC BTS CAPD CDC CF CFP CFU/cfu CHW CI CL
acid-alcohol-fast bacilli American Academy of Pediatrics abacavir air changes per hour advocacy, communication and social mobilization adrenocorticotropic hormone (corticotropin) adenosine deaminase adverse event acid-fast bacilli antigen acquired immunodeficiency syndrome airborne infection isolation Amplified Mycobacterium Tuberculosis Direct antigen presenting cell adult respiratory distress syndrome American Public Health Association annual risk of (tuberculosis) infection antiretroviral treatment (therapy) antiretrovirals American Thoracic Society area under the concentration-time curve bronchial artery embolization bronchoalveolar lavage Bacillus Calmette-Gue´rin bacterial meningitis body mass index broncho-oesophageal fistulae base pair biological safety cabinet British Thoracic Society continuous ambulatory peritoneal dialysis Centers for Disease Control and Prevention cystic fibrosis culture filtrate protein colony forming units community health worker confidence interval confidence limit
CMI CMV CNS COPD CPT CRF CRISPA CRP CSF CSO CT CXR CYP450 DALY db DC DC-SIGN DMC DOT DOTS DR DRS DST DTH DVR DWI E EBA ECG EFV EIB ELISA ELISPOT EMB ENT EPI EQA ESAT ESR
cell mediated immunity (or immune response) cytomegalovirus central nervous system chronic obstructive pulmonary disease co-trimoxazole preventive therapy case-report form clustered regularly interspaced short palindromic repeats C-reactive protein cerebrospinal fluid civil society organization computed tomography (scan) chest radiograph cytochrome P450 disability-adjusted life-years decibel dendritic cell dendritic cell-specific intracellular adhesion molecule-3 grabbing nonintegrin Data Monitoring Committee directly observed treatment (therapy) directly observed treatment, shortcourse Direct Repeat drug resistance surveillance drug susceptibility test delayed type hypersensitivity direct variable repeat diffusion weighted imaging ethambutol early bactericidal activity electro cardiogram efavirenz erythema induratum of Bazin enzyme-linked immunosorbent assay enzyme-linked immunospot ethambutol ear, nose and throat Expanded Programme on Immunization external quality assessment Early Secreted Antigenic Target erythrocyte sedimentation rate
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ABBREVIATIONS
ESRF ETH EU EUS FAS FBO FDA FDC FDG-PET FEV1 FIND FLAIR FliP FNA FNAB FNAC FTT GATB GCP GDF GFATM GFR GLC GLP GM-CSF gp H HAART HAI HBC HCW HþE HEPA HHV HIV HLA HPA HPLC HR HRCT HSP IC ICH ICP ICSI IDPs IDSA IDU
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end-stage renal failure ethionamide European Union endoscopic ultrasound fatty acid synthase faith-based organisation Food and Drug Administration fixed-dose combination 18 F-fluoro-2-deoxy-D-glucose positron emission tomography forced expiratory volume-1 second Foundation for Innovative New Diagnostics fluid-attenuated inversionrecovery fast ligation-mediated PCR fine needle aspiration fine needle aspiration biopsy fine needle aspiration and cytology failure to thrive Global Alliance for TB drug development Good Clinical Practice Global Drug Facility Global Fund to fight AIDS, Tuberculosis and Malaria glommerular filtration rate Green Light Committee Good Laboratory Practice granulocyte-macrophage colonystimulating factor glycoprotein isoniazid highly active antiretroviral therapy healthcare-associated infections high-burden country healthcare worker Haematoxylin and Eosin (stain) high-efficiency particulate air (filters/filtration) human herpes virus human immunodeficiency virus human lymphocyte antigen hypothalamo-pituitary adrenal high-performance liquid chromatography hazard ratio high resolution computed tomography heat shock protein informed consent International Conference on Harmonisation intracranial pressure intracytoplasmic sperm injection internally displaced persons Infectious Diseases Society of America injection drug user
IEC IFN IGRA IL IM IMP IMR INGO INH iNOS INR IPT IRB IRD IRIS IS ISTC ITT IUATLD IVU IWGMT kb kDa KS kV LAM LAMP LDH LED LEV LIP LJ LP LPS LRP LSPs LTBI LTCF LTR MAC MAI MBL M. bovis MDG MDR MGIT MHC MIC MIRUs MOTT MRC
Independent Ethics Committees interferon interferon-gamma release assay interleukin intramuscular Interventional Medical Product Infant Mortality Rate international non-governmental organizations isoniazid inducible nitric oxide synthetase international normalized ratio isoniazid preventive therapy Institutional Review Board immune restoration disease immune reconstitution inflammatory syndrome insertion sequence International Standards for Tuberculosis Care intention to treat International Union against Tuberculosis and Lung Disease intravenous urogram International Working Group on Mycobacterial Taxonomy kilobase kiloDalton Kaposi sarcoma kiloVolt lipoarabinomannan loop-mediated isothermal amplification lactate dehydrogenase light emitting diode local exhaust ventilation lymphoid interstitial pneumonitis Lo¨wenstein-Jensen lumbar puncture liopolysaccharide Luciferase reporter phages large-sequence polymorphisms latent tuberculosis infection long-term care facility long terminal repeat Mycobacterium avium complex Mycobacterium avium intracellulare mannose-binding lectin Mycobacterium bovis Millennium Development Goal multidrug-resistant Mycobacterial Growth Indicator Tube major histocompatibility complex Minimal inhibitory concentration Mycobacterial Interspersed Repetitive Units mycobacteria other than (typical) tuberculosis Medical Research Council
ABBREVIATIONS
MRI MRS MTB MTBC MTD M. tuberculosis MVA NAA NAATs NALC NANDA-International NAT NGO NICE NIH NIOSH NK cells NNRTI NO NOD2 NPV NRL NRTI NSAID nsSNPs NTCA NTP NTCP NVP OR PAF PAL PAMPs PAS PAS (in Chapter 21 & 87) PBMC PCP PCR PET PFR PGL PGRS PHC PI PK
magnetic resonance imaging magnetic resonance spectroscopy Mycobacterium tuberculosis Mycobacterium tuberculosis complex Mycobacterium Tuberculosis Direct Mycobacterium tuberculosis Modified vaccinia Ankara nucleic acid amplification nucleic acid amplification tests N-acetyl-L-cysteine North American Nursing Diagnosis AssociationInternational N-acetyltransferase non-governmental organisation National Institute for Health and Clinical Excellence National Institutes of Health National Institute for Occupational Safety and Health natural killer cells non-nucleoside reverse transcriptase inhibitor nitric oxide nucleotide oligomerization binding domain 2 gene negative predictive value national reference laboratory nucleoside reverse transcriptase inhibitor non-steroid anti-inflammatory drug non-synonymous SNPs National Tuberculosis Controllers Association National Tuberculosis Programme National Tuberculosis Control Programme nevirapine odds ratio population attributable fraction Practical Approach to Lung Health pathogen-associated molecular patterns para-aminosalicylic acid Periodic acid-Schiff (stain) peripheral blood mononuclear cells Pneumocystis jiroveci pneumonia polymerase chain reaction positron emission tomography particulate filter respirator persistent generalized lymphadenopathy polymorphic GC-rich repetitive sequence Primary Health Care protease inhibitor pharmacokinetic
PLWHA PMTCT PNT PPAs PPD PPM PPV PRR PWBs PZA QFT-G R RCT RD R&D RES RFLP RIF RMP RNTCP S SAE SC SCC SCID SI SIADH SLD SLE SM SNPs sSNPs SOP SRL STAG STIR SUR SUV T TAG TB TBM TCH TCR TDF TGF-b Th1/Th2 The Union TIR
people living with HIV/AIDS prevention of mother-to-child transmission papulonecrotic tuberculid Participatory Poverty Assessments purified protein derivative public-private mix positive predictive value pattern recognition receptor patient-wise drug boxes pyrazinamide QuantiFERONW-TB Gold rifampicin randomized controlled trial Regions of Difference (genome) research and development reticulo-endothelial system restriction fragment length polymorphism rifampicin rifampicin Revised National Tuberculosis Control Programme (India) streptomycin serious adverse event subcutaneous short-course chemotherapy severe combined immunodeficiency Spreading Index syndrome of inappropriate antidiuretic hormone (secretion) second-line drugs systemic lupus erythematosus streptomycin single nucleotide polymorphisms synonymous SNPs standard operational procedure Supra-Regional Laboratory/ Supra-National Reference Laboratory Scientific and Technical Advisory Group short Tau inversion recovery standardized uptake ratio standardized uptake value thioacetazone Treatment Action Group tuberculosis tuberculous meningitis thiophen-2-carboxylic acid hydrazide T-cell receptor tenofovir disoproxil fumarate transforming growth factor-b T-helper type 1/T-helper type 2 International Union Against Tuberculosis and Lung Disease toll/interleukin-I receptor
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ABBREVIATIONS
TLR TNF TNF-a Treg TSH TSRU TST TU TUR-P UK UN UNHCR UNICEF UPJ US USA (or US)
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toll-like receptor tumor necrosis factor tumor necrosis factor-alpha regulatory T cells thyroid stimulating hormone Tuberculosis Surveillance and Research Unit tuberculin skin test tuberculin units transurethral resection of the prostate United Kingdom United Nations United Nations High Commission for Refugees United Nations Children Fund ureteropelvic junction ultrasound United States of America
USPHS UVGI VATS VCT VDR VNTR VOC WHA WHO WHO-TDR
XDR X-ray Z ZN
United States Public Health Service ultraviolet germicidal irradiation video-assisted thoracoscopic surgery voluntary counseling and testing VitD3 receptor variable nucleotide tandem repeats volatile organic compounds World Health Assembly World Health Organization World Health organization – Special Programme for Research and Training in Tropical Diseases extensive(ly) drug-resistant radiograph pyrazinamide Ziehl-Neelsen (stain)
SECTION 1
HISTORY AND EPIDEMIOLOGY OF TUBERCULOSIS
CHAPTER
The history of tuberculosis
1
Past, present, and challenges for the future Thomas M Daniel
Most of the technologically advanced world has seen more than a century of declining incidence of tuberculosis (TB). The less developed world has not been so fortunate, and in those populous regions TB incidence is increasing. In acquired immunodeficiency syndrome (AIDS)-stricken regions – sub-Saharan Africa, for example – TB case rates now are 50–100 times those in North America and Europe. Spurred by immunodeficiencies resulting from human immunodeficiency virus (HIV) infection, these case rates will continue to increase in coming decades. The history of TB reveals that this disease has swept across large regions of the globe in slowly moving epidemic waves with periods measured in centuries. The factors contributing to the rise and decline of these waves are only partly known and are difficult to control in the absence of massive social and political changes. There is, however, much that we might learn from considering the historical spread of TB and the ways in which those countries now favoured with low TB incidences managed their high-incidence problems in their pasts.
ORIGINS The genus Mycobacterium has a slow rate of mutation, and this fact has enabled the development of hypotheses concerning the origins and evolution of Mycobacterium tuberculosis. There is some inferential reason to suspect that the genus, as represented by Mycobacterium ulcerans, may have existed 150 million years ago in the Jurassic period.1 Gutierrez and her colleagues2 at the Pasteur Institute have concluded that the progenitor of M. tuberculosis emerged from an array of mycobacterial species about 3 million years ago, presumably infecting early hominids and other primates in prehistoric times. It seems likely that all modern members of the M. tuberculosis complex evolved from a common ancestor 15,000–20,000 years ago.3,4 Mycobaterium bovis and other species in the complex split off from the central line at later times. Figure 1.1 presents the phylogenetic tree developed by Gutierrez and her colleagues. The hypothesized genome of the common progenitor more closely resembles M. tuberculosis than other mycobacterial species. Thus it is presented as a straight line from the hypothesized progenitor in Fig. 1.1. The position in time of the common progenitor implies that whatever diversity had occurred during preceding millennia became severely constricted before giving rise to modern species. Present-day TB is caused by six or seven clades – strains with common ancestors – of M. tuberculosis, which have separate geographic origins.5–7 Dating methods applied to members of two of these strains suggest that they emerged in their present form between 250 and 1,000 years ago.6
The earliest archaeological evidence of human TB comes from Egyptian art and mummies; there is ample evidence of spinal TB (Pott’s disease) as early as 5,500 years ago.8–10 While early workers attributed these infections to M. bovis, there is now good evidence from studies of amplified DNA recovered from mummies that M. tuberculosis was the cause of disease in ancient Egyptians.11,12 There are unequivocal references to TB in the Old Testament books of Deuteronomy and Leviticus at the time when Jews were in exile in Egypt.13 In fact, although the archaeological record is sparse or non-existent, there is reason to believe that TB was widespread, if not uniformly distributed, in Africa long before Arabians and Europeans entered the continent.14 There is general agreement that TB first appeared as a human disease in East Central Africa and that it travelled with early peoples as they migrated into Asia Minor and across the globe. There are imprecise prehistoric references to TB from India and China, but no archaeological evidence.15 Migrating early peoples reached the Americas across the land bridge connecting Siberia and Alaska and along its coast, perhaps in several waves, reaching as far south as Chile by 15,000 years ago. Tuberculosis was common in a number of western hemisphere locations before the arrival of Columbus and the Spanish conquistadores.16 As in Egypt, Andean mummies have yielded mycobacterial DNA. In both Africa and the Americas the TB epidemic wave seems to have crested and receded at early times, leaving naive populations susceptible to the reintroduction of TB by European colonizers.
WORLD HISTORY During my elementary school education, which took place during the 1930s, several earnest teachers embarked upon lessons of world history for me and my classmates. Each time the courses started with classical Greece, perhaps after a passing mention of Egyptian pharaohs, progressed to Rome, skipped hurriedly over the Middle Ages, and arrived at the Industrial Revolution at about the time the school year ended. This time course might well serve as a model for the rising wave of TB that crested in Europe and North America in the nineteenth century. In classical Greece, Hippocrates, Plato, and Aretaeus described TB, and the word phthisis for pulmonary TB is Greek.15 ‘Phthisis makes its attacks chiefly between the age of eighteen and thirtyfive’, Hippocrates wrote.17 Tuberculosis was described by Galen, the Greek physician who settled in Rome and became its preeminent physician. He recommended fresh air, milk, and sea voyages
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Numerous polymorphisms in house-keeping genes
Common ancestor of the M. tuberculosis complex Loss of 26 spacers present in M. canettii
can
M. canetti
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ancestral
TbD 1
RD 9
M. tuberculosis
modern
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RD 7 RD 8
RD 10 M. africanum
RDmic Rights were not granted to include this content in electronic media. Please refer to the printed book. RD12 RDseal RD 13
RD 4
M. microti oryx seal
goat M. bovis
RD 1 RD 2
classical BCG Tokyo
RD 14 BCG Pasteur
Fig. 1.1 Proposed scheme for the evolution of modern strains of Mycobacterium tuberculosis complex organisms based on the presence or absence of conserved deleted regions and on sequence polymorphisms in five selected genes. All modern strains of M. tuberculosis are shown as direct descendants of a common ancestor hypothesized to have existed 15,000–20,000 years ago. Reproduced with permission from Brosch R, Gordon SV, Marmiesse M, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. PNAS 2002;99:3684–3689. Copyright 2002 National Academy of Sciences, USA.
for his TB patients, treatment modalities that would persist well into the nineteenth and twentieth centuries. With the fall of the Roman Empire in the fifth century AD, Europe entered a millennium that has been called the Dark Ages. Written records of disease are virtually non-existent. However, there is evidence of bony TB from archaeological sites throughout Europe.18 There is also abundant evidence that scrofula – TB of the cervical lymph nodes – was common in mediaeval Europe. Beginning with the Frankish king Clovis in 496, European rulers practiced healing of this affliction by the royal touch, and later rulers supported some of the large expenses of the throne by charging the thousands of supplicants who sought their cures.16 Protocols became established that probably did much to verify the TB nature of the adenopathy. Much of the scrofula may have been bovine TB resulting from the ingestion of contaminated milk. The Renaissance began in southern Europe and moved northwards. With it, our record of TB re-emerges, perhaps simply because the record is clearer, but more likely because increasing urbanization led to rising TB incidences. St. Francis died of TB in 1226; Baruch
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Spinoza succumbed in 1677.16 In 1660 John Bunyon called TB ‘The Captain among these Men of Death’.19 At that time, case rates in London probably reached 1,000–1,250/100,000/year.20 As the epidemic wave of TB crested in Europe and North America in the eighteenth and nineteenth centuries, the disease became romanticized.16,21 Byron is said to have remarked, ‘I should like to die of consumption’. ‘Why?’ he was asked. ‘Because the ladies would all say, “Look at that poor Byron, how interesting he looks in dying.”’21 Fre´de´ric Chopin suffered from TB throughout his adult life, dying of cardiorespiratory failure secondary to that destructive disease in 1849. His lover, Georges Sand, called him her ‘poor melancholy angel’.15 Charles Dickens wrote, ‘There is a dread disease . . . in which the struggle between body and soul is so gradual, quiet, and solemn . . . [that as] the mortal part wastes and withers away, so the spirit grows light and sanguine.’22 Perhaps the contrast between the affluence of those who profited from the Industrial Revolution and the grinding poverty and tortured life circumstances of those newly crowded into factories and slums who were most likely to be afflicted mandated a rosier view of TB.
CHAPTER
The history of tuberculosis
CONQUESTS AND EMPIRES Even before Europe emerged from the Dark Ages, European seamen were exploring the world’s oceans and their rulers were claiming hegemony over the lands they discovered. By the sixteenth and seventeenth centuries, conquests, colonization, and empire building were underway on large scale. Tuberculosis went with the Europeans, and it found fertile ground in the populations of much of the world that they conquered. Although TB had reached most of the globe in prehistoric times, it had long since receded from the Americas and much of Africa, leaving the peoples of those regions immunologically naive with respect to M. tuberculosis. Following Charles Darwin’s exploration of Tierra del Fuego, the British established a Protestant Mission at Ushuaia. Local Fuegians were relocated from their villages to this mission. In the winter of 1884, half of them died; TB was the principal cause of death.23 This tragic story was repeated many times in Alaska, Amazonia, and throughout the western hemisphere.16
EBB TIDE All epidemics wane as susceptible individuals decrease in the population, perhaps because death claims those most susceptible, perhaps because survivors display immunity. The time scale of the European and North American TB epidemic was such that it is more likely that other factors were the determinants of the decrease in TB incidence. Tuberculosis crested in Europe and North America at the middle of the nineteenth century and has been falling since that time to present historic low case rates.15 Figure 1.2 presents the decline of TB deaths in comparison with deaths from all causes in England and Wales between 1850 and 1910. Tuberculosis deaths declined more rapidly than those from all causes. Thomas McKeown, a highly respected population scientist, examined many possible causes for this decline and concluded that better nutrition played the major role.24 Leonard Wilson argued that removal of infectious individuals to treatment facilities was a major factor.25
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DISCOVERY OF THE CAUSE Tuberculosis so commonly appeared in multiple members of a family that it was easily concluded that it was a familial, inherited disease. This view predominated well into the nineteenth century in northern Europe, although contagiousness of TB was generally accepted in Mediterranean countries. Chopin was ejected from the house he had rented in Mallorca because, as Georges Sand wrote, ‘Phthisis [is] extremely rare in those latitudes, and, moreover considered contagious!’15,27 Sand and Chopin, escaping from the winter of Paris in hopes of ameliorating Chopin’s TB, considered the Spanish view outlandish. In 1720 Benjamin Marten published a remarkably clairvoyant book entitled, A New Theory of Consumptions: More Especially of a Phthisis or Consumption of the Lungs. ‘The original and Essential Cause, then,’ he wrote, ‘may possibly be some certain species of Animalcula or wonderful minute living creatures.’28 His terminology suggests that he was referring to the animalcula that had been described by Anton van Leeuwenhoek in the scurf of his teeth in 1626. It was Jean-Antoine Villemin, a French military surgeon, who convincingly demonstrated the infectious nature of TB. He injected a rabbit with material from the pulmonary cavity of an individual who had died of TB and observed that the animal had extensive TB when it was sacrificed and autopsied 14 days later.29 The great pioneer of bacteriology, Robert Koch (Fig. 1.3), demonstrated conclusively that a bacterium, which he called Bacillus tuberculosis and is now known as Mycobacterium tuberculosis, is the
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E. R. N. Grigg concluded that genetic herd immunity which developed as a result of selection influenced by the high death rates in young TB adults resulted in the falling incidence.26 Whatever the cause, the decline was dramatic, but it was limited to the populations of western Europe and a few of those regions which they colonized, such as Australia.
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Fig. 1.2 Declining death rates for TB, left-hand scale (dashed line), and all causes, right-hand scale (solid line), as deaths/million/year for England and Wales from 1850 to 1910. Reproduced with permission from Davies RPO, Tocque K, Bellis MA, et al. Historical declines in tuberculosis in England and Wales: improving social conditions or natural selection. Int J Tuberc Lung Dis 1999;3:1051–1054.
Fig. 1.3 Robert Koch. Pencil drawing by Theresa S. K. Chung.
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HISTORY AND EPIDEMIOLOGY OF TUBERCULOSIS
aetiological agent of TB.30 His dramatic presentation of his findings on 24 March 1882 was immediately hailed, and he was acclaimed throughout the world.
DIAGNOSIS Since the time of Koch, the diagnosis of TB has rested primarily on the microbiology laboratory. Staining and culturing techniques introduced by Koch were soon improved upon, although not fundamentally changed. They remain the benchmarks of diagnosis to the present. Koch’s studies of TB led to his report of tuberculin, as noted below. He recognized its diagnostic potential, and Danish veterinarians soon were using it to diagnosis tuberculosis in cattle.31 In 1907 Viennese paediatrician Clemens Freiherr von Pirquet (Fig. 1.4), one of the founders of the science of allergy, developed the intracutaneous tuberculin test much as we know it today. Using it he recognized that many of the children in his clinic were latently infected.15 The further work of Florence Seibert and others in the 1930s led to the production of tuberculin-purified protein derivative, the antigen used today for tuberculin skin testing. In November 1895 Conrad Wilhelm Ro¨ntgen, a distinguished physicist interested in radiation, discovered X-rays.32 Within a month he had imaged his wife’s hand. The American inventor Thomas Alva Edison developed the first practical fluoroscope, making clinical radiology a practical reality.33 In May 1897, scarcely 18 months after Ro¨ntgen’s discovery, Francis Williams reported on the fluoroscopic examination of the lungs in more than 100 patients at the Boston City Hospital.34 During the Second World War, France, the United States, and Germany introduced radiographic screening of military recruits for TB. After the war,
radiographic surveys for TB case finding were commonplace for about 25 years before declining incidences made them unproductive. Chest radiology remained important for the evaluation of tuberculous disease under treatment, however.
THE SEARCH FOR A CURE Koch, now famous and revered, followed his announcement of the cause of TB with news of his discovery of a substance that would ‘render harmless the pathogenic bacteria . . . without disadvantage to the body’.35 His product was tuberculin, a concentrated, bacteria-free, filtrate of liquid cultures of M. tuberculosis. While tuberculin was ineffective in treating disease, it became of great importance in the diagnosis of tuberculous infection. If no specific remedy was at hand, then treatment must rely on such long-favored measures as rest, fresh air, sea voyages, and a healthy diet. None of these measures benefitted the dying poet John Keats, however.15 Herman Brehmer opened the first sanatorium for TB patients in Goerbersdorf in the Silesian Mountains of Prussia in 1859. Others followed; Davos in the Alps of Switzerland and Saranac Lake in the Adirondacks of New York became especially well known. There is no convincing evidence that sanatorium care benefitted tuberculous patients. It may have reduced transmission of M. tuberculosis in some communities, however. If rest for the body was good, perhaps rest for diseased lungs would ameliorate TB. As early as 1696, Giorgio Baglivi observed that a patient with pulmonary TB improved after a sword wound resulted in a pneumothorax. Pneumothorax was first introduced for therapy by Carlo Forlanini in 1894 with beneficial results.36 The procedure was rapidly accepted and widely used to collapse pulmonary cavities during the next 50 years. Pneumoperitoneum was used for lower lobe cavities. About the same time, thoracoplasty came into use in those cases in which satisfactory collapse could not be achieved by pneumothorax.
CHEMOTHERAPY
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Fig. 1.4 Clemens von Pirquet. Pencil drawing by Theresa S. K. Chung.
4
The idea that it might be possible to find an agent that was specifically curative was espoused by Paul Ehrlich, who heard Koch’s presentation. He improved on Koch’s staining techniques and reasoned that if it was possible to stain organisms differently than tissues, it ought to be possible to find a drug that would attack the microbes but not the host. His work led to treatments for trypanosomiasis and syphilis. In 1932 Gerhardt Domagk, a pathologist working at the laboratories of Bayer, the German chemical company, discovered Prontosil, the first sulphonamide. Others followed, and a new era of anti-infective drugs was born. During the Second World War Domagk continued to work, and his efforts led to thioacetazone, the first mycobacteriostatic drug.37 Shortly thereafter Jorgen Lehman in Sweden discovered para-amino salicylic acid (PAS), also mycobacteriostatic. Selman Waksman (Fig. 1.5) with his junior colleagues Albert Schatz and Elizabeth Bugie discovered streptomycin in 1943, the first mycobactericidal drug and an early member of a class of drugs that Waksman called antibiotics.15 The drug was first used the following year by Corwin Hinshaw and William Feldman to treat a patient who had failed collapse therapy. Her response was dramatic. It was soon discovered that drug resistance could be prevented by using two drugs;
CHAPTER
The history of tuberculosis
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1
Report, in which it recommended that BCG should be used as widely as possible. Many trials of BCG efficacy have been conducted, some more rigorous than others. There is a striking disparity of results.39 This disparity is illustrated in Fig. 1.6, which is taken from a review by Paul Fine. Ultimately, an expert consensus emerged that BCG is useful in the prevention of miliary and meningeal TB in young children but has no epidemiological impact and no utility in prevention-oriented TB control programmes. Epidemiologists of the US Public Health Service never embraced BCG. Rather, they focused on prophylactic treatment of latent TB with isoniazid, an approach first suggested by Edith Lincoln.40 Large randomized control studies demonstrated the efficacy of this preventative measure in a variety of populations.41 Other countries have been slow to follow the American lead, however, and current control strategies in most nations emphasize treatment under direct observation using optimal drug regimens to reduce the further spread of tubercle bacilli.
CHALLENGES
Fig. 1.5 Selman Waksman. Pencil drawing by Theresa S. K. Chung.
streptomycin was coupled with PAS. Isoniazid was discovered almost simultaneously by three pharmaceutical companies in 1952 and rifampicin in 1963. With these bactericidal agents the modern treatment era was born. Other drugs followed and their therapeutic roles and optimum drug regimens were developed in clinical trials conducted in many countries.
PREVENTION AND CONTROL Without dismissing the importance of their efforts at case finding and treatment, public health workers interested in TB sought measures that might prevent this disease. With knowledge of Edward Jenner’s vaccinia prevention of smallpox and Louis Pasteur’s immunization treatment of rabies, Albert Calmette decided to turn his efforts at the Pasteur Institute in Lille, France, to developing a vaccine against TB. Together with his colleague, Camille Gue´rin, he began efforts to attenuate M. bovis by serial passage in 1902.15,38 During the devastating German siege of Lille in 1914 and the subsequent German occupation, they managed to maintain their cultures. In 1921 Calmette, now in Paris, was ready to try the vaccine known as Bacillus Calmette-Gue´rin (BCG) in a human subject. He approached Drs. Benjamin Weill-Halle´ and Raymond Turpin at the Hoˆpital Charite´, and, on 18 July 1921, the new vaccine was administered to a 3-day-old infant whose mother had just died of TB and who would be raised by its tuberculous grandmother. The infant lived and thrived. During the next 4 years more than 100,000 doses of BCG were administered, and the TB death rate in vaccinated children was thought to be reduced by 10-fold. BCG came into widespread use in Europe following the Second World War, and in December 1973 the World Health Organization Expert Committee on Tuberculosis issued its Ninth
History tells the story of things past. The future of TB must concern all of us now. Whatever the past may have taught us, we face a future challenged by rising TB incidence in much of the world. That HIV infection fosters the spread of TB and that multidrugresistant disease is an increasing problem add to the challenges and call for new initiatives. New drugs and a better vaccine are needed. The spread of TB is now being approached with new tools made possible by genetic typing of mycobacteria. What we learned by contact tracing has been augmented with new knowledge, for now it is possible to connect sources and targets of air-borne tubercle bacilli with great certainty. The contacts are not always obvious, and often are buried in the forgotten past. New approaches to the diagnosis of TB are being made possible by new knowledge of the antigens of mycobacteria. There is a vast panoply of these proteins; some are limited to specific species or strains, while others are widespread among members of the genus. ESAT-6, for example, is an antigen that has been lost from BCG, so it is possible to use the presence or absence of immune recognition of it to distinguish BCG infections from true tuberculous infection. Immunization has served since the time of Edward Jenner as a major weapon in the battle against infectious diseases. However, BCG has fallen short of initial hopes for controlling TB. As more is learned about the immunopathogenesis of TB, it is becoming more possible to target candidate vaccines against specific components of the tubercle bacillus, perhaps increasing protective efficacy. New vaccines are currently in development; field trials to assess their efficacy will pose large challenges. Drug discovery efforts have long neglected TB, but this has changed in recent years. New agents targeting new microbial receptors are being produced by pharmacologists now alerted to the challenges of multidrug-resistant TB. Research workers – immunologists, epidemiologists, microbiologists, pharmacologists, molecular biologists, experimental pathologists – are attacking these challenges. One can hope that expanding knowledge emanating from their laboratories will produce new and unanticipated tools for control of the ‘Captain among these Men of Death’.
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500 300 200 100
Vaccine efficacy (%) 0 20 40 50 60
70
80
90
Population Haiti British school children N. American Indians USA (Chicago infants) Puerto Rico gen. pop. S. India (Madanapalle) USA (Georgia + Alabama) S. India (Chingleput) USA (Illinois children) USA (Georgia children)
Controlled trials
900
Case control studies
Brazil (Sao Paulo) Brazil (Belo Horizonte) Argentina (Buenos Aires) Cameroun (Yaounde) Canada (Manitoba Indians) Indonesia (Jakarta) Burma (Rangoon) Sri Lanka (Colombo) Colombia (Cali) Argentina (Santa Fe)
Contact studies
´ Togo (Lome) Thailand (Bangkok)
Fig. 1.6 Summary of the estimates of the efficacy of BCG vaccine against TB in randomized controlled trails, case–control studies, and householdcontact studies with 95% confidence intervals. Reproduced with permission from Fine PEM. The BCG story: Lessons from the past and implications for the future. Rev Infect Dis 1989;11(suppl):S353–S359.
REFERENCES 1. Hayman J. Mycobacterium ulcerans: An infection from Jurassic time? Lancet 1984;2:1015–1016. 2. Gutierrez MC, Brisse S, Brosch R, et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PloS Pathog 2005;1:e5. 3. Kapur V, Whittam TS, Musser JM. Is Mycobacterium tuberculosis 15,000 years old? J Infect Dis 1994;170: 1348–1349. 4. Brosch R, Gordon SV, Marmiesse M, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 2002;99:3684–3689. 5. Sola C, Filliol I, Gutierrez MC, et al. Spoligtype database of Mycobacterium tuberculosis: Biogeographic distribution of shared types and epidemiologic and phylogenetic perspectives. Emerg Infect Dis 2001;7:390–396. 6. Hirsh AE, Tsolaki AG, DeReimer K, et al. Stable association between strains of Mycobacterium tuberculosis and their human populations. Proc Natl Acad Sci USA 2004;101:4871–4876. 7. Gagneux S, DeReimer K, Tran V, et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006;103: 2869–2873. 8. Cave AJE. The evidence for the incidence of tuberculosis in ancient Egypt. Br J Tuberc 1939; 33:142–152.
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9. Morse D, Brothwell DR, Ucko PJ. Tuberculosis in ancient Egypt. Am Rev Respir Dis 1964;90:5224–5241. 10. Morse D. Tuberculosis. In: Brothwell D, Sandison AT (eds). Diseases in Antiquity. A Survey of the Diseases, Injuries and Surgery of Early Populations. Springfield, IL: CC Thomas, 1967. 11. Nerlich AG, Haas CJ, Zink A, et al. Molecular evidence for tuberculosis in an ancient Egyptian mummy. Lancet 1997;350:1404. 12. Crube´zy E´, Ludes B, Poveda J-D, et al. Identification of Mycobacterium DNA in an Egyptian Pott’s disease of 5400 years old. C R Acad Sci III 1998;321:941–951. 13. Daniel VS, Daniel TM. Old Testament biblical references to tuberculosis. Clin Infect Dis 1999; 29:1557–1558. 14. Daniel TM. The early history of tuberculosis in central East Africa: Insights from the clinical records of the first twenty years of Mengo Hospital and review of the relevant literature. Int J Tuberc Lung Dis 1998;2:1–7. 15. Daniel TM. Captain of Death: The Story of Tuberculosis. Rochester, NY: University of Rochester Press, 1997. 16. Daniel TM. The origins and precolonial epidemiology of tuberculosis in the Americas: can we figure them out? Int J Tuberc Lung Dis 2000;4:395–400. 17. Coar T. The Aphorisms of Hippocrates with a Translation into Latin, and English. Birmingham, AL: Gryphon Editions, 1982. Sectio VIII. 18. Roberts CA, Buikstra JE. The Bioarchaeology of Tuberculosis. A Global View on Reemerging Disease. Gainesville, FL: University of Florida Press, 2003.
19. Bunyon J. The Life and Death of Mr. Badman. New York: R.H. Russell, 1900. 20. Krause AK. Tuberculosis and public health. Am Rev Tuberc 1928;18:271–322. 21. Priestly JB. Tom Moore’s Diary [a selection edited, with an introduction]. Cambridge: Cambridge University Press, 1925. 22. Dickens C. Nicholas Nickleby. London: Penguin Books, 1986. 23. Martinic M. The meeting of two cultures. In: McEwan C, Borrero LA, Prieto A (eds). Patagonia: Natural History, Prehistory and Ethnography at the Uttermost End of the Earth. Princeton, NJ: Princeton University Press, 1997: 110–126. 24. McKeown T. A historical appraisal of the medical task. In: McLachlan G, McKeown T (eds). Medical History and Medical Care: A Symposium of Perspectives. London: Oxford University Press, 1971: 29–55. 25. Wilson LG. The historical decline of tuberculosis in Europe and America: Its causes and significance. J Hist Med Allied Sci 1990;45:366–396. 26. Grigg ERN. The arcana of tuberculosis with a brief epidemiologic history of the disease in the U.S.A. Part III. Am Rev Tuberc Pulm Dis 1958;78: 426–453. 27. Sand G. George Sand and Chopin: A Glimpse of Bohemia [a letter written to M. Francois Rollinat dated March 8, 1838; trans. Lewis Buddy]. Canton, PA: The Kirgate Press, 1902.
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The history of tuberculosis 28. Doetsch RN. Benjamin Marten and his ‘new theory of consumptions’. Microbiol Rev 1978;42:521–528. 29. Major RH. Classic Descriptions of Disease, 3rd edn. Springfield, IL: CC Thomas, 1945. 30. Koch R. Die Aetiologie der Tuberculose [a translation by Berna Pinner and Max Pinner with an introduction by Allen K. Krause]. Am Rev Tuberc 1932;25: 285–323. 31. Edwards PQ, Edwards LB. Story of the tuberculin test from an epidemiologic viewpoint. Am Rev Respir Dis 1960;81(suppl):1–47. 32. Glasser O. Wilhelm Conrad Ro¨ntgen and the discovery of the roentgen rays. In: Glasser O (ed.). The Science of Radiology. Springfield, IL: CC Thomas, 1933:1–14.
33. Eisenberg RL. Radiology: An Illustrated History. St. Louis, MO: Mosby Year Book, 1992. 34. Williams FH. The Ro¨ntgen rays in thoracic disease. Am J Med Sci 1897;114:661–687. 35. Koch R. A further communication on a remedy for tuberculosis. Deutsche Medicinische Wochenschrift, November 15, 1890. English translation published in BMJ 1890;2:1193. 36. Brown L. The Story of Clinical Pulmonary Tuberculosis. Baltimore, MD: Williams and Wilkins, 1941. 37. Ryan F. The Forgotten Plague: How the Battle against Tuberculosis Was Won – and Lost. Boston, MA: Little, Brown, 1992. 38. Daniel TM. Leon Charles Albert Calmette and BCG vaccine. Int J Tuberc Lung Dis 2005;9:205–206.
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39. Comstock GW. Field trials of tuberculosis vaccines: how could we have done them better? Controlled Clin Trials 1994;15:247–276. 40. Lincoln EM. The effect of antimicrobial therapy on the prognosis of primary tuberculosis in children. Am Rev Tuberc 1954;69:682–689. 41. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1970;17:28–106.
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2
Transmission of Mycobacterium tuberculosis Ashwin S Dharmadhikari and Edward A Nardell
INTRODUCTION AND HISTORICAL PERSPECTIVE Considering the centuries during which TB has been afflicting humanity, awareness that the disease is the result of a transmissible airborne infection is surprisingly recent. Although scientists such as Aristotle and his contemporaries believed that TB was contagious, they had no understanding of what caused it or exactly how it was spread. During the Middle Ages through to the seventeenth century, clinical practice and societal laws in Europe attested to the fact that the contagiousness of TB was suspected, if imperfectly understood. In Italy and Spain, cases of TB had to be reported to city authorities, and, when a patient with TB died, his personal belongings were burned in order to eradicate any traces of the disease that might spread to others. Moreover, physicians of the time, such as Valsalva and Morgagni, refused to perform autopsies on victims of TB, concerned that the procedure would spread the disease, as indeed it does.1 In the seventeenth century, however, a contrary view began to emerge. Eminent scientists and clinicians in Europe started to question whether TB was really transmissible. As proof, they offered observations that many healthcare workers who came into contact with TB patients did not themselves acquire the disease. Under situations ideal for transmission, they reasoned, how could TB possibly be considered a transmissible disease? Instead, noting the clustering of cases within families, they concluded that infection with TB was probably a hereditary phenomenon.1 Given the long latency periods that routinely occur between exposure and disease development, firm conclusions about transmissibility were understandably elusive. By 1910, decades after Koch discovered the tubercle bacillus, Chapin, in his influential book The Sources and Modes of Infection argued against the airborne mode of transmission of any organism: Bacteriology teaches that former ideas in regard to the manner in which diseases may be airborne are entirely erroneous; that most diseases are not likely to be dust-borne, and they are spray-borne for only 2 or 3 feet, a phenomenon which after all resembles contact infection more than it does aerial infection as ordinarily understood.2
Chapin did concede that, if any infection was airborne, it would likely be TB. But, in Thomas Mann’s 1927 novel The Magic Mountain, visitors to the fictitious alpine sanatorium lived with patients for weeks at a time with no apparent fear of contagion.3 As recently as 1932, Fishberg wrote that it was not risky for ‘healthy adults to be coughed at by patients suffering from pulmonary or laryngeal
8
tuberculosis’.4 The partial immunity acquired by infection early in life undoubtedly contributed to the misleading observation that many of those exposed did not develop disease. By 1947, the American Public Health Association (APHA) stated that ‘conclusive evidence is not available at present that the airborne mode of transmission is predominant for any particular disease’.5 Instead, it was postulated that TB might be spread by direct contact with infected sputum. Public health campaigns to discourage spitting were a logical consequence. The prevailing perception through the early 1900s, therefore, was that the airborne spread of TB beyond the immediate proximity of the source was unlikely. Yet even as many in the medical, public health, and scientific communities accepted Chapin’s view on airborne transmission, other researchers were working to better understand the propagation of infections, including TB. It was not until the late 1950s, however, a full decade after the APHA’s conclusion, cited above, that the tide of scientific opinion once again turned on this matter. Among the landmark investigations in this area were those of William Firth Wells, who while working as a sanitary engineer at Harvard University first conceptualized how certain infectious agents such as measles and TB might become airborne and travel from person to person. In his seminal 1934 paper entitled ‘On air-borne infections. II. Droplets and droplet nuclei’, Wells introduced the notion that transmissible infections fell into two major categories: those spread by local, direct, person-to-person contact and those spread more widely without direct contact by the airborne route.6 In 1931 Wells had developed an air centrifuge, a device that allowed him to concentrate airborne microorganisms from air samples. He had been commissioned by the Massachusetts Department of Health to investigate the aetiology of respiratory infections among textile mill workers. He speculated that the source of these infections was bacteria from contaminated standing water that had been aerosolized to keep dust down in the mill. Using his air sampler, he identified the same organisms in the air and in the standing water.7 The next intellectual leap was to theorize that aerosols produced by coughing and sneezing could also be responsible for person-to-person airborne transmission. He was assisted in this investigation by then Harvard medical student Richard Riley, with whom he shared credit for making the distinction between ordinary large respiratory droplets and so-called droplet nuclei – the dried residua of larger respiratory droplets. He ultimately published a comprehensive exposition of his theories and observations in his now classic 1955 text ‘Airborne contagion and air hygiene’, much of which remains valid to this day.8 Riley later updated and summarized this work in his 1961 monograph Airborne Infection and Control.9
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Transmission of Mycobacterium tuberculosis
The distinction between airborne and droplet-borne (contact) spread of infection blurs for some organisms, and a predominant mode is sometimes difficult to establish. The gold standard definition of airborne infection is transmission between individuals who have not had direct or indirect contact through contaminated fomites or surfaces. Smallpox, for example, is generally believed to be spread by direct contact with virus shed from cutaneous sores, but this cannot explain spread between patients on different floors of a German hospital where there was no direct or indirect person-to-person contact. A patient with respiratory mucosal involvement was believed to be responsible.10 Smallpox is now thought to be spread predominantly through large droplets, but with a poorly defined but definite potential for airborne spread. Smallpox is also considered a potential bioterrorism agent, presumably through aerosol attack. Several factors determine whether a given infectious agent travels from person to person through large or small respiratory droplets, and often both mechanisms appear to play a role. Besides smallpox, other infections with ambiguous or unclear modes of transmission include the common cold, Legionella, and influenza. In contrast, Mycobacterium tuberculosis (MTB) is almost exclusively spread by the airborne route, for several reasons peculiar to its pathogenesis. Most importantly, TB infection usually begins in the alveolar macrophage, the very cells intended to destroy invading pathogens. MTB has evolved mechanisms to evade killing by immunologically naı¨ve macrophages, which, ironically, provide the essential intracellular environment for its initial growth. The respiratory mucosa provides no such haven for MTB and is quite resistant to infection. The requirement for MTB to reach the alveoli of the peripheral lung essentially defines particles in the size range 1–3 mm. Such particles have so little inertia that they more likely evade impaction on the upper respiratory mucosa, which also means that they are light enough to have a negligible settling tendency in ordinary room air. Submicron particles are also generated by coughs and even quiet breathing, but are too small to contain tubercle bacilli or to settle on the alveolar surface. Larger respiratory droplets could contain several tubercle bacilli, but, unless they desiccate into droplet nuclei, they are less likely to reach the vulnerable outer reaches of the lung (Table 2.1). Wells detailed the increasingly rapid evaporation of larger into smaller particles as the ratio of surface area to mass increases, culminating in the dried residue of droplets, which he called droplet nuclei, as already noted. Another determinant of the transmission mode of a microorganism is the dose required to cause infection. For MTB, the dose is believed to be as little as a single organism, favouring its spread by minute airborne particles. For other infections such as some common bacterial pneumonias, host defences are more effective and doses larger than
2
can be carried by airborne particles dispersed in air may be required. People frequently experience microaspirations of mouth bacterial flora without ill effects, but, with gross aspiration containing larger numbers of organisms, pneumonia can result. It is believed that some respiratory pathogens, such as Pneumococcus and Staphylococcus, first colonize the upper respiratory tract where concentrations of organisms reach sufficiently high numbers to cause infection by aspiration. Most bacterial respiratory pathogens and many viruses appear to be spread by large respiratory droplets, justifying the contact precautions employed in hospitals and clinics. Perhaps the best way to prove that an infection is predominantly airborne is to successfully interrupt transmission by air disinfection alone. Wells showed unequivocally in the early 1940s that the transmission of measles was airborne and could be substantially interrupted in schools by the use of upper room ultraviolet germicidal irradiation (UVGI).11 Yet the experimental evidence that TB was airborne and could be interrupted did not emerge until studies conducted by Riley between 1958 and 1962 at the Baltimore Veterans Administration Hospital were published. Bringing to fruition a study design that had been conceived by Wells, Riley carried out a series of experiments using patients with active pulmonary TB (including untreated, treated, and drug-resistant cases) and highly susceptible guinea pigs to show definitively that TB was airborne and that its transmission could be interrupted by germicidal irradiation within the ventilation duct system. Riley used a six-bed hospital TB ward that was renovated in such a way that exhaust air from the ward passed through one or two penthouse exposure chambers containing hundreds of guinea pigs (Fig. 2.1). There was no other contact between the patients and the guinea pigs. Riley used guinea pigs because these animals were so exquisitely vulnerable to MTB that exposure to dilute artificial aerosols (which permitted inhalation of single infectious droplet nuclei) was sufficient to establish pulmonary infection. Over the course of the first 2 years of Riley’s study, an average of 150 guinea pigs per month breathed TB-infected air from the patient ward and subsequently became infected, as determined by conversion of their tuberculin skin test, with subsequent bacteriological or histological confirmation. The timing of guinea pig infections relative to patient occupancy on the ward combined with matching of drug susceptibility patterns of human and animal bacterial isolates allowed the infectious source of most of the guinea pig infections to be determined.12 Since the guinea pigs’ only exposure to TB was breathing the air ventilated to the animal chamber from the patient ward, this experiment proved that TB was an airborne infection. A second 2-year experiment was designed to show that other factors, such as contact with the animal handlers, were not responsible for the guinea pig infections.13 The initial
Table 2.1 Key distinguishing features of droplet nuclei and respiratory droplets Droplet nuclei transmission (airborne infection)
Respiratory droplet transmission (an extension of direct contact)
1- to 5-mm-diameter particles (dried residua of larger particles) Remain suspended indefinitely Alveolar deposition Contain few microbes UVGI susceptible in air Examples: TB, measles
>100-mm-diameter particles Settle out within 1 m of the source Upper airway deposition Contain many microbes UVGI resistant on surfaces Examples: Staphylococcus respiratory syncytial virus
UVGI, ultraviolet germicidal irradiation. Rom & Garay, Tuberculosis, 2nd edition. Lippincott Williams and Wilkins, 2003.
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Rights were not granted to include this content in electronic media. Please refer to the printed book.
Fig. 2.1 A schematic diagram of the hospital unit, ventilation ducts, and guinea pig exposure chambers used in the Riley experiments. Riley RL, Wills FW, Mills CC, et al. Air hygiene in tuberculosis: quantitative studies of infectivity and control in a pilot ward. Am Rev Tuberc Pulmonary Dis 1957;75:420–431. # American Thoracic Society.
2-year experiment was repeated with half the ward air being heavily irradiated with UVGI before reaching the guinea pigs. Despite the same handlers and other conditions, no infections occurred in the guinea pigs protected by germicidal UV. Additionally, Riley and colleagues were able to show that patients on the ward varied greatly in infectiousness, that drug-resistant strains were less infectious, and that effective TB treatment rapidly reduced infectiousness.
EPIDEMIOLOGICAL DATA ON THE DETERMINANTS OF TUBERCULOSIS TRANSMISSION Successful passage of the TB bacillus from one person to the next requires an infectious source case, a virulent microorganism, a vulnerable host, and favourable environmental conditions. Upon closer inspection, there are complex factors that contribute to this process, including factors that determine the strength and infectivity of the source, the integrity of the host defences of the exposed individual, intrinsic properties of the bacillus itself, including viability, vulnerability or resistance to environmental stressors, virulence factors, genetic mutations, drug resistance, and virulence for a particular host. Figure 2.2 depicts this model of TB propagation. 1. Source factors: Smear + Cough strength and frequency Lung cavitation Effective treatment
Source
2. Environmental factors: Ventilation, room volume, humidity, UV 3. Microbial factors Genetic virulence Airborne M.tb
Fig. 2.2 TB transmission factors.
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Host
An important caveat to this biomedical model, however, is that it only indirectly alludes to some of the biosocial influences that have been associated with TB incidence and prevalence in many parts of the world, such as socioeconomic status, access to healthcare, or crowded living conditions. Nonetheless, the simplified model in Fig. 2.2 helps to frame a discussion of the ways in which the public health, scientific, engineering, and medical communities may understand and attempt to interrupt MTB propagation. Within both high and low TB prevalence areas, high rates of transmission have occurred in congregate settings such as hospitals, clinics, prisons, refugee camps, schools, and shelters. Although the average concentration of airborne TB infectious droplet nuclei in such settings has been estimated to be quite low, there appear to be situations in which airborne concentrations are transiently quite high or contact time of vulnerable individuals is sufficiently long to account for high rates of transmission. In hospitals, for example, the risk of TB transmission to healthcare workers (HCWs) remains an issue in both high- and low-prevalence areas. Ironically, concern has generally been much higher in low-prevalence, resource-rich settings where the risk is generally low and quite unpredictable, often from unsuspected source cases. However, implementation of existing international infection control guidelines is especially urgent in resource-limited settings where an already stretched pool of HCWs, many human immunodeficiency virus (HIV)-infected, is suffering from attrition due to TB or fear of acquiring drug-resistant disease.14,15 The risk of transmission and progression to active TB disease is also extremely high for patients, prisoners, and refugees in regions where both HIV and MTB infections are common. Of all congregate settings, the risk of TB transmission for HCWs has been especially well documented in the medical literature. In the 1930s and 1940s, Israel, a lung specialist, carried out an epidemiological study in which he tracked nurses and physicians working in an urban Philadelphia hospital over several years for TB exposure and infection, using a tuberculin skin test (TST) reaction of 5 mm induration as the criterion for infection.16 At the time of joining the hospital staff, approximately one out of three nurses and physicians had a positive TST. Since these individuals had not yet had occupational TB exposure, Israel used this rate of TST positivity to represent the latent infection rate from household exposure for the socioeconomic group from which these nurses and doctors hailed. Israel then tracked annual rates of TST positivity and conversion over 3 years for the cohort and found that, by the end of 3 years, nearly all the nurses and doctors had become TST positive and that about 10% had developed clinical TB disease. He surmised that this rate of TST conversion represented an estimate of occupational exposure intensity to unsuspected TB cases in an urban hospital. He emphasized exposure to unsuspected cases of TB because the standard of care at that time was to rapidly transfer known or suspected TB cases to specialized sanatoria for long-term care. More contemporary studies of the epidemiology of latent TB infection show that while 5% of the US population is TST positive, HCWs in urban American hospitals have a 20–30% TST positivity rate, whereas their counterparts in US community hospitals have just slightly lower TST positive rates.17 A study by the US Centers for Disease Control (CDC) has shown that TST conversion rates among US HCWs is 1% annually – deemed unacceptably high in a low-prevalence country. However, a carefully done, multicenter, prospective study of skin test conversions among HCWs conducted by the CDC found weak correlation with patient exposure, but a strong correlation with foreign birth
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Transmission of Mycobacterium tuberculosis
and BCG vaccination, suggesting lingering skin test boosting as a cause of skin test conversion despite base-line two-step testing intended to minimize the effects of boosting.18 However, other studies have documented higher than average risks among certain categories of HCWs, including respiratory therapists, pathologists, TB laboratory workers, nurses, and physicians.19 Among doctors, one study found that fellows in training who did bronchoscopy, a cough-generating procedure, were at much higher risk than colleagues who did not, such as infectious disease fellows, even though both specialists saw patients with TB.20–34 Between 1985 and 1992, there was a resurgence in the rates of TB in North America and western Europe, largely attributable to outbreaks in congregate settings such as homeless shelters, residential facilities for patients with acquired immunodeficiency syndrome (AIDS), prisons, and healthcare facilities and to a breakdown in public health TB control programmes.35–42 Using restriction fragment length polymorphism fingerprinting (RFLP) data and drug resistance patterns to determine which strains were represented in the source cases and the secondary infections in these outbreaks, it was shown that up to 30–40% of the observed cases of TB in New York City, for example, were due to recently transmitted infection rather than the result of reactivation of old foci of infection.43 Prior to these data, it was commonly believed that the large majority of new cases of TB in low-prevalence settings like the United States were due to reactivation disease rather than recent transmission. However, with advances in epidemiological and molecular investigations it became clear that well-localized and recent transmission in congregate settings contributed significantly to the rise in TB rates. After the epidemic came under control, Freiden et al.44 considered improved infection control as well as improved treatment to have been essential factors. In 1994, in response to the rise in TB rates and the emergence of multidrug-resistant TB (MDR-TB), the CDC published comprehensive guidelines for improved control of institutional TB transmission.45 The guidelines promoted a three-tiered hierarchical control strategy adapted from industrial hygiene: administrative, environmental/engineering, and personal protective equipment. These strategies are discussed in detail later in this book in chapters on TB infection control.
HUMAN SOURCE FACTORS Some patients with TB appear to be much more infectious than others based on the investigation of their contacts. Substantial epidemiological, clinical, and experimental data support these observations. Beyond a few conventional criteria, however, there are still generally no reliable ways to predict which patients will be more or less infectious to others. Those conventional criteria include the presence of lung cavities on chest radiographs; active, forceful coughing; sputum smears that are positive for acid-fast bacilli; and absence of effective drug treatment. These same criteria are generally used by hospitals to determine who gets isolated and how long such isolation lasts. While a review of the immunopathology of TB infection is beyond the scope of this chapter and is covered elsewhere in this textbook, a few concepts deserve mention here. Dannenberg46 has argued that lung cavitation, the end result of liquefaction necrosis due to delayed type hypersensitivity (DTH), is the event responsible for ongoing propagation of MTB in human populations. It has been estimated that lung cavities may harbour 108–109 organisms in the extracellular debris
2
associated with liquefaction necrosis. When the caseous foci of pulmonary TB rupture into a bronchi, countless MTB gain access to the large airways, and thus to the outside environment. In the prechemotherapy era, TB physicians focused on cavity formation as a sentinel event portending a downhill clinical course, presumably due to a larger bacterial burden, chronic cough, reduced lung function, and also a propensity to haemorrhage – the most feared and often fatal event. Rest as well as surgery and a variety of mechanical collapse therapies were all intended to effect cavity closure, with mixed success. In theory, if it were possible to prevent lung cavitation while retaining the beneficial aspects of DTH and acquired cell-mediated immunity (CMI), transmission would be lessened. The predisposition to drug resistance associated with spontaneous mutations occurring among such large numbers of organisms would also be lessened (see Microbial Factors, below). While HIV coinfection is associated with less lung cavitation (i.e. less DTH), it is also associated with less CMI, and large numbers of organisms still occur in lung tissue, associated with rates of transmission not much different than among patients without HIV and with lung cavities.47 The site of TB disease also determines whether and how infectious a source case may be. In his classic air-sampling study, Riley13 observed that one patient with laryngeal TB infected 15 guinea pigs during the 3 days he resided on the experimental ward, far more than other patients with pulmonary TB even though they resided on the ward for longer periods of time. Tuberculosis disease in other parts of the body, such as the bone and kidneys, for example, is normally not infectious because these sites do not communicate with the environment. However, in certain circumstances even extrapulmonary TB can be infectious, as illustrated by the case of a thigh abscess that was drained and then irrigated with a high-pressure water jet, or several reports of autopsies associated with extensive spread of infection, presumably the result of aerosol-generating procedures.21,30 Fennelly and colleagues have focused on the human infectious source determinants of transmission (Fig. 2.2). Building upon earlier reports by Loudon48 that overnight cough frequency of TB patients correlated with the rates of transmission to household contacts, Fennelly49 examined differences in the rates of culturing airborne MTB using a novel cough aerosol-sampling system. Effective treatment, he reported, was associated with a decline in the number of cough-generated aerosol cultures from samples obtained from MDR-TB patients within the first 3 weeks of treatment. However, among 12 sputum smear-positive patients who were evaluated, only four cough samples yielded positive cultures, reinforcing the notion that factors beyond sputum smear status alone are likely playing a role in transmission. He also measured the size distribution of cough-generated, culturable particles, confirming in his experimental system earlier animal experiments that showed that 1- to 2-mm particles were those most likely to serve as vehicles for MTB.49,50 Source factor determinants require further research. For example, it is generally believed that patients who have negative sputum smears are likely to be less infectious than those with a sputum that is smear positive. In clinical practice, two or three negative sputum smears are used as the main criteria for ending respiratory isolation. Yet, as shown by Fennelly, only a fraction of sputum smear-positive patients generate culturable aerosol. Other, poorly understood transmission factors are likely at work. Differences in sputum quality, for example, might influence transmission. Less viscous sputum might be more easily aerosolized into droplet nuclei than thick sputum. The physical or chemical properties of respiratory secretions could also influence transmission by shielding MTB organisms from injury during the violent process of aerosolization
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and airborne transport through a generally hostile environment. A better understanding of such factors might permit a more accurate assessment of patient infectiousness, or lead to novel infection control interventions, such as agents to modify sputum physical characteristics in order to reduce respiratory particle generation rate, or change particle size.51 Little is known of the effects on MTB transmission of ambient temperature, humidity, oxygen tensions, irradiation, or air pollution52,53 A better understanding of these factors might lead to interventions to render the environment less favourable for MTB survival during transport.54 A final source factor that requires mention is treatment status. With effective treatment, most patients become non-infectious within about 2–3 weeks.55–58 On Riley’s experimental ward, patients on at least 2 weeks of effective treatment were less likely to infect guinea pigs. In Madras, India, additional household converters ceased after about 2 weeks of effective treatment.59 These findings support current respiratory isolation guidelines. However, when therapy has been ineffective, as occurred during the 1985–1992 TB resurgence when patients with unsuspected and inadequately treated MDR-TB were prematurely released from isolation, transmission continued. Effective disease treatment remains the single most important intervention to prevent MTB transmission.
MYCOBACTERIAL FACTORS, STRAIN DIFFERENCES, AND INTERACTIONS WITH SOURCE, ENVIRONMENT, AND HOST As mycobacteria multiply during the course of infection, they acquire point mutations, frame shift mutations, deletions, and genetic sequence insertions as a result of chance DNA transcriptional errors and recombinations. As discussed earlier, there may be as many as 108 or 109 organisms within a lung cavity, and, within this population, genetic mutations may occur at a rate of 1 in 107 to 1 in 1010 per bacterium per generation.60 These genetic mutations can be associated with a variety of phenotypic outcomes, including alterations in drug resistance, nutrient uptake, metabolism, or interaction with host immune cells, that is, altered virulence. How often do these mutations result in reduced mycobacterial fitness, how often do compensatory mutations occur that restore fitness to the wild-type state, and how important are these microbial determinants of infection or disease amid the many other factors depicted in Fig. 2.2? These are among the most important questions being addressed by molecular epidemiological and laboratory researchers. Anecdotal observations, combined with molecular typing data, suggest that some strains propagate more readily or are more ‘fit’ than others. In the natural history of TB infection, there are several stages that might be altered by genetic mutations that could influence the propagation of TB, including the ability of the bacillus to:
12
initiate infection as measured by an immune response, i.e. infectivity and DTH stimulation; evade the host immune system and replicate within a host and cause disease, i.e. virulence; disseminate haematogenously and to cause lung cavitation, i.e. virulence and DTH-induced tissue destruction; and travel between hosts, i.e. transmissibility, including resistance to the stresses of aerosolization and airborne transport.
In 1998, Valway et al.61 reported on the results of a contact investigation in the setting of an unusual outbreak of TB. Interestingly, while the rate of skin test conversion was unusually high and the reactions unusually large among exposed individuals, the rate of disease development was lower than expected, suggesting that this strain of TB was highly infectious, a strong stimulator of DTH, but not particularly virulent. Conversely, the strong induced host response itself might explain the lower rate of disease progression. Several decades earlier, Middlebrook and Cohn62 described transmission patterns for isoniazid (INH) susceptible and resistant strains of MTB among guinea pigs exposed via the aerosol route. INH resistant strains were less virulent for the guinea pigs than the susceptible strains, as evidenced by smaller and less numerous foci of infection on autopsy, fewer organs involved, a milder clinical course, and prolonged survival. Early on, researchers attributed the loss of virulence of INH resistant strains to a loss of catalase activity, the enzyme responsible for metabolizing INH from a prodrug to its metabolically active form.63–65 Subsequent work has found associations between the type of KatG mutation responsible for catalase activity and the apparent virulence of the organism. As an example, it was shown that, although both point mutations and deletions in the gene sequence disrupt the production of catalase, the deletions confer a more profound reduction in catalase levels, a higher degree of resistance to INH, and a more marked attenuation in virulence than point mutations.66 In contrast to these observations for INH mutations, mutations which lead to pyrazinamide resistance alone tend not to alter the fitness of MTB.67 Whether mutations which contribute to drug resistance necessarily reduce the reproductive fitness of the MTB has recently been the subject of considerable debate. Ordway et al.68 examined 15 different clinical isolates of MTB, some of which were fully drug sensitive, INH resistant, or multidrug resistant. They found that, although growth rates in experimentally infected mice varied for each of the 15 isolates, these growth rates did not correlate with the extent of drug sensitivity or resistance.68 Likewise, Cohen and colleagues69 recently evaluated epidemiological data available on transmission of MDR-TB using mathematical models to determine whether drug resistance mutations also result in a loss of reproductive fitness. In their analysis they conclude that the fitness of drug-resistant strains is quite heterogeneous and that attempting to discover an average degree of reproductive fitness for MDR-TB upon which to base programmatic and policy decisions may be misleading.69 Instead, they argue, it is important to determine the distribution of highly resistant and less resistant strains, so that outbreaks can be averted and handled appropriately. As a real-life example of this heterogeneity, we might consider another contact investigation conducted by Texeira et al.70 in Brazil, who evaluated rates of TST conversion among household contacts of index cases of MDR-TB. They found no association between the degree of drug resistance and rates of TST conversion or disease development among the household contacts, even though the drug-resistant index cases were infectious for a longer period of time than the drug-sensitive cases in their study. Using IS6100 pattern molecular typing techniques, they also confirmed that the secondary cases of TB among household contacts were from the same strain as the index case for any given household, thereby eliminating any doubt that secondary cases in a household were from a non-household exposure.70 As discussed elsewhere in this volume, developments in the molecular biology and genetics of MTB have permitted closer
CHAPTER
Transmission of Mycobacterium tuberculosis
analysis of the interplay of genes, proteins, and bacterial enzymes in the life cycle of this organism. We mention this here only in relation to transmission. Mycobacterial growth in the face of exogenous stressors has been shown to be dependent upon the elaboration of gene products called sigma factors, which regulate defence regulons within the mycobacterial genome. Laboratory studies in which several sigma factors were mutated demonstrated that mutation of the sigma factors had no impact on the ability of the H37Rv strain of mycobacterium to grow in culture dishes or within in vitro macrophage systems, but had a substantial impact on the in vivo growth and replication of H37Rv within a guinea pig infection model. Among the factors studied, mutations in SigC affected the adaptive survival of H37Rv in guinea pigs more than mutations in SigF.71
HUMAN HOST FACTORS WHICH AFFECT VULNERABILITY TO TUBERCULOSIS INFECTION Once the TB bacillus finds an entry into the human lung, its interaction with the host immune system and the impact of the host’s other comorbid medical conditions ultimately determines whether infection is established and whether it progresses to clinical disease. Substantial immunological research has begun to elucidate key steps in the human immune system’s attempt to contain and eliminate TB. Simply stated, once MTB breaches the structural defences of the upper airways and reaches the distal lung, innate mechanisms involving macrophages are the first defence against infection, followed by the acquired CMI and DTH, which together usually contain further spread of infection within the host. Defects in any portion along this elaborate and still incompletely understood defence pathway could render a host more vulnerable to MTB infection, thereby enhancing transmission. Compared with what is known about the immune defences operative during active TB, relatively little is known about the immune response that contains latent MTB infection. Similarly, the events that trigger reactivation of latent MTB infection are poorly understood. CD4 T cells certainly have an important role in this process, since numerous studies document the higher rates of reactivation in HIV-infected individuals.72–74 There is debate, however, about whether HIV infection increases the risk of acquiring TB infection in the first place since this appears to be predominantly determined by macrophage function.75 Exposure to both silica dust and silicosis increases the rate of reactivation TB.76–78 Inhaled silica particles damage alveolar macrophage cell membranes, the same cells which MTB typically encounters upon inhalation and deposition in the distal lung. Allison and Hart79 showed that sublethal doses of silica enhanced the growth of MTB in macrophage cultures, and guinea pig exposure studies revealed that inhalation of quartz (a chief component of silica dust) reactivated TB lesions that were healing.80 Still other studies suggest that humoral and cell-mediated immunity may also be altered in silica exposure.81 One would expect silica exposure to enhance MTB transmission as well as disease progression. It is known from human postmortem studies in which single isolated tubercles are found in the lungs that even a single inhaled droplet nucleus is sufficient in some individuals to initiate MTB infection. Yet as seen by TST or interferon gamma release assay (IGRA) results, not all exposed individuals acquire TB infection, even after comparable types of exposures. Observations like these
2
underscore the variability in human susceptibility to TB, which is generally attributed to differences in immune function, genetics, and concomitant health conditions that predispose to infection and disease. Epidemiological studies by Stead and colleagues82,83 specifically suggest an enhanced risk of MTB infection, but not disease reactivation, associated with ethnic or racial background. The authors maintained that these factors were surrogates for the historical selection of populations with innate MTB resistance resulting from the evolutionary pressure of the several hundred-year-old TB epidemic in Europe and North America. Persons in central Africa, Aboriginals, and others isolated from this epidemic pressure remained vulnerable because there was no such selection.82,83 It has long been an accepted tenet of medicine that, once infected with MTB, the latent infection is lifelong, with a small but persistent risk of reactivation to active disease. Occasional observations of skin test reversions in the absence of anergy, with or without treatment, had been dismissed as the exceptions to the rule. However, these observations are now supported by reversions in IGRA results. The possibility that transient MTB infection may be part of the pathogenesis of the disease has several implications for transmission. First, skin test surveys may greatly underestimate transmission in populations since infected persons may have already reverted their skin test or IGRA back to negative by the time they were tested. Second, if infection can be transient, progression to disease may depend on reinfection to a degree not previously suspected. Indeed there is evidence that what appears to be high rates of reactivation TB disease among recent arrivals to the United States from high-prevalence areas may in fact represent recent infection or reinfection.84 Finally, if natural MTB infection is often transient, and reinfection is important to pathogenesis, then perhaps vaccines may not be as beneficial as hoped.
MATHEMATICAL MODELLING OF M. TUBERCULOSIS TRANSMISSION With few exceptions, every case of TB results from the airborne transport of MTB from an infectious source to a vulnerable host. Primarily an intracellular pathogen, MTB is adapted to replicate extracellularly in necrotic lung cavities, to endure the rigors of aerosolization in mucus as tiny respiratory droplets, to survive the process of rapid drying into droplet nuclei, and to remain infectious after airborne transport through a variety of harsh environments. Potentially lethal environmental exposures include the extremes of air temperature and humidity, ambient levels of air pollution, and natural ozone and irradiation (Fig. 2.2). Little is known about these adaptive processes, but the selective pressure is strong since only adapted strains can propagate. Finally, organisms surviving the gauntlet of airborne transmission face innate and adaptive host defences honed, in some human populations, by generations of natural selection. Virulence, the ability of the pathogen to overcome host defences and cause infection, is also selected for by the necessity of transmission. Microbes, of course, adapt much faster than can humans, even to the antimicrobials invented to tilt the contest in our favour. The mathematical modelling that follows attempts to quantify the relationship between the infectious doses generated by the source case(s) and the number of infected humans, but ignores the fact that most tubercle bacilli released from the source case are unlikely to cause infection due to factors cited earlier. In addition, probability plays a role in whether a vulnerable host inhales an infectious dose of MTB.
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In an attempt to characterize the transmission process as a probability that a vulnerable host will acquire TB infection, Wells and Riley (Richard’s brother, Edward, an engineer) developed a mathematical model that expands upon and modifies the Soper mass balance equation for epidemiological investigations, incorporating the following operational assumptions: 1. steady-state conditions in which the infectious source is constant; 2. complete air mixing within a defined volume or space being studied; 3. equal susceptibility among exposed individuals to infection; 4. Poisson’s law of small chances which employs the natural logarithm e; 5. uniform virulence of organisms released into the air space; and 6. random distribution of infectious particles within a defined space. This model states that for a single generation of infection: C ¼ Sð1 eIqpt=Q Þ; where: ¼ number of new cases, ¼ number of susceptibles exposed, ¼ natural logarithm, ¼ number of infectious sources, ¼ number of quanta (infectious doses) generated per unit time in minutes, p ¼ human ventilation rate in L/minute, t ¼ exposure duration, and Q ¼ infection-free ventilation in the room in L/second. C S e I q
Although this model applies to situations that meet the assumptions above (i.e. a single room or enclosed space with a defined ventilation), it can be applied, although with less validity, to spaces served by a single central ventilation system (i.e. HVAC system) and whose air spaces are connected – an essential component for infections which are airborne. The larger the space being considered, the less evenly distributed (mixed) airborne particles may be, thus also potentially reducing the validity of this model for that air space. Despite these limitations, the model has been useful in examining the relative importance of transmission factors in real-life exposure situations. In epidemiological investigations of epidemics in which C, S, I, p, t, and Q were known or estimated, values for q could be calculated as a representation of the infectiousness of the index source case. This was done for a few scenarios of TB transmission: the patients
on Riley’s TB ward in the 1950 experiment with guinea pigs, an office outbreak, and a bronchoscopy case on a patient with TB in an intensive care unit (Table 2.2). What follows is a discussion of how the Wells–Riley equation has been used to compare the intensity of exposure to TB and how it can inform approaches to reducing transmission. In the first situation, Riley’s TB patients were receiving TB drug treatment and the infectiousness values represent that of the entire six-bed ward. In the second scenario, a 30-year-old woman returned to work in a welfare office for an additional month before she was diagnosed with cavitary, sputum smear-positive TB, at which time contact with fellow employees ended.85 Of 67 co-workers who were initially tuberculin skin test negative, 27 (40%) had conversions to positive upon repeat testing 3 months later. One non-infectious secondary case resulted in a worker who had declined treatment of latent infection. The office building had been the subject of repeated air quality complaints, and several air quality assessments had been done before and after the TB exposure. A mathematical analysis of the exposure was prompted by the suspicion of several workers that inadequate ventilation was responsible for the large number of infected workers. All values of the Wells–Riley equation were known or estimable except q, the number of infectious quanta generated by the source case. By calculation, the source generated 13 infectious quanta per hour. Further calculations showed that outdoor air ventilation at the low end for acceptable air quality (15 cubic feet per minute (cfm) per occupant, based on average room CO2 values of 1000 ppm) contributed to transmission. However, the model was useful also for indicating that doubling the ventilation would reduce the risk of infection by approximately half (Fig. 2.3). Thirteen workers would still have been infected, according to the model. Moreover, an additional doubling of ventilation, to 60 cfm per occupant, would again reduce the risk by half, leaving approximately six workers unprotected. Both the potential of a moderately infectious patient to infect many contacts over a prolonged period of time and the limitations of building ventilation to prevent transmission were demonstrated, within the assumptions and limitations of the model. For the third scenario, Catanzaro86 applied the Wells–Riley equation to an episode of transmission in an intensive care unit where an unsuspected patient, initially smear negative for TB, underwent intubation and bronchoscopy. During the 2½ hours of the procedures, 10 of 13 susceptible room occupants became infected. By calculation, the source produced a remarkable 250 infectious quanta per hour. However, the ventilation rate in the intensive care unit was extremely low, and further calculations predicted substantial improvements by increases in ventilation that were
Table 2.2 Transmission factors and exposure conditions for three different scenarios using the modified Wells–Riley equation Factors
VA hospitals
Office buildings
Bronchoscopy
Source (I) Exposure time (t) Susceptibles (S) Air sampled Infected (C) Ventilation (Q) Infectivity (q) Concentration
6 patients 730 days 120 guinea pigs 693,000 cf 63/120 (52%) 38 cfm/person 1.25 qph 1/11,000 cf
1 patient 6.7 days 67 people 230,000 cf 27/67 (40%) 15 cfm/person 13 qph 1/8500 cf
1 patient 150 min 13 people 688 cf 10/13 (77%) 11.5 cfm/person 249 qph 1/70 cf
Source: Friedman: Tuberculosis: Current Concepts and Treatment, 2nd edition. Informa Healthcare, 2000.
14
CHAPTER
Transmission of Mycobacterium tuberculosis The effect of ventilation on the probabilty of infection
PProbabilty of infection (%)
100 80
P=1q
60 40 Nardell
0
Catanzaro
0
2000 4000 6000 Q Germ-free ventilation (cfm)
8000
Fig. 2.3 Two different examples of transmission and the effect of
ventilation. # Joint Commission Resources: Joint Commission Journal on Quality and Patient Safety. 20(1):25–31, 1993. Reprinted with permission.
achievable (Fig. 2.3). The episode illustrates the ever-present risk of the unsuspected case, the wide range of infectivity, and the potential for environmental controls to greatly reduce transmission when existing ventilation is low.
FUTURE PROSPECTS AND OTHER IMPORTANT CONSIDERATIONS IN INFECTION CONTROL (BOX 2.1) Although the basic mechanism of MTB transmission has been understood for more than 50 years, there have been no real advances in infection control over at least that long. Such advances will likely require renewed interest and new research on the basic aerobiology of MTB. Each component shown in Fig. 2.1 is a potential target for novel infection control innovations. For example, new interventions may reduce the production of airborne particles or reduce their viability. New environmental interventions may inactivate MTB in its vulnerable airborne state. New
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Box 2.1 Infection control strategies in relation to source, environmental, and host transmission factors Infection control is covered in a separate chapter. Here, for completeness, we list how the traditional control and prevention strategies fit into the source, organism, environment, and host model that we have used.
·lqpl/Q
20
2
Control measures focused on the infectious source Administrative measures: case surveillance, triage, isolation, and diagnosis. Case treatment, both pharmacological and surgery in selected cases. Contact investigation and treatment of LTBI. Masks on patients. Cough suppression. Control measures focused on the organism Case treatment. Drug susceptibility testing. Control measures focused on the environment Air disinfection by ventilation, filtration, or germicidal irradiation. Dilution. Isolation. Control measures focused on the host Immunization—preventive. Immunomodulation—boosting already infected persons to better control the pathogen. Nutrition. Antiretroviral therapy for HIV coinfection. Respiratory protection.
vaccines and administration routes may reduce the chance of infection or reinfection. A major challenge, however, is that TB is predominantly a disease of resource-limited countries. Innovations must be effective and they must also be affordable where they are most needed. Finally, greater efforts are needed to increase awareness of the importance of transmission, and to implement existing guidelines as well as future novel interventions to prevent transmission. The convergence of the HIV and TB epidemics, including drug-resistant strains, in many parts of the world is providing a strong incentive to end the neglect of this vital aspect of TB control, but much work remains to be done.
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65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81. 82.
83.
84.
85.
86.
from isoniazid-treated patients. Am Rev Tuberc 1954;70(5):852–872. Peizer LR, Widelock D, Klein S. Effect of isoniazid on the viability of isoniazid-susceptible and isoniazidresistant cultures of Mycobacterium tuberculosis. Am Rev Tuberc 1954;89(6):1022–1028. Li Z, Kelley C, Collins F, et al. Expression of katG in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs. J Infect Dis 1998;177(4):1030–1035. Behr M. Genetic diversity of the Mycobacterium tuberculosis complex. In: Rom WN, Garay SM (eds). Tuberculosis, 2nd edn. Philadelphia: Lippincott Williams & Wilkins, 2004. Ordway DJ, Sonnenberg MG, Donahue SA, et al. Drug-resistant strains of Mycobacterium tuberculosis exhibit a range of virulence for mice. Infect Immun 1995;63(2):741–743. Cohen T, Sommers B, Murray M. The effect of drug resistance on the fitness of Mycobacterium tuberculosis. Lancet Infect Dis 2003;3(1):13–21. Teixeira L, Perkins MD, Johnson JL, et al. Infection and disease among household contacts of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5(4):321–328. Karls RK, Guarner J, McMurray DN, et al. Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis. Microbiology 2006;152(Pt 6):1591–1600. Markowitz N, Hansen NI, Hopewell PC, et al. Incidence of tuberculosis in the United States among HIV-infected persons. The Pulmonary Complications of HIV Infection Study Group. Ann Intern Med 1997;126(2):123–132. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320(9):545–550. Selwyn PA, Sckell BM, Alcabes P, et al. High risk of active tuberculosis in HIV-infected drug users with cutaneous anergy. JAMA 1992;268(4):504–509. Hopewell PC, Chaisson RE. Chapter 20: Tuberculosis and human immunodeficiency virus infection. In: Reichman LB, Hershfield ES (eds). Tuberculosis: A Comprehensive International Approach, vol. 144, 2nd edn. New York: Marcel Dekker, 2000. Cowie RL, Langton ME, Becklake MR. Pulmonary tuberculosis in South African gold miners. Am Rev Respir Dis 1989;139(5):1086–1089. Hnizdo E, Murray J. Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners. Occup Environ Med 1998;55(7): 496–502. Sherson D, Lander F. Morbidity of pulmonary tuberculosis among silicotic and nonsilicotic foundry workers in Denmark. J Occup Med 1990;32(2):110–113. Allison AC, Hart PD. Potentiation by silica of the growth of Mycobacterium tuberculosis in macrophage cultures. Br J Exp Pathol 1968;49(5):465–476. Gardner L. Studies on experimental pneumoconiosisthe reactivation of healing primary tubercles in the lung by inhalation of quartz, granite and carborundum dusts. Am Rev Tuberc 1929;20:833–875. Uber CL, McReynolds RA. Immunotoxicology of silica. Crit Rev Toxicol 1982;10(4):303–319. Stead WW. Genetics and resistance to tuberculosis. Could resistance be enhanced by genetic engineering? Ann Intern Med 1992;116(11):937–941. Stead WW, Senner JW, Reddick WT, et al. Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engl J Med 1990;322(7):422–427. Cohen T, Murray M. Incident tuberculosis among recent US immigrants and exogenous reinfection. Emerg Infect Dis 2005;11(5):725–728. Nardell EA, Keegan J, Cheney SA, et al. Airborne infection. Theoretical limits of protection achievable by building ventilation. Am Rev Respir Dis 1991;144(2):302–306. Catanzaro A. Nosocomial tuberculosis. Am Rev Respir Dis 1982;125(5):559–562.
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3
The global epidemiology of tuberculosis Catherine J Watt, S Mehran Hosseini, Knut Lo¨nnroth, Brian G Williams, and Christopher Dye
NATURAL HISTORY OF TUBERCULOSIS TRANSMISSION, INFECTION, DISEASE Tuberculosis is a rare disease, whose prevalence is measured or estimated in cases per 100,000 population. TB is also a slow-moving disease – the time scale of epidemics is decades rather than weeks or years. The natural history of TB helps us understand the driving forces behind these ‘slow epidemics of a rare disease’,1 and the temporal and geographical patterns in its distribution. In Fig. 3.1, arrows represent the processes by which individuals enter and leave each of the states represented by the boxes. An individual can be uninfected, latently infected, or can have primary or post-primary disease. Infection with Mycobacterium tuberculosis, the causative agent of TB, results from inhaling droplets containing the bacilli, which are produced when a person with infectious TB coughs, talks, or sneezes (see Chapter 14 for a more detailed discussion). A widely used rule of thumb in TB epidemiology is that each untreated, infectious TB case infects, on average, about another 10 individuals each year.2,3 The estimated prevalence of smearpositive disease was just under 0.1% (90 per 100,000) in 2005,4 which corresponds to an annual risk of infection of just under 1%. A recent assessment of new infections caused by all infectious TB cases (treated and untreated) suggests an average of six new infections per case, which would imply an even lower annual risk of infection.5 Of infected individuals, only about 5% (in the absence of other predisposing conditions) develop ‘progressive primary’ disease following infection.6 Progression is typically slow, with time to development of primary disease averaging 3–4 years.7 For the remainder, who enter the pool of ‘latently infected’ individuals, there is a low annual risk of developing TB by ‘reactivation’ of infection. Whether latent bacteria remain viable for the full lifespan of all infected people is unknown, but the risk of reactivation certainly persists into old age for many. Infection is associated with only partial immune protection from reinfection.7–9 Thus, particularly in areas where infection transmission is high, infected persons remain at risk of disease resulting from reinfection. At the population level, the relative importance of primary disease, of post-primary disease resulting from reactivation and of post-primary disease following reinfection varies according to past and current patterns of transmission and breakdown to
disease. The majority of individuals infected with M. tuberculosis (but not with HIV) do not develop TB disease; the lifetime risk of pulmonary disease among infected individuals has been estimated at 12% for England and Wales in the second half of the twentieth century.8 It is this large pool of infected, healthy individuals and the typically long interval from acquiring infection to developing disease which give the slow-moving epidemics of TB their momentum, and mean that they generally respond slowly to control efforts. While the low rate of infection and breakdown to disease make TB a relatively rare disease, it is principally the high case-fatality rate which makes it one of major public health significance. Left untreated, and in the absence of HIV, about two-thirds of smearpositive cases will die, mostly within 2 years.3 For untreated smear-negative cases, case fatality rates are lower: 10–15%.10,11 Even on treatment, over 10% of smear-positive patients die in settings where adherence to treatment is low, or rates of HIV infection or drug resistance are high, although in other settings as few as 2% of smear-positive patients die while on treatment.4
RISK FACTORS The rates at which individuals move along the various arrows from one box to another in Fig. 3.1 determine the burden and distribution of disease. Factors which affect those rates, or which affect the proportion of individuals who take each path when an arrow branches, will in turn affect the size and dynamics of the epidemic. These ‘risk factors’ result from inherent characteristics of the biology of the human host and of the mycobacterial pathogen and from characteristics of the environment. Some key risk factors and their effects are shown in Table 3.1. While the association between certain risk factors and TB disease is clear, it is in practice difficult to determine which part of the life cycle of TB is affected by a particular risk factor (e.g. whether it is the risk of infection or the risk of breakdown to disease which is affected). The problem of confounding further complicates the study of risk factors; factors such as crowded living conditions, malnutrition, and exposure to indoor air pollution from cooking fires are clearly all linked to poverty, and difficult to study independently. The likelihood of transmission depends largely on the proximity and duration of contact with an infectious TB case, and is therefore increased by poorly ventilated, overcrowded housing. People in close contact with infectious cases (family members, health workers, prisoners) are at elevated risk of infection.
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Birth
Pre-exposure vaccination
Uninfected (susceptible)
Protected
Exposure and infection Preventive treatment
Postexposure vaccination
Latently infected Cure (spontaneous or following treatment)
Reactication or re-infection
Primary or post-primary disease Death
Fig. 3.1 Processes of transmission, infection and disease for TB.
Table 3.1 Risk factors for tuberculosis Risk factor
Affects
Sources
Crowded living conditions Smoking Malnutrition
Exposure to infectious cases
12, 13
Susceptibility to infection Susceptibility to infection, likelihood of developing primary disease, likelihood of breakdown from latent infection, likelihood of recovery from disease Susceptibility to infection Exposure to infectious cases, likelihood of developing primary disease, likelihood of breakdown from latent infection, likelihood of recovery from disease Susceptibility to infection, likelihood of breakdown, likelihood of recurrence Severity and infectiousness of disease, likelihood of treatment failure or relapse Exposure, susceptibility to infection, likelihood of developing primary disease, or of breakdown to disease from latent infection, type of disease Exposure, susceptibility to infection, likelihood of breakdown to disease, type of disease, health-seeking behaviours, tendency to default from treatment Susceptibility to infection, or to certain types of disease
14–17 18–20
Indoor air pollution Alcohol HIV Diabetes Age Sex/gender Genetic factors
Susceptibility to tuberculosis may be affected by factors such as tobacco smoking, silicosis, exposure to smoke from cooking fires and excessive alcohol use as well as by HIV infection, but it is difficult in practice to distinguish between the effect of such factors on susceptibility to infection and the likelihood of progression to disease. Malnutrition influences breakdown to disease,18 although to what extent requires careful investigation in order to distinguish pre-existing malnutrition from wasting resulting from TB. Nutrition is likely also to influence the likelihood of recovery from disease. HIV infection has a dramatic effect on the likelihood of breakdown to disease,24–27 increasing the likelihood of breakdown from a lifetime risk of between 10% and 20% to an annual risk of over 10%.7,8,37,38 Both age and sex have biological and social effects which are difficult to distinguish. The risk of developing primary disease is
18
21, 22 23 24–27 28 29 11, 30–33 34–36
lower in children than in adults,6,39 and children are more likely to develop severe forms of disease in organs other than the lungs (e.g. tuberculous meningitis). Young women (15–44 years) may be more likely than men to develop active TB following infection, but the socially driven effects of gender are generally more marked than the biological effects of sex.11,31–33 Men and women experience different environmental risk factors, and demonstrate different health-seeking behaviours and tendencies to adhere to treatment.40
Population attributable fractions The overall contribution of an individual risk factor to determining the path of the global TB epidemic depends both on the strength of the effect of that risk factor and on how widespread that risk factor is. By quantifying the relative risks associated with various risk factors and the prevalence of those risk factors one can calculate the
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The global epidemiology of tuberculosis
population attributable fraction (PAF) for those risk factors. The study of risk factors with high prevalence, and which can be altered (not, for example, age and sex), is one possible approach to identifying activities which have the potential to help prevent TB. In taking this approach, however, it is important to acknowledge that the sum of the PAFs for a set of risk factors can be greater than 1. Furthermore, the size of the PAF gives no indication of how quickly one would see the effect of any intervention aimed at the risk factor in question. Bearing these limitations in mind, a comparison, for example of smoking and HIV, illustrates the value of considering the prevalence of a risk factor as well as the relative risk. The relative risk of TB associated with HIV is almost certainly considerably higher than that associated with tobacco smoking. However, the prevalence of smoking in the 22 countries which account for 80% of the annual incidence of TB is estimated at 18%,41 compared with an estimated prevalence of HIV of 1.1%.42 Thus preliminary estimates suggest that the PAF for smoking is several times that for HIV globally. Only in the World Health Organization (WHO) African region is the PAF for HIV higher than that for smoking, and even there the PAF for smoking is substantial. These preliminary results suggest that much could be gained in terms of preventing TB by addressing tobacco smoking, and by exploring other prevalent but preventable risk factors.
TUBERCULOSIS CONTROL The path of TB epidemics is clearly determined not only by the biological and social phenomena discussed above under Risk Factors, but also by explicit efforts to control the disease. Prior to the development of antibiotic therapy for TB, the main methods of control available were reducing transmission by isolating infectious patients, and increasing the likelihood of spontaneous recovery by providing patients with rest and improved nutrition. Both these aims were achieved by treating TB patients in sanatoria, where case-fatality rates were about 50%.3 Modern TB control is based on early detection and treatment, particularly of infectious cases. Treatment is generally effective; the average global cure rate was 84.7% for smear-positive cases treated in 2005 by programmes following international recommendations.4 Treatment has, therefore, a direct impact on the prevalence of disease and on mortality. Furthermore, transmission is reduced, as infectious cases quickly become non-infectious once treatment is started. In addition to the primary goal of TB control (early diagnosis and treatment), national TB programmes or health authorities can (and, to varying degrees, do) influence the flow of individuals along the paths shown in Fig. 3.1 in the following ways: by implementing appropriate ‘infection control’ strategies (ensuring adequate ventilation in healthcare centres, minimizing contact between infectious and susceptible individuals in order to reduce transmission43,44); by providing preventive treatment (isoniazid preventive therapy, IPT) to infected individuals who do not have TB disease (thus returning them from the latently infected pool to the pool of susceptibles); by collaborating with national acquired immunodeficiency syndrome (AIDS) programmes to identify and provide appropriate care for HIV-infected TB patients; and by providing nutritional support to TB patients and their families, thus improving their nutritional status and perhaps increasing the likelihood of recovery for patients, decreasing the likelihood of infection for family members and encouraging patients to complete treatment. Finally, roughly 100 million infants (>80% of the
3
annual cohort) are vaccinated each year with Bacillus CalmetteGue´rin (BCG), the effect of which is mainly to prevent serious forms of disease in children: meningitis and miliary TB. The potential of existing and possibly future tools for reducing the burden of TB, particularly with reference to international targets, is discussed further below.
GLOBAL AND REGIONAL BURDEN AND TRENDS Based on surveys of the prevalence of infection and of disease, on assessments of the performance of surveillance systems and on death registrations, there were an estimated 9.2 million new cases of TB in 2006, of which 4.1 million were smear-positive.4,45,46 The WHO African region had the highest estimated incidence rate (363 per 100,000 population), but the majority of TB patients live in the most populous countries of Asia. Five countries – Bangladesh, China, India, Indonesia, and Pakistan – have almost half the world’s population (46%) and produced about half (48%) of all new TB cases arising worldwide in 2006. Figure 3.2 illustrates the global distribution of new TB cases in 2006, in terms of numbers and rates per 100,000 population. Much of the work of the WHO and partners focuses on the 22 countries known as the high-burden countries (HBCs). These are the countries which, in 2002, were estimated to have had the highest numbers of incident TB cases in the year 2000: Afghanistan, Bangladesh, Brazil, Cambodia, China, the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Kenya, Mozambique, Myanmar, Nigeria, Pakistan, Philippines, the Russian Federation, South Africa, Thailand, Uganda, the United Republic of Tanzania, Viet Nam and Zimbabwe.45 Changes in estimates due to new data or techniques, and likely changes in incidence rates and population sizes, mean that this list no longer exactly matches the list of the 22 countries with the largest number of new cases each year, but it is still true that, between them, the HBCs account for 80% of new TB cases arising annually. Table 3.2 shows the estimated incidence and prevalence of TB and mortality from TB for 2006. Globally an estimated 1.7 million people died from TB in 2006, 231,000 of them infected with HIV. Estimates of TB incidence, prevalence and mortality are uncertain, and rely to varying degrees on assumptions about the quality of surveillance data, about the quality and impact of treatment and about the duration of disease and case-fatality rates.45,46 New methods for evaluating the burden of TB and impact of control are needed. In our view these should be based principally on assessments of the quality of surveillance systems, backed by data obtained from surveys of the prevalence of disease. These methods and the resulting data would help to meet increasing demands from donor agencies (such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria) to demonstrate the impact of the activities which they fund, and of international experts to increase the transparency surrounding statistics provided through databases such as those of the WHO (e.g. http://www.who.int/tb/country/global_tb_database, and http://www.who.int/whosis) and of the United Nation Statistical Division (http://mdgs.un.org).47 A recently established task force on measurement of TB will guide work on improving estimates of the burden of TB and the impact of control.48 Estimates of the incidence of multidrug-resistant TB (MDR-TB; caused by strains of M. tuberculosis resistant to at least isoniazid and rifampicin) are even more uncertain than those of overall TB incidence. Drug susceptibility testing is not widely available, although
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Estimated numbers of new cases, 2006
Estimated number of TB cases per year (all forms) No estimate 0–999 1000–9999 10,000–99,999 100,000–999,999 1,000,000 or more
Estimated TB incidence rate, 2006
Estimated TB cases per year (all forms) per 10, 000 population No estimate 0–24 25–49 50–99 100–299 300 or more
Fig. 3.2 Estimated incidence (numbers and rates) of TB cases, 2006.
WHO guidelines for incorporating the diagnosis and treatment of drug-resistant TB into the routine activities of national TB control programmes are likely to lead to improved information about the proportion of TB cases which are MDR.49 Current estimates (based on multivariate analysis) are that 489,000 cases of MDR-TB arose in 2006 among new and previously treated TB cases.50 Extensively drug-resistant TB (XDR-TB) is defined as TB due to bacilli resistant to any fluoroquinolone, and at least one of three injectable second-line drugs (capreomycin, kanamycin, and amikacin), in addition to isoniazid and rifampicin.51 The magnitude of the XDR-TB problem globally is not yet known. Where the transmission of M. tuberculosis has been stable or increasing for many years, the incidence rate is relatively high among
20
infants and young adults, and most cases are due to recent infection or reinfection. As transmission falls, the caseload shifts to older adults, and a higher proportion of cases comes from the reactivation of latent infection. Therefore, in the countries of Western Europe and North America that now have low incidence rates, indigenous TB patients tend to be elderly, while patients who are immigrants from highincidence countries tend to be young adults. Allowing for the difficulties of diagnosing childhood TB, estimation exercises indicate that there are relatively few cases among 0–14 year olds; while this age group accounts for nearly 30% of the world’s population, it accounts for only 12% of estimated cases. In 2006, countries reported 1.6 million smear-positive TB cases among men, but only 884,000 among women. In some instances
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The global epidemiology of tuberculosis
3
Table 3.2 Estimated TB incidence, prevalence and mortality, 2006 WHO region
Incidence (per year) All forms
Africa The Americas Eastern Mediterranean Europe South-East Asia Western Pacific Global
Prevalence (all forms) Smear-positive
Number (thousands) (% of global total)
Per 100,000 population
Number (thousands)
Per 100,000 population
2,808 (31) 331 (4) 570 (6)
363 37 105
1,203 165 256
155 18 47
433 (5) 3,100 (34) 1,915 (22) 9,157 (100)
49 180 109 139
194 1,391 860 4,068
22 81 49 62
women have poorer access to diagnostic facilities,30 but the broader pattern also reflects real epidemiological differences between the sexes: while there is some evidence that young adult women (15–44 years) are more likely than men to develop active TB following infection, this effect is typically outweighed by the much higher exposure and infection rates among adult men.11,31–33
Tuberculosis prevalence and death rates have probably been falling globally for several years, and it is likely that the TB incidence rate had reached a peak worldwide in about 2003 (Fig. 3.3). However, because the populations of the countries heavily affected by TB are still growing, the total number of new TB cases arising each year was also still slowly increasing in 2006.4 This rather static picture of the global epidemic close to its peak conceals much variation in the dynamics of TB among regions. The countries of sub-Saharan Africa and the former Soviet Union showed striking increases in case loads during the 1990s. These rises offset the fall in case numbers in other parts of the world, principally West and Central Europe, the Americas and the Eastern Mediterranean regions. Industrialized countries are typically seeing fewer cases among nationals each year, but steady or rising numbers of cases among immigrants. In 12 out of 28 Western European countries providing data in 2005, the majority of TB patients were foreign-born or foreign citizens.52 Prevalence
Per Number 100,000 (thousands) population
Per 100,000 population
4,234 398 826
546 44 152
639 41 108
83 4.5 20
478 4,975 3,513 14,424
54 289 199 219
62 515 291 1,656
7.0 30 17 25
Mortality
300
Incidence 144
280 260 240 220
1995
2000
2005
cases per 100,000 pop/year
33 deaths per 100,000 pop/year
cases per 100,000 pop
Number (thousands)
An estimated 1.7 million people died of TB in 2006. Tuberculosis is the world’s second largest killer among infectious agents, behind HIV/AIDS.53 In terms of years of healthy life lost, TB remains among the top 10 causes of illness, death and disability. The 231,000 TB deaths in people infected with HIV were 14% of all TB deaths and 10% of AIDS deaths in 2006, and the vast majority (205,000) were in Africa.4 Death registrations have been increasing in former Soviet countries since the 1980s, but falling in Central Europe, Latin America and the industrialized world. Estimates suggest that, while TB deaths were probably increasing during the 1990s, driven mainly by the steep rise in HIV-related mortality in Africa, the global TB death rate peaked before year 2000. This was after prevalence began to fall, but before the peak in incidence (Fig. 3.3). In Eastern Europe (principally countries of the former Soviet Union), case reports increased dramatically in the early 1990s. This resurgence can be explained by economic decline and the failure of TB control and other health services since 1991,54 along with other factors such as alcoholism, cardiovascular disease and the mixing of prison and civilian populations.55–57 Over the past 3–6 years, the increase in notification rates has stopped or reversed in Estonia, Romania, Kazakhstan, Kyrgyzstan, Latvia, Lithuania and the Russian Federation, suggesting a levelling off in the incidence of TB in the region.4 It is estimated that 13% of all new TB cases arising each year in Eastern Europe, and 46% of re-treatment cases, are MDR.50 Drug
TRENDS
200 1990
TB mortality (per year)
31 29 27 25 23 1990
1995
2000
2005
140 136 132 128 124 120 1990
1995
2000
2005
Fig. 3.3 Estimated global prevalence, mortality and incidence rates, 1990–2006. Note different y axes.
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IMPLEMENTATION OF THE STOP TUBERCULOSIS STRATEGY Progress in TB control has been measured principally in terms of the implementation of DOTS (see Chapters 106 and 107).63,64 Data collected by the end of 2007 allowed the WHO to assess in which countries and regions the targets for 70% case detection and 85% treatment success, originally set for 2005, were met by the end of 2006.4,65
Case detection Over the 12 years 1994–2006, a total of 30 million TB patients were diagnosed and reported under DOTS. In 2006, DOTS programmes worldwide reported 5.3 million new and relapse cases,
22
WHO target 70 60 50 40 30
Average rate of progress 1995–2000
DOTS begins 20 10 0 1990
1995
2000
2005
2015
2010
Year
Fig. 3.4 Case detection of new smear-positive cases and of all new cases under DOTS, 1995–2006. Open circles mark the number of new smearpositive cases notified under DOTS 1995–2006, expressed as a percentage of estimated new cases in each year. The solid line through these points indicates the average annual increment from 1995 to 2000 of about 134,000 new cases, compared with the average increment from 2000 to 2006 of about 243,000 cases. Closed circles show the total number of smear-positive cases notified (DOTS and non-DOTS) as a percentage of estimated cases.
among which 2.5 million were smear-positive. This gives a smear-positive case detection rate of 61% (95% confidence interval (CI) 55–75%), short of the 70% target. The estimated case detection rate by DOTS programmes increased almost linearly from 12% globally in 1995 to 23% in 2000. Case detection then accelerated, though it has slowed somewhat since 2004 (Fig. 3.4). The global acceleration in case detection has been driven principally by South-East Asia (mostly India) since 2000, supported by the Western Pacific Region (mostly China) since 2002. However, only eight of the 22 high-burden countries (including China), 77 countries and territories in total and one WHO region (Western Pacific) reached the 70% target by 2006.4,65
Treatment success Of 2.4 million smear-positive patients registered for treatment under DOTS in 2005, 2.0 million (84.7%) were successfully treated (i.e. cured, as judged by sputum smear conversion, or completed treatment without final smear examination), just short of the 85% target. The global treatment success rate under DOTS has been high since the first observed cohort in 1994 (77% of 245,000 patients), and has remained above 80% since 1998 (Fig. 3.5).4,65 Treatment success target: 85% 85
2500
80 2000 75 70
1500
65
1000
60 500 55 50 1993
Thousands of patients treated
TUBERCULOSIS CONTROL: IMPLEMENTATION, TARGETS AND PROJECTIONS
80 Case detection rate, smear-positive cases (%)
resistance is likely to be a byproduct of the events that led to TB resurgence in these countries, not the primary cause of it, for three reasons. First, resistance is generated initially by inadequate treatment due, for example, to interruption of the treatment schedule, the use of low-quality drugs or the use of high-quality drugs at low dosage. Second, resistance tends to build up over many years, but there was a sudden increase in TB incidence in Eastern European countries after 1991. And third, although formal calculations have not been done, resistance rates are probably too low to attribute all of the increase in caseload to excess transmission from treatment failures. Tuberculosis notification rates, and probably incidence, have been rising dramatically in Africa since 1990. It is likely that this increase is largely due to HIV infection;45 in 2006 an estimated 22% of new TB cases arose in people infected with HIV, and the HIV prevalence among new TB cases was over 40% in eight countries.4 The HIV epidemic is probably now in decline in most countries of sub-Saharan Africa,42 and it appears that the incidence of TB may also have reached a peak.4 Based on case reports, TB has been in decline in Western Europe for 150 years.1,29 There are numerous plausible explanations for this decline, and it is not possible to determine the exact contribution of the various factors. The first main explanation is that transmission fell when housing conditions improved and people began to live at lower density in better ventilated housing, and when patients were isolated in sanatoria.12 Contact rates may also have fallen as the average age of cases increased.13 Secondly, it is likely that improved nutrition led to reduced susceptibility to disease.18–20,58 The failure of the case-fatality rate to decline before the widespread introduction of anti-TB drugs in the late 1940s suggests that improved nutrition had little effect on the outcome of disease. Thirdly, it has been proposed, but not demonstrated, that M. tuberculosis has become less pathogenic.59–61 The decline in case notifications slowed in many developed countries around 1990 and has stopped or almost stopped falling in some countries, notably Hong Kong, Japan, Singapore, the United Kingdom and the United States. This is likely to be the result of at least two phenomena – first, more cases are arising by reactivation from an aging TB epidemic in an aging human population; second, an increasing proportion of notified cases is in immigrants.62
Treatment success rate
1
0 1995
1997
1999
2001
2003
2005
Fig. 3.5 Treatment success rate (closed circles) and numbers of patients treated (open circles), new smear-positive cases treated under DOTS, 1994–2005.
CHAPTER
The global epidemiology of tuberculosis target: 15% or less (success 85% or more) Africa The Americas Eastern Mediterranean Europe South-East Asia Western Pacific 0 Died
Failed
Defaulted
15 % of cohort Transferred
30 Not evaluated
Fig. 3.6 Unsuccessful treatment outcomes for new smear-positive cases treated under DOTS, 2005, by WHO region.
For patients diagnosed in 2005, the 85% target was reached by eight of the 22 high-burden countries, and by two WHO regions (South-East Asia, Western Pacific). In the four regions that did not meet the target, the reasons for poor results were, as shown in Fig. 3.6, high rates of death (Africa, Europe), treatment failure (Europe) and unknown outcomes through default, transfer without follow-up or no evaluation (Africa, Americas, Eastern Mediterranean, Europe).
IMPACT OF DOTS ON INCIDENCE, PREVALENCE AND MORTALITY Although the decline in TB has almost certainly been accelerated by good chemotherapy programmes, which have been implemented for decades in countries such as Chile, Cuba and Uruguay, there have been few recent, unequivocal demonstrations of impact in high-burden countries. This is because large-scale public health programmes are not carried out as controlled experiments, and because there are other factors that influence transmission or susceptibility to disease (housing, nutrition, coinfection and others; see discussion under Risk Factors, above). However, Morocco and Peru provide two persuasive examples. Between 1994 and 2000, the incidence of pulmonary TB among Moroccan children 0–4 years of age fell at more than 10% per year, suggesting that the risk of infection was falling at least as quickly (Ministry of Health Morocco, unpublished data). The average age of TB cases has been rising for over 20 years in Morocco. And yet the overall reduction in pulmonary TB was only 4% per year, in part because of the large reservoir of infection in adults. In Peru, DOTS was launched in 1991, and high rates of case detection and cure pushed down the incidence rate of pulmonary TB by 6% per year.66 Indirect assessments of the effect of DOTS suggest that 70% of the TB deaths expected in the absence of DOTS were averted in Peru between 1991 and 2000. There have been few direct measures of the reduction in TB prevalence over time. The Republic of Korea carried out seven surveys at 5-year intervals between 1965 and 1995, during which time the prevalence of bacteriologically positive cases (smearand/or culture-positive) disease fell from 940 per 100,000 to 219 per 100,000.67 Prevalence surveys done in China in 1990 and in 2000 showed the reduction in the prevalence per capita of all forms of TB in DOTS areas was 32 percentage points (95% CI 9–51%) greater than the reduction in other parts of the country.68 A national survey in Indonesia in 2004 found that the prevalence
3
of smear-positive TB had fallen by a factor of 3 since a set of regional surveys were carried out between 1979 and 1982.69,70 But not all of this reduction can be attributed to the DOTS programme, or even to the direct effects of chemotherapy. Some investigations of the impact of DOTS programmes have shown that, after several years of implementation, incidence is not falling as expected. Viet Nam has apparently exceeded the targets for case detection and treatment success since 1997, and yet the case notification rate remained approximately stable over that period.71 Closer inspection of surveillance data shows that, while case notification rates are falling among adults aged 35–64 years (especially women), they are increasing among 15–24 year olds (especially men).4 These increases and decreases in different age groups, and for men and women, are almost equal in magnitude. This pattern of change in case notifications by age and sex is also visible in routine surveillance data from Sri Lanka. In Indonesia and Myanmar, TB patients in the age group 15–54 years are becoming younger on average, but the average age should be increasing if transmission and incidence are falling.4 Some states of India have been implementing DOTS since 1998, and yet there was no detectable decline in case notification rates at state level by 2006 (Revised National TB Control Programme, personal communication). The case notification rates in different states and in different years are closely correlated with the number of TB suspects examined. This suggests that the number of cases diagnosed and reported is determined by the performance of the public health service, as well as by the true incidence of TB (and contrasts with the situation in Peru, described above, where the number of TB cases found was decreasing despite an increasing number of suspects examined). The southern states of Kerala and Tamil Nadu show an increase in the average age of TB cases, which may reflect falling transmission. This has yet to be translated into a clear demonstration of falling incidence across a whole state, though transmission and prevalence have been reduced on the smaller scale of Tiruvallur District in Tamil Nadu.72,73 Calculations carried out for the WHO’s 2008 report on Global TB Control suggest that, although prevalence and death rates are falling globally, the rate of decline is not fast enough to meet the Millennium Development Goals (MDGs) by 2015.4 While the surveillance data from certain Asian countries show some worrying signs, the biggest challenges in cutting TB burden are in subSaharan Africa and Eastern Europe.
ACHIEVING THE MILLENNIUM DEVELOPMENT GOALS BY 2015 Since the launch of the DOTS strategy during the 1990s, a series of specific, emerging problems in TB epidemiology and control have demanded specific solutions. These include M. tuberculosis and HIV coinfection, drug resistance, the quality of treatment in the private sector and the need to evaluate the epidemiological impact of TB control (not simply the implementation of DOTS). For this reason, DOTS has been extended as the Stop TB Strategy, with the additional elements listed in Table 105.2 of Chapter 105.4,63 The blueprint for implementing the Stop TB Strategy over the next decade is The Global Plan to Stop TB, 2006–2015, discussed in detail in Chapter 106.74 The plan imagines and compares three scenarios. Scenario 1: No DOTS. This assumes that the strategy was never introduced in any region, so chemotherapy would continue as it was pre-DOTS, with variable rates of case detection
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and typically lower rates of cure. This gives a baseline against which to compare gains that have already been made, and which might be made in future. Scenario 2: Sustained DOTS. Case detection and treatment success increase until 2005, and then remain steady until 2015. Approximately 50 million patients would be treated under DOTS between 2006 and 2015, as compared with over 20 million in the previous decade, 1996–2005. Scenario 3: Enhanced DOTS. Case detection and treatment success continue to increase beyond 2005, up to 2015. As in scenario 2, roughly 50 million patients would be treated between 2006 and 2015 (a higher proportion of patients treated sooner means that, as a result of reduced transmission, there are fewer patients later). To reach high rates of case detection and cure requires various additions to the basic DOTS strategy, including communitybased care, a syndromic approach to diagnosing and treating TB among other respiratory conditions, and improved collaboration between public and private health sectors. To improve the management of drug-resistant disease, more patients will be given drug sensitivity tests, and around 800,000 MDR-TB patients will be treated with regimens including second-line drugs. HIV testing and counselling will be provided to 29 million TB patients, and antiretroviral therapy (ART) and cotrimoxazole preventive therapy offered to 3.2 million. Approximately 200 million people infected with HIV will be screened for TB, and 24 million will be offered IPT.
projections also show that, over the 10 years from 2006 to 2015, the impact of the enhanced DOTS strategy, assuming full implementation, would be almost as great in Africa and Eastern Europe as in other regions of the world: a reasonable goal in all regions would be to halve prevalence and death rates between 2005 and 2015. To that end, the implementation of the enhanced DOTS strategy will be especially important in Africa and Eastern Europe, where the incremental benefits of enhanced DOTS (scenario 3) compared with sustained DOTS (scenario 2) are greatest. Indeed, the proportional reduction in TB cases under scenario 3 (as compared with scenario 2) would be greater in Eastern Europe than in any other region. The proportional reduction in deaths would be greatest in Africa (high HIV countries) and Eastern Europe. In regions of the world other than Africa and Eastern Europe, a higher proportion of the benefits to be obtained over the next 10 years come from sustaining what has been achieved over the past 10. And TB epidemiology in these other regions, notably Asia, governs the global trend. Thus, enhanced DOTS (scenario 3), as compared with sustained DOTS (scenario 2), would save only an additional 2.7 million deaths globally over the next decade. But if scenario 3 is considered to be the logical extension of the programme of global DOTS expansion that began in the early 1990s, then enhanced DOTS will save an additional 13.7 million deaths between 2006 and 2015 (compared with scenario 1). In continuing this programme of DOTS expansion, most cases and deaths saved will be in the South-East Asia and Western Pacific Regions.
The potential impact of scenario 3, as compared with scenarios 1 and 2, has been evaluated with a mathematical transmission model describing how the planned interventions determine incidence, prevalence and death rates through time.9,75–77 Model calculations show that scenarios 2 and 3 should both satisfy MDG target 8, to ensure that the incidence rate of TB is falling globally. In fact, the annual incidence of new cases appears to have peaked and may already have been in decline in 2006.4 Ambitious plans for the South-East Asia and Western Pacific regions are expected to generate relatively rapid declines in incidence rate of 7–9% per year by 2015. To halve prevalence and death rates between 1990 and 2015 will be more challenging. Projections suggest that these targets can be met globally with full implementation of the enhanced DOTS strategy (scenario 3), but not in Africa or Eastern Europe. Based on the calculated rate of decline in mortality from 2006 to 2015 in the African countries most affected by HIV, the target death rate would not be reached before 2025. If the rate of decline in mortality slows, as it has in Europe and North America, then the target will be reached even later than 2025. In Eastern Europe, prevalence rates are also expected to remain high compared with 1990 levels because a relatively high proportion of patients have chronic TB, which is commonly multidrug resistant. In Africa, in the absence of ART, patients infected with HIV do not suffer from TB for long; their illness typically progresses quickly, and they are either cured or die.78 The widespread use of ART will alter the dynamics of the coepidemic in ways which are not yet fully understood. The bleak outlook for TB control in Africa and Eastern Europe arises in large part from the choice of 1990 as the MDG reference year. In that year, TB incidence rates in these two regions were close to their lowest levels for at least half a century, and most of the recent rise in incidence happened during the 1990s. While not ignoring the epidemiology of the recent past, more relevant here is the impact of interventions in the near future. The same
ELIMINATING TUBERCULOSIS IN THE TWENTY-FIRST CENTURY
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This discussion of control via the Stop TB Strategy has focused on the chemotherapy of active disease, because drug treatment is likely to remain the principal option for TB over the next decade. In the longer term, TB elimination might be achieved through a combination of measures to prevent infection, to stop progression from infection to active disease and to treat active disease. An examination of the principles of TB elimination would show how we may exploit, or even drive, the development of new drugs, diagnostics and vaccines.79–81 Mathematical modelling shows that, with the diagnosis and treatment of 70% of new infectious cases arising each year and a cure rate of 85%, the incidence rate is expected to fall from a steady state at about 10% annually for the first 10 years, and more slowly thereafter.82 This is the pattern of decline observed in Western European countries after effective TB drugs became available during the 1950s. The net effect is to reduce the incidence rate by a factor of about 10 over a period of 45 years. Applying this result to TB in regions of the world other than sub-Saharan Africa, the incidence rate by 2050 would still be of the order of 100 per million population. A reduction of this magnitude would be an important achievement for public health, but it leaves an incidence rate mid-century that is still about 100 times greater than the elimination target. This is similar to the result obtained under scenario 3 of the Global Plan to Stop TB. To eliminate TB by 2050 (outside sub-Saharan Africa), the incidence rate must fall at an average of 15% annually. This rate of decline might be achieved for a few years, but it is unlikely to be sustainable. The reason, as observed earlier, is that when transmission and incidence fall, a growing proportion of cases arise from the slow reactivation of long-standing latent infections, rather than from the rapid progression of recent infections. Thus, the initial rate of decline in incidence is controlled by primary
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The global epidemiology of tuberculosis
progression, but the long-term rate of decline is governed by reactivation. Combinations of interventions can, in principle, push TB closer to elimination, but some combinations are more effective than others. An exploration of the likely impact of pre-exposure vaccination (to prevent infection) combined with the treatment of TB patients (which also reduces infection) reveals that the effects of the two approaches are similar when used alone, and intensifying either control method yields sharply diminishing returns. The two methods are somewhat more effective in combination, but the additional impact is small. This is because drug treatment to stop transmission at source has effects similar to those of vaccination, which protects those exposed to infection. One intervention partly substitutes for the other; they do not act independently or synergistically. Therefore, a pre-exposure vaccine will be most useful in addition to treatment when the detection rate of active TB cases is low, and vice versa. The campaign to eliminate TB will be more effective if two interventions attack different aetiological pathways. The treatment of latent TB, by either preventive drug therapy or post-exposure vaccination, is relatively ineffective when used alone, but powerful in combination with the treatment of active TB or with preexposure vaccination. When these combined approaches are implemented intensively, TB incidence can be forced close to or below the elimination threshold by 2050.
CONCLUSIONS The countries of sub-Saharan Africa and Eastern Europe (mainly the former Soviet Union) suffered large increases in TB during the 1990s, but there are signs that the incidence rates in these two regions, and, as a result, globally, are now stable or falling. This would mean that MDG target 8 has already been satisfied, 10 years in advance of the 2015 deadline. But there are two important caveats. First, the decline in incidence per capita was slower than the increase in human population in 2006; consequently, the total number of new cases was still rising each year. And second, prevalence and mortality rates are not being reduced quickly enough to meet the MDGs by 2015. These are sharp reminders that, despite having treated more than 30 million patients between 1994 and 2006, DOTS has so far had limited epidemiological impact. It is clear, too, that the fall in case load in some countries is only partially due to the impact of DOTS. In sub-Saharan Africa, the incidence of HIV infection was probably at its highest during the 1990s, and the fall in HIV incidence has weakened the main driving force behind the TB epidemic. In Eastern European countries, many components of the TB control system (diagnostic services, drug supplies, etc.) have been restored after the collapse of the Soviet Union. But this is unlikely to be the full explanation for the stabilization in case notifications in Eastern Europe, because the initial resurgence could also have been due to changes in susceptibility among people who were malnourished, stressed and unemployed. In many countries of Latin America, the Eastern Mediterranean region and Asia, TB case notification rates were falling well before the implementation of DOTS programmes.
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The epidemiological impact of DOTS has been discernible in a few countries (e.g. Peru, China), but remains a matter of conjecture in most. There will always be analytical difficulties in distinguishing the impact of public health intervention outside a randomized controlled trial. Nonetheless, surveillance in India, Indonesia, Myanmar, Sri Lanka and Viet Nam raises doubts about whether the fall in incidence in Asia will be as great as expected from the post-war experience in Europe,3 or as anticipated by mathematical models.9,83 The causes of, for example, rising incidence rates among young adults are not yet clear. HIV infection plays a part, but is unlikely to be the full explanation. There is a strong case for re-examining some basic assumptions about TB epidemiology, such as the magnitude of reactivation and reinfection rates in relation to risk factors including indoor air pollution, drug resistance, malnutrition, diabetes and tobacco smoking.84–89 None of these observations are reasons for abandoning DOTS or the Stop TB Strategy. Rather, the strategy must be reinforced as the only feasible mechanism for achieving the MDGs by 2015. In evaluating progress towards those goals, it will be vital to measure epidemiological impact through a combination of survey methods and surveillance. Periodic population-based surveys of the prevalence of active disease and infection can reveal trends, which could be attributable to specific interventions. Tuberculosis deaths need to be counted in more countries, and, more accurately, either as a component of general cause-of-death surveys or through systems of routine death registration.90 The evidence from surveys of prevalence and deaths should be supplemented by fuller analyses of the huge body of surveillance data that is routinely collected by national control programmes (following the example of Peru). Beyond the Stop TB Strategy, beyond the Global Plan and beyond the MDGs, TB elimination in the twenty-first century will require a new armoury of diagnostics, drugs and vaccines. Tuberculosis cannot be eliminated by 2050 solely by cutting transmission, no matter how well current programmes of drug treatment are implemented. To eliminate TB on this time scale it will be essential to stop the progression from latent infection to active disease, in addition to preventing new infections. This is unlikely to be possible on a large scale unless existing procedures to carry out preventive therapy can be greatly simplified, or replaced. That will require, first, a diagnostic test for latent infection that is more sensitive and specific than the current tuberculin skin test but easy to administer and read. That need might be satisfied, in part, by interferon-g release assays.91 Preventive therapy also requires a course of treatment shorter than 9 months. In this context, a 3-month treatment regimen now appears feasible with combinations of drugs such as isoniazid with rifapentine.92 A major step forward in preventive therapy would be a test to identify which infected people are at relatively high risk of progressing to active disease. The alternative to preventive therapy is immunization, but TB elimination will be possible only with a vaccine that is far superior to BCG. The ideal, dual-action vaccine would prevent both new infection (pre-exposure) and reactivation of latent infection (postexposure). But whatever technological solutions are devised to neutralize latent infection they must be combined with methods to stop transmission. Only by attacking both aetiological pathways can we hope to eliminate TB within the next half century.
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85. Ponce-De-Leon A, Garcia-Garcia Md Mde L, GarciaSancho MC, et al. Tuberculosis and diabetes in southern Mexico. Diabetes Care 2004;27:1584–1590. 86. Coker R, McKee M, Atun R, et al. Risk factors for pulmonary tuberculosis in Russia: case-control study. BMJ 2006;332:85–87. 87. Kim SJ, Hong YP, Lew WJ, et al. Incidence of pulmonary tuberculosis among diabetics. Tuberc Lung Dis 1995;76:529–533. 88. Jick SS, Lieberman ES, Rahman MU, et al. Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum 2006;55:19–26. 89. Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005;171:1430–1435. 90. Whiting DR, Setel PW, Chandramohan D, et al. Estimating cause-specific mortality from communityand facility-based sources in the United Republic of Tanzania: options and implications for mortality burden estimates. Bull World Health Organ 2006; 84:940–948. 91. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part I. Latent tuberculosis. Expert Rev Mol Diagn 2006; 6:413–422. 92. Schechter M, Zajdenverg R, Falco G, et al. Weekly rifapentine/isoniazid or daily rifampin/ pyrazinamide for latent tuberculosis in household contacts. Am J Respir Crit Care Med 2006; 173:922–926.
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Molecular methods and their application in tuberculosis epidemiology Christopher RE McEvoy, Robin M Warren, and Paul D van Helden
INTRODUCTION It is now over 50 years since the introduction of the first effective antituberculosis chemotherapy. Despite this TB remains a major global health concern which is exacerbated by the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic, the emergence of drug-resistant TB strains, and inefficient health services combined with poverty and malnutrition in developing nations. Worldwide, it is estimated that TB is responsible for over 1.6 million deaths per year.1 Molecular epidemiology aims to complement classical epidemiology by determining the natural history and disease dynamics of Mycobacterium tuberculosis strains. Its purpose is to determine the genetic relatedness between isolates and the introduction of molecular tools has greatly increased accuracy to the point where the movements of specific strains and substrains can now be followed through both time and space. These studies can help determine genetic and environmental risk factors that may then aid health authorities in implementing the most effective control and treatment approaches as well as highlighting weaknesses in current control methods. Molecular epidemiology may be used to answer a variety of questions relating to TB infection, transmission, and control. Some of these include:
Where does disease transmission occur? What is the average latency period between infection and disease? What is the proportion of cases caused by endogenous reactivation versus exogenous reinfection? Do different strains show different pathologies? Do different strains show differences in transmission dynamics? Are drug-resistant strains able to transmit as efficiently as drug-susceptible strains? Are some strains more likely to become drug resistant than others? Are some strains more susceptible to anti-TB agents? How often does mixed infection (more than one strain) occur? What are the population risk factors and do these change between populations? How frequently does laboratory-based error occur?
Prior to the use of molecular methods, researchers in TB epidemiology were limited to bacterial factors such as colony morphology, growth rates in vitro, drug resistance profiles, and phage typing for differentiating between populations of M. tuberculosis. These aspects,
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while providing some valuable information at the time, lacked the specificity needed to define the vast majority of TB strains and thus the application of epidemiologically based TB research was greatly limited. It was not until the mid-1980s, over a century after Robert Koch’s seminal discovery that TB is caused by an infectious agent, that molecular biological methods and knowledge of the M. tuberculosis genome were sufficiently advanced to usher in a new range of epidemiological tools. Since that time a variety of molecular-based methods have been described, each with its own particular advantages and disadvantages. Each one, however, is far superior in its strain discrimination ability than previous methods. Thus, since the early 1990s our knowledge of the epidemiological characteristics of the current TB epidemic has grown rapidly and scientists have been provided with unprecedented insights into the factors that drive it. This has resulted in many previously held dogmas being challenged and has, in turn, assisted greatly in public health interventions. For additional information on the molecular epidemiology of TB readers are directed to a recent review by Mathema and co-authors.2
THE GENOME OF M. TUBERCULOSIS AND REGIONS OF EPIDEMIOLOGICAL SIGNIFICANCE The genome of M. tuberculosis holds all the information required for it to grow and reproduce or, in the view of the epidemiologist or clinician, to transmit and cause disease. This information is unique to each individual organism and can thus, in theory, be used to follow the natural history, including the growth, spread, and transmission, of any single lineage. The ultimate epidemiological tool would consist of the total genetic sequence of each TB isolate. While DNA sequencing technology is advancing at a spectacular rate and this may be a viable approach in the future it is not currently feasible and researchers are therefore compelled to concentrate on the small regions of the genome that are most informative. A disadvantage for the TB epidemiologist is that the genomes of all M. tuberculosis strains are remarkably homogeneous.3 Mycobacterium tuberculosis belongs to a closely related group of species known as the M. tuberculosis complex (MTBC) (Fig. 4.1). Recent genetic evidence has suggested that all members of this group are derived from the clonal expansion of a single progenitor that underwent a severe evolutionary bottleneck 20,000–35,000 years ago.4,5 The extreme genetic similarity exhibited by all members of the
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M. bovis BCG
M. bovis
M. caprae
M. pinnipedii
M. microti
M. africanum
M. tuberculosis modern
M. tuberculosis ancestral
M. canetti
Molecular methods and their application in tuberculosis epidemiology
4
methods available it is important that the most appropriate method or combination of methods be selected for the specific study in question. This will depend on factors including the size and geography of the study group, the genetic and cultural makeup of the population, the time period analysed, and whether the study is tracking endemic disease or a disease outbreak. The section below lists the most common genotyping methods used in the molecular epidemiology of TB. In each case background information on the genetic basis for the method, a brief methodology, and advantages and disadvantages of the method are discussed.
IS6110 RFLP ANALYSIS
Fig. 4.1 Phylogenetic tree of the M. tuberculosis complex (MTBC) determined from the analysis of the presence/absence of conserved deleted regions and of DNA polymorphisms in selected genes. Mycobacterium canetti split from the MTBC prior to an evolutionary bottleneck, which has resulted in high genomic homology between MTBC members. Adapted from Brosch R, Gordon SV, Marmiesse M, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 2002;99(6):3684–3689. Copyright 2002 National Academy of Sciences, USA.
MTBC is demonstrated by the fact that the average sequence divergence between the two MTBC species M. tuberculosis and Mycobacterium bovis is less than 0.05% while the divergence between two strains of Escherichia coli is 1.6%.6,7 This fact has led to the recent proposal that members of the MTBC be reclassified as host-adapted ecotypes of the same species.8 Genomic regions that differ between TB strains and which can be exploited by molecular epidemiologists do occur however. These polymorphic regions, termed markers, are often located in non-coding regions and many involve repetitive sequences that vary in copy number. Apart from ease of use, cost, and standardization issues, an ideal genetic marker evolves at a constant rate in all strains, is selectively neutral, and exhibits extensive polymorphism so that convergent evolution (the same marker profile being displayed in unrelated strains) is avoided. Crucially, the ideal marker will evolve at a rate fast enough to distinguish between epidemiologically unrelated strains but slow enough to show no or limited differences between epidemiologically related strains. While no single marker satisfies all these criteria, many markers have been shown to display characteristics sufficient to be exploited for epidemiological purposes.
CURRENT GENOTYPING METHODS USED IN EPIDEMIOLOGICAL STUDIES OF TUBERCULOSIS There are many molecular methods available for TB epidemiological research, each of which presents its own distinct characteristics of discrimination ability, labour intensiveness, cost, speed, and ease of intra- and interlaboratory standardization. Given the variety of
The genome of M. tuberculosis contains numerous distinct small insertion sequences (ISs).9,10 These genetic elements encode a transposase that enables the element to ‘jump’ from one region to another. Thus these elements are mobile and in addition to displaying positional polymorphism they may also show polymorphism in the number of elements per genome. IS6110 is a MTBC-specific 1355-bp IS originally described by Thierry and colleagues10 that presents at 0–25 copies per genome. IS6110 restriction fragment length polymorphism (RFLP) methodology involves the following steps. Briefly, DNA is extracted and purified from the M. tuberculosis isolate, and it is then restricted with PvuII. PvuII cuts the genomic DNA into convenient sized fragments and also recognizes a single site within the IS6110 sequence. Following agarose gel electrophoresis and Southern blotting of the restricted DNA onto a nylon membrane, a labelled hybridization probe that recognizes an IS6110-specific site at the 30 end of the sequence is applied. Visualization of probebinding sites is then achieved using autoradiography. The results take the form of a biological barcode or fingerprint with the number of bands representing the number of IS6110 elements in the isolates’ genome and the position (size) of each band relating to its position of integration relative to the downstream PvuII site (Fig. 4.2). Because of its high interstrain polymorphism (in both a positional and numerical sense), and convenient mutation rate, IS6110 RFLP has become the most widely used genetic marker in TB epidemiology and is recognized as the international standard for M. tuberculosis genotyping. A standardized methodology has been implemented and dedicated computer software programmes have enabled results to be internationally standardized, thus allowing for interlaboratory comparisons.11 These results can then be used to construct dendrograms that illustrate the genetic relatedness of isolates obtained from a patient population of epidemiological interest (Fig. 4.3). However, several limitations to the technique apply. The standardized RFLP methodology requires at least 2 mg of DNA and subculturing of sputum samples is therefore required. Because of the slow-growing nature of M. tuberculosis this is extremely time consuming. The fingerprinting method itself, although technically quite simple, is also a laborious procedure and this, in conjunction with the long bacterial growth phase, results in a turnaround time of at least 5 weeks. The length of time that this method requires means that it cannot track epidemiological events in real time and is unsuitable for tasks such as rapid outbreak management. Another disadvantage of this technique is its inability to provide reliable typing for low IS6110 copy number (<6) strains since the resolution of the method is inversely proportional to the number of elements present.
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DNA. The method has only recently been described and it remains to be seen whether it becomes used generally in laboratories worldwide. Possible impediments to its use include the current lack of a standardized protocol for both the methodology and results analysis and the inherent disinclination of laboratories to move from older well-established and reliable techniques. As with many PCR-based genotyping methods DNA purity may also be an issue since poor quality DNA is difficult to amplify. The limitation of the IS6110 RFLP method in genotyping low copy number strains also applies equally to this method.
SPOLIGOTYPING
Fig. 4.2 Autoradiograph of IS6110 RFLP fingerprinting patterns for
13 clinical isolates of M. tuberculosis along with the standard laboratory strain H37Rv577 (far right). Each band represents an individual IS6110 element with the different band positions representing different locations within the genome. Strain relatedness can generally be inferred from the similarity of RFLP patterns.
PCR-BASED METHODS OF IS6110 GENOTYPING In an attempt to overcome the time and labour shortcomings that hinder IS6110 RFLP genotyping, several polymerase chain reaction (PCR)-based IS6110 genotyping techniques have been developed. An overview of the reproducibility and discriminatory power of these methods has been published by Kremer and colleagues.12 They found that in blinded tests conducted by laboratories with experience in the chosen technique, most of these methods suffered to varying degrees from poor reproducibility and/or discriminatory power. One method, fast ligation-mediated PCR (FLiP)13 (a further development of the previously described mixed-linker PCR),14 shows considerable promise however. This method is reported to allow IS6110 strain typing in under 7 hours from less than 1 ng of starting DNA and has only slightly less discriminatory power than conventional IS6110 RFLP analysis. The comparative methodology study by Kremer and colleagues also found it to be extremely reproducible.12 In addition, it has the potential to be adapted for automated analysis using fluorescent primers and, although no standardized protocol has been suggested, there are no reasons why this could not be done. The method involves the restriction of genomic M. tuberculosis DNA with HhaI followed by ligation of a DNA linker molecule to the fragment ends in a single reaction. In one strand the linker contains uracil in place of thymidine and specific amplification is obtained by digestion of this strand with uracil N-glycosylase followed by PCR using one primer specific for IS6110 and a second primer complementary to the linker ligated to the restricted genomic
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The direct repeat (DR) chromosomal region is found in the genomes of all MTBC members and comprises multiple identical 36-bp directly repeated sequences (DRs) interspersed by unique spacer regions ranging from 35 to 41 bp in length.15 One DR and its adjacent spacer is termed a direct variable repeat (DVR). Extensive polymorphism is observed between M. tuberculosis isolates within this region. Polymorphism may result from homologous recombination between DR sequences (either adjacent or distal), IS6110 insertions (which are extremely common within the DR region), homologous recombination between DR-associated IS6110 elements, and single nucleotide polymorphisms (SNPs) within the DR spacer regions. Apart from spacer SNPs all of the above mutations result in the deletion of DRs from the genome. Spacer oligonucleotide typing, or spoligotyping, is a simple technique used to determine the presence or absence of 43 spacer regions in M. tuberculosis isolates.16 Membranes are first spotted with synthetic oligonucleotides specific for each of the spacer regions. These are then hybridized with labelled spacer regions PCR-amplified from the isolate of interest resulting in a binary pattern that can be visualized using chemoluminescence and autoradiography. This genotyping method has two major attributes that have resulted in it becoming the most commonly used PCR-based strain discrimination method. The first relates to its simplicity, speed, reproducibility, and ease of use. Since it is based on the PCR reaction only minute quantities of starting DNA are required; thus the lengthy culturing step required for IS6110 RFLP is avoided and the typical time taken for a result to be obtained is less than 2 days. In addition, the robustness of the PCR reactions means that DNA purity is less of an issue and impure DNA, paraffin-embedded material, and material from Ziehl-Neelsen stainings, as well as DNA from other non-viable specimens, can be used. Spoligotyping’s second major attribute concerns the simplicity of its binary (present/absent) output. This means that data can be easily digitized, interpreted, and compared in an interlaboratory fashion. A global spoligotyping database (SpolDB4) has been launched, which by late 2006 contained over 39,295 different spoligotype entries from 122 countries and a Web-based programme, SPOTCLUST, that places spoligotypes into families, has recently been developed.17,18 The major drawback of spoligotyping is that it generally lacks the extensive discriminatory power of many other alternative genotyping methods. For example, the W-Beijing lineage, an extremely large and important group of strains that have attracted special attention due to their ability to cause frequent epidemic outbreaks, may be divided into many families of strains and substrains based on IS6110 RFLP and MIRU/VNTR (see below) marker variation. IS6110 RFLP in particular is capable of detecting hundreds of similar yet unique genotype patterns, enabling the
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Molecular methods and their application in tuberculosis epidemiology
4
Fig. 4.3 Dendrogram of IS6110 fingerprint patterns. IS6110 RFLP analysis was performed on 63 M. tuberculosis isolates taken from various regions of South Africa. Fingerprint patterns are ordered by similarity in a dendrogram that was constructed using GelCompar software (Applied Math, Kortrijk, Belgium) analysis. The scale at the top left-hand side represents a similarity index. Isolates showing similar fingerprints are grouped into family clusters.
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detection of clustering and family groupings. In contrast, spoligotyping reveals W-Beijing isolates to possess extremely similar or identical genotypes that all lack spacers 1–34.19 Spoligotyping has, however, been shown to be able to discriminate between many lS6110 low copy number strains that IS6110 RFLP analysis is unable to do.20 Thus, a combination approach using both IS6110 RFLP and spoligotyping has been shown to provide an extremely accurate and discriminatory genotyping method for M. tuberculosis isolates.21
Unfortunately the PGRS is found in the genome at a far higher frequency than IS6110 (61 copies in H37Rv) and this results in extremely complex fingerprints that may show variation in band intensity. For this reason reproducible scoring and computerization of results is difficult. This, coupled with the time-consuming and labour-intensive methodology (as for IS6110 RFLP genotyping), has greatly restricted its use.
MIRU/VNTR ANALYSIS
Both large and small deletion events are common in the M. tuberculosis genome and result in approximately 5% of genes and 4% of the entire genome being variably absent in clinical isolates.27 Genomic deletions may occur through recombination between IS elements as well as other unknown mechanisms. Large sequence deletions are considered to be unique events that occur once in the phylogeny of a lineage. Since these events are irreversible they arise sequentially and, if an assumption of selective neutrality is made, they allow the epidemiologist to genotype strains and construct strain phylogenies (Fig. 4.1).4,27–29 For example, Tsolaki et al.29 have defined a genetic deletion unique to the W-Beijing strain family that can therefore serve as a useful marker. Furthermore, additional deletions subdivide this family into four subgroups. On a more distant evolutionary scale, the MTBC species may be defined by specific deletion events present in the lineage of each species.4 In particular, ‘modern’ M. tuberculosis has been found to have undergone deletion of the ‘M. tuberculosis specific deletion 1’ (TbD1) genomic region while all ancestral strains and species possess this locus. While the power of large deletion analysis has been demonstrated in evolutionary and phylogenetic studies, its use in epidemiology remains in its infancy. In some cases a unique deletion associated with a single strain is known in advance and a simple deletion-specific PCR assay can enable the tracking of the strain through a population.29,30 However, in most epidemiology studies where numerous strains are encountered the analysis of multiple deletions is required. The use of multiple deletion-specific PCRs in multiple isolates is laborious and costly and microarray-based methods also suffer from technical complexity and high cost.27,28,31 A method designed for high-throughput analysis of genomic deletions has recently been reported.32 In this method, termed deligotyping, 43 variably deleted regions were chosen and amplicons of these regions generated from the isolate of interest were hybridized to a membrane spotted with these target sequences. This method is extremely similar to spoligotyping and shares its advantages including speed, simplicity, and an easily interpretable binary result. Care must be taken in the choice of deletion regions selected for analysis, however, since many deletions occur in ‘hot-spots’ and can occur independently in epidemiologically unrelated strains resulting in convergent evolution. By mapping deletion events onto a synonymous SNP-based phylogenetic tree Alland and colleagues33 have made progress in determining which events can be traced to a unique ancestral event (and therefore are probably selectively neutral and suitable for phylogenetic/genotype studies) and those that occur independently multiple times, thus precluding them as genotypic markers. Small deletions may also represent useful epidemiological markers but these are difficult to detect using current methods. A new microarray-based method, termed high-density DNA tiling arrays, promises to aid in their detection. This method is also amenable for SNP detection (see below). Its usefulness has recently been reported in investigating diversity between E. coli strains.34
Analysis of the complete M. tuberculosis genome has revealed the presence of 41 variable nucleotide tandem repeats (VNTRs).22 These represent DNA sequences of 40–100 bp that are directly repeated in a manner reminiscent of eukaryotic minisatellites. In the original study, Supply and colleagues22 found that 12 of these VNTRs, termed mycobacterial interspersed repetitive units (MIRUs), exhibited polymorphisms between isolates based on differences in repeat unit number. PCR analysis using primers flanking each MIRU is a simple method of genotyping and the 12-MIRU system of genotyping has become a widely used epidemiological tool. Apart from its simplicity other advantages are that results can be digitized, allowing for easy interlaboratory comparisons and that mixed infections are easily identified due to the sensitivity of the PCR reaction. However, in most cases the discrimination power of this method, even when used in conjunction with spoligotyping, is less than for IS6110 RFLP typing. Also, the number and combination of MIRUs used has varied among researchers and this, along with differences in nomenclature used to describe the MIRUs, has led to some confusion in the interpretation and comparison of results. Supply and co-workers have recently proposed a 15-loci set for routine epidemiological analysis that is claimed to have the same discriminatory power as IS6110 genotyping when used alongside spoligotyping.23 A further nine MIRU loci are proposed for isolates requiring higher resolution discrimination.23 It is still necessary to thoroughly evaluate these loci and research into the most informative and practical MIRU sets for use in specific settings, including low- and highincidence communities, is ongoing. The discriminatory power of MIRU genotyping is directly proportional to the number of loci analysed but additional loci also increase the time, cost, and labour required. In order to streamline the approach a multiplex PCR system using fluorescently labelled primers in combination with capillary fractionation and computerized automation of genotyping has been described, although this may not be widely adopted because of its cost and complexity.24
PGRS RFLP The polymorphic GC-rich repetitive sequence (PGRS) consists of a 96-bp consensus sequence that is found to be both numerically and positionally polymorphic within the M. tuberculosis genome. Like the IS6110 RFLP technique, PGRS RFLP also utilizes DNA restriction followed by gel electrophoresis, Southern blot hybridization, and sequence-specific probe recognition. It has been demonstrated to show identical banding patterns between closely related strains while being able to distinguish between epidemiologically unrelated strains.25 In some cases the method has been shown to be more discriminatory than IS6110 RFLP, especially when low copy number IS6110 strains are considered.26
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GENOMIC DELETION ANALYSIS
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Molecular methods and their application in tuberculosis epidemiology
SNPs Sequencing analysis of M. tuberculosis genomic regions has revealed very little genetic diversity compared with most other bacterial organisms.3,35,36 Despite this, more than sufficient SNP variation exists to exploit for genotyping purposes. SNPs may be divided into two categories. Non-synonymous SNPs (nsSNPs) occur in intragenic regions and are associated with amino acid changes. Hence they may alter the phenotype of the organism and be subject to selection pressure. Synonymous SNPs (sSNPs) either occur in intergenic regions or occur in intragenic regions without altering the amino acid sequence. They are generally considered to be selectively neutral, especially in comparison with genotypic markers that generate large chromosomal alterations such as IS6110 integrations and large deletion events. sSNPs are also unlikely to undergo convergent evolution and their mutation rate is hypothesized to be relatively constant, enabling them to be used to measure divergence times. These attributes make them attractive targets for epidemiological and phylogenetic studies. The methodologies generally used to detect SNPs, such as the SNaPshot primer extension method (used by Gutacker et al.37) and hairpin primer assays are PCR-based.37,38 They therefore benefit from the advantages of all PCR-based methodologies. Several studies have demonstrated the usefulness of SNP genotyping in the construction of phylogenetic trees of M. tuberculosis strains (Fig. 4.1).3,37–41 In the most extensive of these, Filliol and colleagues41 employed 212 SNPs to determine the phylogenetic relationships between 294 M. tuberculosis and 29 M. bovis isolates collected globally. All isolates were found to divide into one of six phylogenetically distinct groups and a minimal subset of just six highly informative SNPs was found to be able to discriminate all isolates into their specific groups. This finding may have important consequences since analysis of the large number of SNPs (often in the hundreds) used in most studies is expensive and time consuming despite it being PCR-based and a single standardized SNP set is required for interlaboratory comparisons.
THE INTERPRETATION OF MOLECULAR EPIDEMIOLOGY DATA The genomes of all species are continually evolving and this must be considered when interpreting molecular epidemiology data. It is generally considered that patient-derived isolates that display identical, or near-identical (fewer than two band shifts in an IS6110 fingerprint), genotypes (termed clusters) represent examples of recent transmission where infection in the recent past (i.e. within 2 years) has resulted in relatively rapid progression to disease. Genotypes that do not match those of other cases are considered to reflect reactivation of an infection that occurred many years prior to disease onset. By determining the relative proportion of clustered TB cases in a community an estimate of the proportion of either recent (using the ‘n1’ calculation) or ongoing (using the ‘n’ calculation) transmission can be made.42,43 These calculations are widely used as public health tools to estimate the efficacy of public health programmes. Several potential sources of error should be considered when interpreting epidemiological results. First, it is important to note the mutation rate of the marker being analysed before a decision on the clustering status of M. tuberculosis isolates is made. For example, slowly evolving markers, such as spoligotypes, may
4
show identical genotypes in epidemiologically unrelated strains. A marker that displays a high mutation rate (such as IS6110) will be more discriminatory although it then follows that genotype similarity measures in the definition of a cluster need to be relaxed. Second, undersampling of the population may result in an apparent reduction of strain clustering. This may subsequently lead to an underestimation of the frequency of recent transmission.44 Third, study duration is an important variable in epidemiology calculations. The difficulty of predicting events that occurred before or after the study duration (‘edge effects’) is particularly relevant to TB, which may remain latent for several years between initial infection and disease. Because of this, a 2-year lead-in and lag phase is recommended during which strains already present in the community (during the lead-in phase) and newly detected strains (during the lag phase) are disregarded. Finally, studies must ideally account for population migrations into or out of the study community. This is particularly relevant in mobile, high-incidence communities since immigrant patients will often be infected with strains not present in the community. This can then result in a false diagnosis of reactivation and an underestimation of the frequency of recent transmission.
THE APPLICATION OF MOLECULAR EPIDEMIOLOGY TO TUBERCULOSIS Molecular epidemiology has now clarified many aspects of TB dynamics that were impossible to determine using previous methods. Below we list several of these and show how molecular epidemiology has expanded our knowledge of each.
THE TRANSMISSION AND REACTIVATION DYNAMICS OF TUBERCULOSIS By comparing clinical isolates using clustering analysis, epidemiologists can estimate the proportion of disease caused by recent transmission (clustered) versus reactivation of latent infection (non-clustered). Several previously held assumptions regarding the dynamics of transmission/reactivation have been challenged since the introduction of molecular epidemiology techniques. It has now been shown, for example, that recent transmission is far more common in low-incidence communities than was previously thought.42,43 Furthermore, the proportion of cases due to recent transmission may be in excess of 70% in higher incidence communities.45 Another surprising finding is that transmission, in both high- and low-incidence settings, is less reliant on repeated close contact than was expected, with a high proportion of cases resulting from casual contact.42,46 Molecular epidemiology techniques combined with patient demographic information have also proved invaluable in establishing risk factors associated with M. tuberculosis transmission between patients. Age, ethnicity, socioeconomic status, and HIV status have all been associated with transmission but not all factors are common to all communities or geographic regions.42 This information suggests that control strategies should target prevention of transmission rather than prophylaxis for the prevention of reactivation.
RECURRENCE OF TUBERCULOSIS Recurrent TB is defined as a secondary disease episode following an initial disease event that has been considered cured. Of primary
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interest to epidemiologists is whether the recurrent disease represents the reactivation of the original strain (demonstrating that treatment was not fully effective) or whether it represents a new infection. When bacterial isolates from both disease episodes are available for analysis, molecular epidemiology techniques are ideal for distinguishing between the two alternative scenarios. Compliance to treatment regimens does not always result in complete sterilization and for many years it was assumed that recurrent TB was the result of the endogenous reactivation of surviving organisms from the initial infection.47,48 This dogma was first challenged using phage typing methods but was not confirmed unequivocally until molecular epidemiology methods were used.49,50 Reports from many geographical regions have demonstrated that the level of exogenous reinfection increases proportionally according to the local disease incidence. In The Netherlands, for example, where TB incidence is low, exogenous reinfection has been reported at 16%, whereas in high-incidence settings such as described by van Rie and colleagues the rate may be up to 75%.50,51 HIV-infected individuals have also been found to be more at risk of exogenous reinfection.52 These findings raise the possibility that certain individuals are predisposed to TB and that an initial disease episode may itself be a predisposing factor for later disease.53 In light of the above information it is suggested that the term ‘relapse’ be avoided unless it has been proven as such by genotyping.
MIXED INFECTIONS Multiple M. tuberculosis strains may be simultaneously present during disease in a patient, through either multiple recent infections or a recent infection combined with reactivation of a primary infection. The strains present in mixed infections rarely contribute equally to the bacterial load with one generally dominating the population. Because of their sensitivity, PCR-based genotyping methods are best employed for detection of the underlying strain. Molecular epidemiology has revealed that in high-incidence communities the frequency of mixed infection can be far higher than previously supposed. Using a PCR-based method to detect the presence of an IS6110 insertion within gene Rv2820 that is unique to the Beijing family lineage, Warren and colleagues54 reported that 19% of patients from a high-incidence community in Cape Town, South Africa, were coinfected with Beijing and non-Beijing strains and 57% of patients infected with a Beijing strain were also infected with a non-Beijing strain. The high frequency of observed mixed infection suggests that a prior M. tuberculosis infection provides little immune protection against subsequent infection. This has implications for disease control measures and vaccine development. Mixed infection has also been shown to be an important mechanism for the development of drug resistance.54
MOLECULAR EPIDEMIOLOGY IN OUTBREAK STUDIES Tuberculosis outbreaks are defined as an unusual increase in disease incidence within a specific community over a defined time period. The determination of the factors that can result in sudden changes in TB incidence are one of the major successes of molecular epidemiology techniques. The ability to differentiate between M. tuberculosis strains has allowed the tracking of outbreak strain transmission events in hospitals, prisons, mines, and communities and has highlighted deficiencies in disease control measures.55 The identification of outbreak strains has also allowed host- or
34
strain-specific risk factors to be determined. The tracking and characterization of drug-resistant outbreak strains has been of particular importance and one example is given in the next section.
DRUG RESISTANCE Drug-resistant isolates of M. tuberculosis were first identified less than 1 year after the first introduction of anti-TB chemotherapy.56 The frequency with which spontaneous drug resistance can develop has forced clinicians to treat TB with an antibiotic cocktail designed to ensure that drug resistance does not develop during treatment. A major contributing factor to the emergence of drug resistance is the inherent toxicity of the drugs combined with the prolonged treatment time (6 months) required by the current treatment regimen. This results in a high proportion of patients who fail to complete their treatment or who complete it at suboptimal levels. This produces the ideal environment for mutant bacterial clones that exhibit decreased sensitivity to the treatment to spread and eventually dominate the population. Outbreaks of multidrugresistant (MDR) (and even so-called extensively drug resistant; XDR) strains are now increasing in frequency in many parts of the world and this has sparked intense public health concerns since they are far more difficult (and costly) to treat, show a higher mortality rate, and may be transmitted to other individuals during the prolonged duration of treatment. Most drug resistance is caused by micromutations (point mutations or small insertions/deletions) in key genes involved in drug metabolism or transport. Fortunately, these genes often display ‘hot-spots’ where the majority of resistance-conferring mutations occur. This allows researchers to focus their analysis on a relatively short DNA sequence. For example, over 95% of rifampin-resistant M. tuberculosis isolates possess mutations within an 81-bp region of the rpoB gene and the majority of these mutations occur at specific defined sites within this region.57 This allows for simple sequencing or PCR-based mutation detection techniques to be implemented in the majority of cases. Isolates that fail to reveal mutations in initial studies may then undergo further analysis either using PCRbased methods directed at less common mutation sites or complete gene sequencing. Many epidemiological studies directed at drug resistance aim to follow a specific drug-resistant outbreak strain. In these cases once the specific resistance-conferring mutation is located a single mutation detection method can be conveniently implemented for the entire study. Molecular epidemiological tools have been used to study many aspects of drug-resistant TB disease dynamics. These include studies that have sought to determine the frequency of drug resistance in specific strains, the frequency of drug resistance in certain populations, patient risk factors for acquiring drug resistance, the proportion of primary (infection by a previously resistant organism) versus acquired (the emergence of drug resistance from a previously drug-susceptible organism de novo) resistance, and the prevalence of specific resistance-associated mutations within a population. The results of such studies have provided valuable insights. For example, studies have shown that primary resistance is most commonly observed, apart from cases involving drug-resistant outbreak strains. High-incidence communities may also display increased rates of acquired drug resistance.59 Molecular epidemiology has also been used to study the hypothesis that MDR invariably produces a fitness cost that results in reduced transmissibility. This generally appears to be true although the study of Bifani and colleagues,58 who followed a large MDR outbreak in New York, has
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Molecular methods and their application in tuberculosis epidemiology
shown that it is not always the case. Studies have also found that the acquisition of drug-resistant TB may be due to reinfection, and that drug resistance may develop as a result of selective pressure after mixed infection.59,60 Studies aimed at determining the relationship between the frequency of drug resistance acquisition and genotype have also been performed with some results suggesting that the Beijing family is more prone to develop drug resistance.61 The tracking of drug-resistant outbreaks has also been aided by molecular epidemiology. An example of the role it can play in understanding an MDR outbreak is provided by Dahle and colleagues.62 In this case 20 individuals, of whom 19 were immigrants from East Africa, were diagnosed with drug-resistant or MDR TB in Oslo, Norway. The initial patient presented with TB that was found to be resistant to the frontline anti-TB drug isoniazid (INH) and 1 year later was hospitalized with disease that was found to have acquired additional resistance to rifampicin. In the following 6 years a further 19 patients presented with TB that was found to be either drug resistant or MDR. IS6110 RFLP analysis revealed all isolates to be clustered, demonstrating recent transmission, and comparisons of the outbreak RFLP fingerprint with those from other countries strongly supported a Somalian origin for the strain. Spoligotyping was used to further confirm the genetic similarity of the 20 isolates. All strains were INH resistant and katG gene (which confers INH resistance when mutated) analysis demonstrated identical sequences, all with three alterations from wild type. All MDR strains (11/20) showed a single point mutation in the rpoB gene conferring rifampicin resistance while all non-MDR strains showed wild-type rpoB sequence. Thus the mutations in drug resistance genes provide explanations for the resistant phenotype as well as further confirming the close relatedness of the strains. Social links were found between 14 of the patients. Thus the study demonstrates that the outbreak strain was imported from Somalia (where it was probably already INH resistant) but acquired multidrug resistance and was transmitted in Norway. The authors use these findings to highlight the high communicability of some drug-resistant and MDR strains, especially among immigrant communities. They also make several suggestions hoped to make health and immigration policies more efficient in preventing future outbreaks.
EVOLUTIONARY AND PHYLOGENETIC STUDIES An important benefit of the introduction of molecular epidemiology has been its ability to provide high-resolution analysis of specific M. tuberculosis strains. It is now known that TB is caused by organisms that represent many different families and that each of these families can be divided into strains and substrains based on genotypic similarities. Several recent reports have shed light on the phylogeny of M. tuberculosis strains.4,37,40,41,63 Some inconsistencies exist, seemingly based on the number of polymorphisms analysed and the extent of sampling, but the studies are generally consistent and, overall, support the division of M. tuberculosis into three major groups that can be subdivided into nine major strains. Of note is the extent of geographic specificity found with certain strains. For example, strains I and II (which include the W-Beijing strains) are found to a greater extent among patients of East Asian origin, supporting this location as the origin of the clade. Molecular epidemiology methods, in particular deletion, SNP analysis, and extensive sequencing, are also useful in the construction of phylogenetic trees representing more distant evolutionary events. These may then be used to determine the time and location of the
4
origin of M. tuberculosis as well as its subsequent spread throughout the world. These studies have found that M. tuberculosis is not derived from M. bovis, as was previously thought, but that the M. tuberculosis lineage predates the emergence of M. bovis (Fig. 4.1).4 Sequence-based studies examining all MTBC members confirm a severe evolutionary bottleneck that occurred in the MTBC 20,000–35,000 years ago and suggest that Mycobacterium canetti and other smooth bacilli group lineages predate this bottleneck while all other MTBC members represent the clonal expansion of one of these progenitor species.4 Moreover, the extant representatives of this ancient group (including M. canetti ) are localized to East Africa and are also human pathogens, suggesting that M. tuberculosis has coevolved with the human lineage since at least the time of early hominids between 2.6 and 2.8 million years ago.5 While the above information is not directly relevant to the study of TB epidemiology it is important because it allows us to establish the rate of change (mutation) of genotypic markers, a factor that influences the interpretation of epidemiological data.
PHENOTYPIC VARIATION BETWEEN M. TUBERCULOSIS STRAINS AND HOST–PATHOGEN COMPATIBILITY Of epidemiological interest is the fact that strains may exhibit phenotypic variation in many aspects of virulence. This phenomenon has been especially highlighted in animal models and can include Box 4.1 Definitions This section provides definitions of terms, particularly molecular, that may not be familiar to the casual reader. Agarose gel electrophoresis: The separation of DNA according to size by the migration through an agarose gel in an electrical field. Cluster: A grouping of two or more TB cases that are proximally and temporarly related. If a cluster is of sufficient size and importance it may be re-evaluated as an outbreak. Genotype: The genetic constitution of an organism, as distinct from its expressed features or phenotype. Insertion sequence: A small, mobile DNA sequence that can replicate and insert copies of itself at random sites within chromosomes. They code for the enzyme transposase, which catalyses their replication. Microarray: A collection of microscopic DNA spots, commonly representing single genes, arrayed on a solid surface by covalent attachment to chemically suitable matrices. Non-coding DNA: DNA regions that do not represent a polypeptide code. These regions may regulate the expression of coding regions, have other more enigmatic functions, or simply be ‘junk’ DNA without any apparent function. Outbreak: See Cluster. PCR (polymerase chain reaction): A technique for massive in vitro amplification of specific DNA fragments. Polymorphism: The occurrence in the same population of multiple discrete allelic states. Repetitive DNA: Nucleotide sequences in DNA that are present in the genome as numerous copies. Much repetitive DNA is tandemly repeated. Selectively neutral: When neither of two (or more) alternative polymorphic variants possesses an evolutionary selective advantage. Southern blot: A technique used for searching for a specific DNA fragment that has been electrophoresed and bound to a nitrocellulose membrane.
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differences in transmission ability, disease manifestation, immunological responses, replication rate, and possibly the frequency of drug resistance and ability to evade vaccination.61,64–71 This implies that a population experiencing a high incidence of TB that presents multiple strains should be viewed as presenting a combination of distinct subepidemics rather than a single uniform epidemic. A recent analysis of the global population structure of M. tuberculosis has shown that different lineages are associated with specific sympatric human populations.28 Furthermore, in mixed, urban settings these lineages were found to be more likely to spread in sympatric than allopatric populations, suggesting host–pathogen compatibility. International databases that collate genotype data gathered throughout the world (such as the global spoligotype database) should be valuable in the further investigation of this interesting phenomenon.17
TRANSMISSION FROM SMEAR-NEGATIVE CASES The Ziehl-Neelsen sputum smear is a rapid, inexpensive diagnostic test for the presence of active TB and it has long been assumed that smear-negative patients are far less infectious.71 The potential for smear-negative patients to transmit disease at a high frequency was confirmed using molecular genotyping methods in 1999.72 In this study at least 17% of TB transmission was found to be from patients who had produced a smear-negative sputum sample.
DETECTION OF LABORATORY ERROR Incorrect sample labelling, contamination of clinical devices, or inefficient measures of cross-contamination control can result in a false diagnosis or the misidentification of drug resistance status and may seriously compromise patient welfare. Burman and
REFERENCES 1. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. Geneva: (WHO/HTM/TB/2007.376). 2. Mathema B, Kurepina NE, Bifani PJ, et al. Molecular epidemiology of tuberculosis: current insights. Clin Microbiol Rev 2006;19(4):658–685. 3. Sreevatsan S, Pan X, Stockbauer KE, et al. Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA 1997; 94(18):9869–9874. 4. Brosch R, Gordon SV, Marmiesse M, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci USA 2002;99(6): 3684–3689. 5. Gutierrez MC, Brisse S, Brosch R, et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog 2005; 1(1):e5. 6. Garnier T, Eiglmeier K, Camus JC, et al. The complete genome sequence of Mycobacterium bovis. Proc Natl Acad Sci USA 2003;100(13): 7877–7882. 7. Perna NT, Plunkett G III, Burland V, et al. Genome sequence of enterohaemorrhagic Escherichia coli O157:H7. Nature 2001;409(6819):529–533. 8. Smith NH, Kremer K, Inwald J, et al. Ecotypes of the Mycobacterium tuberculosis complex. J Theor Biol 2006;239(2):220–225. 9. Gordon SV, Heym B, Parkhill J, et al. New insertion sequences and a novel repeated sequence in the
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Reves73 have shown that M. tuberculosis-associated laboratory errors can occur more frequently than suspected and are often not recognized by laboratory personnel. Genotyping of samples by IS6110 RFLP has frequently enabled errors to be identified. Identification of laboratory error usually occurs when identical RFLP fingerprints are observed from different patients whose samples were processed at a similar time or when serial isolates from the same patient show different fingerprints. The presence of mixed infections, which may be common in high-incidence regions, must also be considered.54 In these cases both isolates may be represented and this can result in the erroneous conclusion of cross contamination.
SUMMARY In recent years our understanding of the structure of the M. tuberculosis genome has grown immensely. The discovery of polymorphic genomic regions combined with molecular methods for their analysis has allowed unprecedented insights into the structure of M. tuberculosis populations and has revealed that it consists of a huge assortment of genetically distinct families, strains, and substrains. This insight has allowed epidemiologists an unprecedented understanding of TB biology and has resulted in many previous assumptions of the disease to be revised. However, health control and treatment measures have benefited in only very few cases and the TB pandemic has continued to worsen. In order to reverse this situation new diagnostic tests, vaccines, and treatment options are desperately needed. The rapid increase in knowledge of many aspects of TB biology provides hope, however, and molecular epidemiology will continue to play a crucial role in our ongoing attempt to fully understand and control the disease. The challenge before us, given this new understanding, is to revise control programmes to reflect this knowledge.
genome of Mycobacterium tuberculosis H37Rv. Microbiology 1999;145(Pt 4):881–892. Thierry D, Cave MD, Eisenach KD, et al. IS6110, an IS-like element of Mycobacterium tuberculosis complex. Nucleic Acids Res 1990;18(1):188. van Embden JD, Cave MD, Crawford JT, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993; 31(2):406–409. Kremer K, Arnold C, Cataldi A, et al. Discriminatory power and reproducibility of novel DNA typing methods for Mycobacterium tuberculosis complex strains. J Clin Microbiol 2005;43(11):5628–5638. Reisig F, Kremer K, Amthor B, et al. Fast ligationmediated PCR, a fast and reliable method for IS6110based typing of Mycobacterium tuberculosis complex. J Clin Microbiol 2005;43(11):5622–5627. Haas WH, Butler WR, Woodley CL, et al. Mixedlinker polymerase chain reaction: a new method for rapid fingerprinting of isolates of the Mycobacterium tuberculosis complex. J Clin Microbiol 1993;31(5): 1293–1298. Hermans PW, van Soolingen D, Bik EM, et al. Insertion element IS987 from Mycobacterium bovis BCG is located in a hot-spot integration region for insertion elements in Mycobacterium tuberculosis complex strains. Infect Immun 1991;59(8):2695–2705. Kamerbeek J, Schouls L, Kolk A, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol 1997;35(4):907–914. Brudey K, Driscoll JR, Rigouts L, et al. Mycobacterium tuberculosis complex genetic diversity: mining the
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Molecular methods and their application in tuberculosis epidemiology 25. Ross BC, Raios K, Jackson K, et al. Molecular cloning of a highly repeated DNA element from Mycobacterium tuberculosis and its use as an epidemiological tool. J Clin Microbiol 1992;30(4):942–946. 26. Chaves F, Yang Z, el Hajj H, et al. Usefulness of the secondary probe pTBN12 in DNA fingerprinting of Mycobacterium tuberculosis. J Clin Microbiol 1996; 34(5):1118–1123. 27. Tsolaki AG, Hirsh AE, DeRiemer K, et al. Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from genomic deletions in 100 strains. Proc Natl Acad Sci USA 2004;101(14):4865–4870. 28. Gagneux S, DeRiemer K, Van T, et al. Variable hostpathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2006;103(8):2869–2873. 29. Tsolaki AG, Gagneux S, Pym AS, et al. Genomic deletions classify the Beijing/W strains as a distinct genetic lineage of Mycobacterium tuberculosis. J Clin Microbiol 2005;43(7):3185–3191. 30. Freeman R, Kato-Maeda M, Hauge KA, et al. Use of rapid genomic deletion typing to monitor a tuberculosis outbreak within an urban homeless population. J Clin Microbiol 2005;43(11):5550–5554. 31. Kato-Maeda M, Rhee JT, Gingeras TR, et al. Comparing genomes within the species Mycobacterium tuberculosis. Genome Res 2001;11(4):547–554. 32. Goguet de la Salmoniere YO, Kim CC, Tsolaki AG, et al. High-throughput method for detecting genomic-deletion polymorphisms. J Clin Microbiol 2004;42(7):2913–2918. 33. Alland D, Lacher DW, Hazbon MH, et al. The role of large sequence polymorphisms (LSPs) in generating genomic diversity among clinical isolates of Mycobacterium tuberculosis and the utility of LSPs in phylogenetic analysis. J Clin Microbiol 2007;45(1):39–46. 34. Jackson SA, Mammel MK, Patel IR, et al. Interrogating genomic diversity of E. coli O157:H7 using DNA tiling arrays. Forensic Sci Int 2007; 168(2–3):183–199. 35. Fleischmann RD, Alland D, Eisen JA, et al. Wholegenome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J Bacteriol 2002; 184(19):5479–5490. 36. Hughes AL, Friedman R, Murray M. Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis. Emerg Infect Dis 2002;8(11):1342–1346. 37. Gutacker MM, Smoot JC, Migliaccio CA, et al. Genome-wide analysis of synonymous single nucleotide polymorphisms in Mycobacterium tuberculosis complex organisms. Resolution of genetic relationships among closely related microbial strains. Genetics 2002;162(4):1533–1543. 38. Hazbon MH. Recent advances in molecular methods for early diagnosis of tuberculosis and drug-resistant tuberculosis. Biomedica 2004;24(Suppl 1):149–162. 39. Alland D, Whittam TS, Murray MB, et al. Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis. J Bacteriol 2003;185(11):3392–3399. 40. Gutacker MM, Mathema B, Soini H, et al. Singlenucleotide polymorphism-based population genetic analysis of Mycobacterium tuberculosis strains from 4 geographic sites. J Infect Dis 2006;193(1): 121–128. 41. Filliol I, Motiwala AS, Cavatore M, et al. Global phylogeny of Mycobacterium tuberculosis based on single
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58. Bifani PJ, Plikaytis BB, Kapur V, et al. Origin and interstate spread of a New York City multidrugresistant Mycobacterium tuberculosis clone family. JAMA 1996;275(6):452–457. 59. van Rie A, Warren R, Richardson M, et al. Classification of drug-resistant tuberculosis in an epidemic area. Lancet 2000;356(9223):22–25. 60. van Rie A, Victor TC, Richardson M, et al. Reinfection and mixed infection cause changing Mycobacterium tuberculosis drug-resistance patterns. Am J Respir Crit Care Med 2005;172(5):636–642. 61. Glynn JR, Whiteley J, Bifani PJ, et al. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg Infect Dis 2002;8(8):843–849. 62. Dahle UR, Sandven P, Heldal E, et al. Deciphering an outbreak of drug-resistant Mycobacterium tuberculosis. J Clin Microbiol 2003;41(1):67–72. 63. Baker L, Brown T, Maiden MC, et al. Silent nucleotide polymorphisms and a phylogeny for Mycobacterium tuberculosis. Emerg Infect Dis 2004; 10(9):1568–1577. 64. Valway SE, Sanchez MP, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998;338(10):633–639. [Published erratum appears in N Engl J Med 1998;338(24):1783.] 65. Dormans J, Burger M, Aguilar D, et al. Correlation of virulence, lung pathology, bacterial load and delayed type hypersensitivity responses after infection with different Mycobacterium tuberculosis genotypes in a BALB/c mouse model. Clin Exp Immunol 2004; 137(3):460–468. 66. Reed MB, Domenech P, Manca C, et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 2004; 431(7004):84–87. 67. Manca C, Reed MB, Freeman S, et al. Differential monocyte activation underlies strain-specific Mycobacterium tuberculosis pathogenesis. Infect Immun 2004;72(9):5511–5514. 68. Chacon-Salinas R, Serafin-Lopez J, Ramos-Payan R, et al. Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 2005;140(3):443–449. 69. Zhang M, Gong J, Yang Z, et al. Enhanced capacity of a widespread strain of Mycobacterium tuberculosis to grow in human macrophages. J Infect Dis 1999; 179(5):1213–1217. 70. Abebe F, Bjune G. The emergence of Beijing family genotypes of Mycobacterium tuberculosis and low-level protection by bacille Calmette-Guerin (BCG) vaccines: Is there a link? Clin Exp Immunol 2006; 145(3):389–397. 71. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954; 69(5):724–732. 72. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999;353(9151):444–449. [Published erratum appears in Lancet 1999;353(9165):1714.] 73. Burman WJ, Reves RR. Review of false-positive cultures for Mycobacterium tuberculosis and recommendations for avoiding unnecessary treatment. Clin Infect Dis 2000;31(6):1390–1395.
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Epidemiology of childhood tuberculosis Robert P Gie, Nulda Beyers, and Donald A Enarson
INTRODUCTION Relatively few accurate data are available on the epidemiology of childhood TB partly because TB is sometimes difficult to diagnose in children and also partly because children are not seen as being important in the epidemiology of TB. However, TB infection and TB disease in children are sentinel events and can give a fairly accurate indication of how well the TB control programme is functioning and of the level of transmission of TB taking place in a community. Children may thus be seen as ‘sentinel’ indicators of the trend for TB in a specific country or region.
DEFINITIONS
TUBERCULOSIS INFECTION Tuberculosis infection has been traditionally identified using the tuberculin skin test, by the Mantoux method. Induration in reaction to the tuberculin skin test, measured as the largest transverse diameter in response to intradermal injection of tuberculin, has been the traditional approach, with reaction sizes of 5 (or 10) mm or greater taken as significant, indicating the presence of infection. This size of reaction was defined as significant in that it has been shown to accurately predict risk of subsequent development of TB following infection.3 In recent years, newer tests such as the interferon-g release assays (IGRAs) have been introduced that promise to have more efficient characteristics than the tuberculin skin test but they have not yet been sufficiently evaluated to know whether these claims will be upheld.
EPIDEMIOLOGY
DEATH FROM TUBERCULOSIS (FATALITY)
Epidemiology is defined as the study of distribution and determinants of health-related states or events in specified populations, and the application of this study to control of health problems.1
While notification of death from any cause while on TB treatment is the event reported routinely in cohort reports on the outcome of TB treatment, they are not sufficiently precise for use in epidemiology. The term ‘fatality’ refers, rather, to death due to the condition. To determine this correctly requires a review and classification of deaths in patients with TB to determine whether the death was due to TB, whether TB was a contributing factor or whether the death was unrelated to TB.4
CHILDHOOD The definition of who is considered a ‘child’ varies from one location to another and is frequently determined in health services for administrative reasons (where and by whom health services are provided). For the purposes of this chapter, all persons aged less than 15 years is considered a child. For reasons that will be illustrated by the discussion of the distribution and determinants of disease, we further classify children by the following age groups: under 2 years of age; 2–4 years of age; and 5–14 years of age.
CASE OF TUBERCULOSIS For purposes of routine notification, it is recommended that every person given treatment for active TB be recorded as a case of TB,2 but that those who are sputum smear-positive and those who have received previous treatment for TB for 1 month or more be reported separately. In the setting where children under 5 years of age are living in the same household with a patient who is sputum smear-positive, the following recommendation is given: ‘Any child in the household under 5 years of age who has symptoms that suggest TB should be given treatment as a case of TB.’
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CURE The definition of cure from TB requires bacteriological proof that the disease is no longer active. In current practice, this implies confirmation of bacteriological conversion, in a patient initially bacteriologically positive, sustained from the fifth month of treatment onwards.2
TRANSITION FRAMEWORK In studying the epidemiology of TB, it is vital to set a framework from which to work. This framework should take into account a model of the transitions that take place in the pathogenesis of TB.5 This is important because each transition has its own predictors and transition probabilities that vary from one setting to another. Key transitions that must be carefully distinguished in understanding the epidemiology of childhood TB are those from
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exposure to infection, from infection to disease, from disease to death and from disease to cure. Conflating several transitions (e.g. studies that entail an analysis of determinants of the transition from exposure to disease) may identify determinants of the two key transitions that are either powerful determinants of a single transition or may fail to identify ‘conflicting’ determinants associated with the two transitions. Mortality studies are particularly fraught as they include all the key transitions.
SOURCES OF INFORMATION Determining the total burden, distribution and determinants of TB in children requires valid and reliable information on the disease. This information may be obtained from a variety of sources. The two main sources of information on the disease are routine notifications of the disease (mandatory in most countries) and information derived from specific scientific investigations and published in the peer-reviewed scientific literature.
PRE-CHEMOTHERAPY LITERATURE Since the introduction of chemotherapy for treatment of TB, the ‘natural history’ of TB in human populations has changed dramatically. Treatment of disease has radically changed the fate of TB by preventing death and permanently curing most patients. Moreover, treatment of infection has drastically reduced the progress from infection to disease particularly in children and most efficiently within households of TB patients where contact investigation is actively pursued. Consequently, because treatment with anti-TB medications purposely aims to change much in the epidemiology of TB, information derived from studies prior to the chemotherapy era (before the Second World War) is particularly relevant in providing a picture of the disease at that time. The transitions most immediately affected by chemotherapy are the transitions from disease to cure or death; transitions from infection to disease and from exposure to infection are affected at later stages of widespread implementation of TB services. Several comprehensive reviews of scientific publications on the TB situation in children prior to the chemotherapy era have been published.6,7 This exercise identified all published articles in the English language literature reporting studies undertaken between 1920 and 1950 that included at least 1,000 children followed for a minimum of 10 years.8–15
ROUTINE NOTIFICATIONS Annual reports on TB notifications are prepared by the World Health Organization (WHO), summarizing information obtained from all countries of the world (the most recent being from 200716). These reports are compiled from information collected routinely at the clinic level, and at district level, using standardized data collection forms, reporting on all individuals put on treatment for active TB in the country from which the report is submitted. These reports provide information on the total number of cases according to whether they are new or re-treatment cases and, for new cases, the number of cases that are sputum smear-positive, sputum smear-negative pulmonary or extrapulmonary. Age-specific reports are provided routinely only for new smear-positive cases and, among these, the information on children is reported for the
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age group under 15 years, combined in the vast majority of settings. As the greatest proportion of cases in children (and particularly in small children) is not sputum smear-positive, these routine reports have limited usefulness in determining the epidemiology of TB in childhood. Other factors further limit the usefulness of these reports. The comprehensiveness of reporting may vary widely and is influenced by the priority given to ensure completeness of the information collected.17 It varies as well by the criteria used to define a case of TB in children,18 and on the extent of active case finding (in particular, household contact investigation) carried out in a particular location. Particular caution must be used in interpreting routinely reported cases as they may specifically under-report more serious forms of disease in children.19
DISEASE PREVALENCE SURVEYS Surveys of disease prevalence should be able to provide useful information on the distribution and determinants of TB in childhood. Despite this, they have provided very limited data upon which study of the epidemiology of TB in childhood can be based. Disease prevalence surveys for the epidemiology of TB in childhood have several inherent limitations. First, TB is a relatively rare disease in most locations. Because of this, the statistical power of such surveys is limited by the necessity of examining a large sample of the population to obtain reliable estimates of disease prevalence. In most instances, such surveys are powered to provide such estimates for only the entire population of a country and do not have sufficient power to study subsets of the population (including subsets of age that permit generalizations concerning children). A second limitation is related to the tools used in such surveys to detect cases. In most surveys, the measurements are based on questionnaires, chest radiographs and bacteriological examination of sputum. These methods are distinctly limited in their usefulness in identifying children with TB. As noted earlier, the majority of children with TB are not sputum smear-positive. Moreover, the symptoms of TB in children are not as straightforward as in adults (in whom they already have significant limitations). Chest radiography is the most useful of the three tools for measurement but even chest radiography has limitations in that standardization of reading of chest radiographs has not been undertaken for children.
TUBERCULIN SKIN TEST SURVEYS The specific public health objective of modern TB services is the reduction in prevalence of infectious TB in order to reduce the incidence of infection in children. The ultimate aim is to create a generation of children that is ‘infection-free’ and, thus, to eliminate TB from the community. Infection is measured classically by the tuberculin skin test survey. Studying the distribution (especially the trend over time) of infection in children is the only way to directly measure progress towards this objective. Tuberculin skin test surveys are usually undertaken in school children and therefore provide important information on TB in childhood.20 The size of induration resulting from the tuberculin skin test has been demonstrated to accurately predict who is most likely to develop TB in future.3 This test is therefore used to identify TB infection. Such surveys have the possibility of determining the burden and distribution of TB infection in children. The target population is school children aged 6–8 years and, as the test identifies the
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prevalence of infection in this age group, the results are a summary of the incidence of infection multiplied by the person-years at risk. Thus, the survey gives an average experience of the children over the entire period of the child’s life (centred on the date defined as the current date minus the mean age of the group of children, divided by 2). In most instances, therefore, the measurement derived from a tuberculin skin test survey measures the average experience over the previous 7 years, centred on 3.5 years prior to the date of the study. This ‘averaging’ thus adds imprecision to the measurement as it obscures (or is adversely affected by) changes that might have taken place over the period studied (whether prevalence of TB is falling – as is the case in the indigenous populations of most industrialized countries – or rising – as is the case in much of sub-Saharan Africa over the past decade). Tuberculin skin test surveys are also limited by poor technique (indicated by ‘terminal digit preference’) and by cross-reactivity of the antigens with those of Bacillus Calmette–Gue´rin (BCG) vaccination and with other environmental mycobacteria. Moreover, as the prevalence of significant tuberculin skin reactions declines, this imprecision becomes greater,21 drastically limiting the usefulness of the test where TB is infrequent. Extensive surveys were undertaken by the WHO in many countries in the 1950s and 1960s, often in preparation for mass campaigns for BCG vaccination. The studies undertaken in Africa during this period have been reported.22 A number of more recent tuberculin skin test surveys have been reported from Africa and India.23–25
HOUSEHOLD CONTACT STUDIES Because exposure is most prolonged and intense among persons living within the household of a TB patient, active investigation to detect those in the household (especially children under 5 years of age) with infection and with TB is recommended.2 Treatment is recommended for all those found to have infection or disease. This policy on the one hand substantially changes the epidemiology of TB by significantly reducing the risk of progression from infection to disease and by permanently curing a high proportion of those with disease. On the other hand, it provides systematic investigation within households (and sometimes more broadly) that provides information on the transition from infection and, to a more limited extent, from infection to disease. Three large studies of household contacts established the basis for this literature.26–28
INTERVENTION TRIALS At the point that interventions were first introduced to address the problem of TB, several very large trials were conducted in which placebo controls were compared with those assigned to an intervention arm of investigation. The trial of preventive chemotherapy for treatment of TB infection in contacts of active cases of TB was undertaken in children.3 The study participants were followed for an extensive period of time after the trial to determine the development of disease. The placebo control group thus provides information on the transition from infection to disease in the absence of intervention.
HEALTH SERVICES RESEARCH The final source of information on the epidemiology of childhood TB comes from a series of health service-based studies of TB in children.
40
GLOBAL ESTIMATES OF BURDEN OF DISEASE IN CHILDREN Several publications have explored the global epidemiology of childhood TB.29,30 Estimates of the global burden of disease vary widely. Nelson and Wells noted that, in 1989, the Expanded Programme on Immunization of WHO reported a total of 1.3 million cases of TB in children under 15 years of age leading to the death of 450,000 children.31 A second report from the WHO estimated that this number was 650,000 cases in children out of 7.5 million total cases in 1990,32 9% of the total estimated cases. A further report providing estimates of the trend expected over the decade 1990–2000 reported that the expected number of cases in the year 2000 would be 10.2 million.33 There are not good estimates of the percentage of cases occurring in children, but it is estimated that the proportion of children with TB is much higher in countries with a high incidence of TB than in low-incidence countries.34 Clearly, the variation in these estimates is much greater than could be explained by biological factors, indicating the extent of uncertainty regarding the size of the problem. Some authors have concluded that reliable estimates of the burden of disease can only be obtained from industrialized countries.35 Even this optimism may be misplaced for the reasons given earlier in discussion of routine notifications as sources of information. Because of the unavailability of actual reports on TB in children, the problem has been addressed using modelling exercises. One such exercise used the reported positive cases in 2000 in the 22 ‘high-burden’ countries (those nations estimated to contain more than 80% of all cases of TB) to estimate the number of all cases expected in children under 15 years of age.36 The total number of expected cases in children under 15 years of age was 884,019, 10.7% of all estimated cases, of which 659,397 (74.6%) were in the 22 high-burden countries. The proportion of children under 15 years of age among all cases varied from 2.7% (Indonesia and Thailand) to 25.3% (Afghanistan and Pakistan), with the largest numbers in India (185,233) and China (86,978). Reports of TB in children in Europe have been published in the UK,37–40 in Scandinavia41,42 and in the USA.43 These reports indicate the role of children as ‘sentinel’ indicators of the trend for TB in general. Other publications have reported on TB in children from Africa.34,44–47
EPIDEMIOLOGY OF TRANSITIONS POPULATION AT RISK The population at risk is influenced by the composition of the population. In developed countries children make up 5% or less of the population while in developing countries children less than 15 years make up between 40% and 50% of the total population.46 In developing countries young adults, who have the highest prevalence of disease, expose a large pool of children to the risk of infection so that as the incidence of TB rises in adults the rise in childhood cases increases exponentially.46 In low-incidence countries TB occurs mainly in older men and with fewer children the case load of children with TB is less than 5%, while in highincidence countries it has been calculated that children are responsible for about 25% of cases.29
CHAPTER
Epidemiology of childhood tuberculosis
FROM EXPOSURE TO INFECTION The majority of but by no means all, children exposed in the same household for prolonged periods to a sputum smear-positive case of TB become infected. The proportion becoming infected has been variously estimated at between 60% and 80%.10,13–15
Demographic factors: age, sex, ethnic group The probability of developing infection is not constant across age in childhood. The probability has been observed to be higher in ages 5–7 years.12 This has been interpreted as indicating a higher risk of becoming infected when children leave their homes and when the social network of the child increases with school entry. From tuberculin surveys in Africa,22 the prevalence of TB infection by age and sex has been reported and the prevalence rises steadily with age. The prevalence of infection is higher in young girls than in boys, but this ratio reverses in later childhood and throughout adult life. Host factors: immunological status As the human immunodeficiency virus (HIV) epidemic progresses in a community the number of children infected with TB increases. In a Kenyan study in districts where the notification rates increased, the HIV prevalence rates in TB patients were greater than 50%, while in districts where the notification rates had not increased the prevalence of HIV infection in TB patients was 28%. In the districts where the notification rates had increased, the TB infection prevalence rates increased strongly (odds ratio (OR) ¼ 3.1, 95% confidence interval (CI) 2.3–4.1).24 Environmental factors: exposure (intensity, proximity, duration), socioeconomic status The probability of being infected among those in contact with a bacteriologically positive case of pulmonary TB is highest if that case is sputum smear-positive (as compared with the sputum smear-negative pulmonary source case),11,14,15,27 and greater if the contact is within the same household.27 Additional factors associated with a higher risk of becoming infected given contact with an active case of TB include the grade of sputum smear-positivity in the source case and the duration of symptoms.10,48,49 While it seems logical that the physical characteristics of the household (size, space, ventilation) should be associated with the probability of becoming infected, this has not been confirmed in studies where it has been investigated, although the peak of infection in winter months might suggest that reduced ventilation in the household during this period might be the cause.15 Moreover, the inverse association of risk of infection following household contact with social class would also suggest that the household characteristics might be a determinant.12,14 Drug resistance Multidrug-resistant (MDR) cases of TB often have a longer duration of illness related to the poor response to treatment than drugsusceptible cases and therefore it is plausible that there may be a longer time for transmission to occur; however, studies of household contacts of such cases have failed to demonstrate a higher probability of infection among children in the household than among those exposed to cases harbouring drug-susceptible organisms.50–54 FROM INFECTION TO DISEASE The risk of developing disease following infection is greatest in the immediate period following infection and declines exponentially with time since infection.3
5
Demographic factors: age, sex, ethnic group The progression from infection to disease (and particularly to severe disease such as disseminated TB and tuberculous meningitis) is substantially more likely in young children (and particularly in infants) than in older children or adults.11,12,15 This has been suggested to be due to immaturity of the cellular immunity in young children.55 Host factors: immunological status Children who are living with HIV infection have been reported to have a higher probability of progressing from infection to disease.56 In an isoniazid (INH) prophylaxis trial in HIV-infected children the prevalence of TB in the placebo arm was 23,700 per 100,000 children.57 This study gives an indication of the tremendous rate of progression to disease in severe immune-suppressed HIVinfected children. The effect of HIV infection in peri-urban areas of Africa is illustrated in an article where over the course of 9 years TB notifications increased by 2.5-fold as the prevalence of HIV infection increased from 6% to 22%. The increase in adolescent TB notifications was even more dramatic. In the initial year of the study no adolescents were notified, whereas notification increased in the last year to 436 cases per 100,000 persons.58 Environmental factors: exposure (intensity, proximity, duration), socioeconomic status Investigation of household contacts of pulmonary TB patients reports a higher rate of progression from infection to disease among contacts infected by sputum smear-positive patients than among those only positive on sputum cultures.27 This has been interpreted as a result of the size of the ‘infecting dose’. In a study from a large urban African city childhood TB notification was inversely correlated with parental education (r ¼ 0.64) and annual income (r ¼ 0.6) and positively with household crowding (r ¼ 0.32).34 Several studies have shown a correlation between childhood TB notification rate and crowding, income, rate of unemployment, infant mortality and social deprivation.59–61 FROM DISEASE TO DEATH Demographic factors: age, sex, ethnic group Owing to the fact that infants are more likely to develop more severe forms of TB following infection than older children, the fatality rate for TB is higher in very young children – in one report 13% of children under the age of 3 months with TB died.62 Such children may die rapidly from their disease, highlighting the importance of rapidly investigating such children who are contacts of active cases of TB in their households in order that their disease may be detected at an early stage or, even better, its appearance prevented by providing preventive chemotherapy. Host factors: immunological status African children with TB who are coinfected with HIV are much more likely to die than those with TB who are HIV-uninfected.63,64 Although it is not clear that death in these cases was due to TB, a substantial proportion of African children dying of respiratory illnesses who are infected with HIV have active TB evident (and often first diagnosed) at postmortem examination.65 This would suggest that TB was a cause of death in these children, likely as a result of the fact that many of them received no treatment. Drug resistance While there are many studies reporting on the outcome of adult patients with MDR-TB there is a paucity of papers addressing this aspect of childhood TB. In recent trials the mortality rate varied
41
SECTION
1
HISTORY AND EPIDEMIOLOGY OF TUBERCULOSIS
from 2.5% to 10%.66,67 The death rate of MDR-TB in HIVinfected children has not been widely reported but Schaaf et al.67 reported that two out of six HIV-infected children treated for MDR-TB died, giving an indication that the mortality in HIVinfected children could be considerably higher.
MDR-TB in HIV-infected children has not been reported but might be worse than that in HIV-uninfected children.67
THE WAY FORWARD QUALITY OF INFORMATION CURRENTLY AVAILABLE
FROM DISEASE TO CURE Demographic factors: age, sex, ethnic group Children with TB due to susceptible organisms would be expected to respond to appropriate treatment regardless of age, sex or ethnic group. However, the results of treatment of children in Malawi are reported to be substantially less satisfactory than those among adults with only 45% with successful treatment, 17% who died while on treatment, and 34% who defaulted or in whom the outcome was unknown.47 In clinical trials the outcome of children treated for TB are excellent with 97% being regarded as successfully treated and only one recurrence.68 Trials like these must be interpreted with care as they include only children treated in peripheral clinics and exclude children admitted to hospital with complicated disease.
Until recently the only childhood TB statistics reported by countries were those of the number of sputum smear-positive cases in children aged 0–14 years. As sputum collection is limited especially in small children and with the proportion of smear-positive cases being small the information on the effect of TB on children is very limited. Little attention has been given to this information, leading to poor quality data. An audit of a number of clinics revealed that 15.7% of children treated for TB were not recorded in the TB register and of those treated 19.4% did not have TB when the case was reviewed.19 This limited study reflects the care that needs to be taken to ensure accurate information.
Host factors: immunological status In culture-proven TB in a hospital-based study the hospital-related mortality was higher among HIV-infected children (17.5%) than among HIV-uninfected children (11.4%).69 Other studies have reported a sixfold higher mortality in HIV-infected children than in HIV-uninfected children receiving treatment for TB with the HIV-infected children having a 38% mortality rate.64 In a study from Malawian children receiving highly active antiretroviral therapy (HAART) the 12-month outcome of children in whom HAART was started because of TB (0.86) was no worse than that among those who had previous TB (0.86) or those who did not have active or previous TB (0.88).70 This indicates that the outcome on HAART is not worsened by active TB or a history of previous TB.
With 95% of children developing disease within 12 months of being infected, the information on childhood TB gives an indication of the recent transmission within communities – and reconfirms that TB infection and TB disease in children are sentinel events indicating the burden of TB and the effects of control strategies in a community. A decrease in the number of childhood cases, especially in those less than 5 years of age, who are mostly infected in their households, would be the first indication that transmission is decreasing in a community. This is one of the reasons the recording of children in the age band 0–4 years is important.
Drug resistance Very little information is known on the outcome of children treated for drug-resistant TB. Recently it was reported that 36 out of 38 (95%) children treated for MDR were cured or presumed cured while only one child died.66 These results are similar to another study from Africa in which 35 of 39 children with culture-confirmed MDR-TB were successfully treated.67 The outcome of
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CHILDHOOD TUBERCULOSIS AS A SENTINEL EVENT
RECENT DEVELOPMENTS The importance of childhood TB as a worldwide problem has been recognized and the WHO has developed new international guidelines for the management of childhood TB.71 The STOP TB Strategy has included a Childhood TB subgroup to ensure that children are included in treatment, recording and reporting strategies. In future children suffering from TB are more likely to be diagnosed, receive treatment and be recorded and reported. With these new data the extent of the childhood TB epidemic will become clearer.
5. Enarson DA, Ait-Khaled N. Tuberculosis. In: Annesi-Maesano I, Gulsvik A, Viegi G (eds). Respiratory Epidemiology in Europe. Huddersfield: Charlesworth Group, 2000: 67–91. 6. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402. 7. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004; 8:278–285. 8. Opie E, McPhedran FM, Putnam P. The fate of children in contact with tuberculosis: the exogenous infection of children and adults. Am J Hygiene 1935;22:644–682.
9. Popoe AS, Sartwell MD, Zacks D. Development of tuberculosis in infected children. Am J Public Health 1939;29:1318–1325. 10. Brailey MA. A study of tuberculous infection and mortality in the children of tuberculous households. Am J Hyg 1940;31:Sec. A1–A43 11. Gedde-Dahl T. Tuberculous infection in the light of tuberculin matriculation. Am J Hyg 1952;56:139–214. 12. Bentley FJ, Grzybowski S, Benjamin B. Tuberculosis in Childhood and Adolescence. The National Association for the Prevention of Tuberculosis. London: Waterlow, 1954: 217–238. 13. Davies PDB. The natural history of tuberculosis in children. Tubercle 1961;42(suppl):1–40. 14. Zeidberg LD, Gass RS, Dillon A, et al. The Williamson County tuberculosis study: a twentyfour-year epidemiologic study. Am Rev Respir Pulm Dis 1962;87:1–41.
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Epidemiology of childhood tuberculosis 15. Miller FJW, Seal RME, Talor MD. Tuberculosis in Children. London: Churchill, 1963: 79–163. 16. World Health Organization. Global Tuberculosis Control. WHO/CDS/TB/2007. Geneva: World Health Organization, 2007. 17. Chiang C-Y, Enarson DA, Yang S-L, et al. The impact of national health insurance on the notification of tuberculosis in Taiwan. Int J Tuberc Lung Dis 2002;6:974–979. 18. Marais BJ, Hesseling AC, Gie RP, et al. The burden of childhood tuberculosis and the accuracy of community based surveillance data. Int J Tuberc Lung Dis 2006;10:259–263. 19. Berman S, Kibel M, Fourie P, et al. Childhood tuberculous meningitis: high incidence in the Western Cape of South Africa. Tuber Lung Dis 1992;73:349–355. 20. Arnadottir T, Rieder HL, Trebucq A, et al. Guidelines for conducting tuberculin skin test surveys in high prevalence countries. Tuber Lung Dis 1996; 77(Suppl):1–20. 21. Neuenschwander BE, Zwahlen M, Kim SJ, et al. Determination of the prevalence of infection with Mycobacterium tuberculosis among persons vaccinated against Bacillus Calmette-Guerin in South Korea. Am J Epidemiol 2002;155(7):654–663. 22. Roelsgaard E, Iversen E, Blocher C. Tuberculosis in tropical Africa: an epidemiological study. Bull World Health Organ 1964;30:459–518. 23. Tanzanian Tuberculin Study Collaboration. Tuberculosis control in the era of the HIV epidemic: risk of tuberculosis infection in Tanzania, 1983–1998. Int J Tuberc Lung Dis 2001;5:103–112. 24. Odhiambo J, Borgdorff M, Kambih F. Tuberculosis and the HIV epidemic: Increasing annual risk of tuberculosis infection in Kenya, 1986-1996. Am J Public Health 1999;89:1078–1082. 25. Tuberculosis Research Center. Trends in the prevalence and incidence of tuberculosis in South India. Int J Tuberc Lung Dis 2001;5:142–157. 26. Shaw JB, Wynn-Williams NW. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954;69:724–732. 27. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975;50:90–106. 28. Van Geuns HA, Meijer J, Styblo K. Results of contact examinations in Rotterdam 1967–1969. Bull Int Union Tuberc 1975;50:107–121. 29. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis 2004;8:636–647. 30. Walls T, Shingadia D. Global epidemiology of paediatric tuberculosis. J Infect 2004;48:13–22. 31. World Health Organization. Expanded Program on Immunization. Update August, 1989. Geneva: World Health Organization, 1989. 32. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organisation. Tubercle 1991;72:1–6. 33. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis incidence and mortality during 1990–2000. Bull World Health Organ 1994;72: 213–220. 34. van Rie A, Beyers N, Gie R, et al. Childhood tuberculosis in an urban population in South Africa: burden and risk factors. Arch Dis Child 1999;80: 433–437.
35. Hershfield E. Tuberculosis in children: guidelines for diagnosis, prevention and management. A statement of the scientific committees of the IUATLD. Bull Int Union Tuberc Lung Dis 1991;66:61–67. 36. Corbett EL, Watt CJ, Wlaker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–1021. 37. Public Health Laboratory Service. Available at URL: www.phls.org.uk/topics_az/tb/data_menu.htm 38. Surinder S, Hawker J, Ali S. The epidemiology of tuberculosis by ethnic group in Birmingham and its implications for future trends in tuberculosis in the UK. Ethn Health 1997;2:147–153. 39. Parslow R, El-Shimy N, Cundall D, et al. Tuberculosis, deprivation and ethnicity in Leeds, UK, 1982–1997. Arch Dis Child 2001;84:109–113. 40. Atkinson P, Taylor H, Sharland M, et al. Resurgence of paediatric tuberculosis in London. Arch Dis Child 2002;86:264–265. 41. Eriksson M, Bennet R, Danielsson N. Clinical manifestations and epidemiology of childhood tuberculosis in Stockholm, 1976-95. Scand J Infect Dis 1997;29:569–572. 42. Rosenfeldt V, Paerregaard A, Fuursted K, et al. Childhood tuberculosis in a Scandinavian metropolitan area 1984-93. Scand J Infect Dis 1998;30:53–57. 43. Ussery XT, Valway SE, McKenna M, et al. Epidemiology of tuberculosis among children in the United States: 1985–1994. Pediatr Infect Dis J 1996;15:697–704. 44. Harries A, Parry C, Nyong’onya M, et al. The pattern of tuberculosis in Queen Elizabeth Central Hospital Blantyre, Malawi: 1986–1995. Int J Tuberc Lung Dis 1997;1:346–351. 45. Kiwanka J, Graham SM, Coulter JBS, et al. Diagnosis of pulmonary tuberculosis in children in an HIV-endemic area, Malawi. Ann Trop Paediatr 2001;21:5–14. 46. Donald P. Childhood tuberculosis: out of control? Curr Opin Paediatr 2002;8:178–182. 47. Harries AD, Hargreaves NJ, Graham SM, et al. Childhood tuberculosis in Malawi: nationwide casefinding and treatment outcomes. Int J Tuberc Lung Dis 2002;6:424–431. 48. Liippo KK, Kulmala K, Tala EO. Focusing tuberculosis contact tracing by smear grading of index cases. Am Rev Resp Dis 1993;148(1):235–236. 49. Golub JE, Bur S, Cronin WA, et al. Delayed tuberculosis diagnosis and tuberculosis transmission. Int J Tuberc Lung Dis 2006;10(1):24–30. 50. Snider DE Jr, Kelley GD, Cauthen GM, et al. Infection and disease among contacts of tuberculosis cases with drug-resistant and drug-susceptible bacilli. Am Rev Respir Dis 1985;132:125–132. 51. Steiner P, Rao M, Mitchell M, et al. Primary drugresistant tuberculosis in children. Correlation of drugsusceptibility patterns of matched patient and source case strains of Mycobacterium tuberculosis. Am J Dis Child 1985;139:780–782. 52. Schaaf HS, Vermeulen HA, Gie RP, et al. Evaluation of young children in household contact with adult multidrug-resistant pulmonary tuberculosis cases. Pediatr Infect Dis J 1999;18:494–500. 53. Schaaf HS, et al. Transmission of multidrug-resistant tuberculosis. Pediatr Infect Dis 2000;19:695–699. 54. Texeira L, Perkins MH, Johnson J. Infection and disease among household contacts of patients with
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multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:321–328. Smith S, Jacobs RF, Wilson CB. Immunobiology of childhood tuberculosis: a window on the ontogeny of cellular immunity. J Pediatr 1997;131:16–26. Thomas P, Bornschlegel K, Singh T, et al. Tuberculosis in human immunodeficiency-exposed children in New York City. Pediatr Infect Dis J 2000;19:700–706. Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomized controlled trial. BMJ 2007;334:136–148. Lawn SD, Bekker L-G, Middelkoop K, et al. Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions. Clin Infect Dis 2006;42: 1040–1047. Drucker E, Alcabes P, Bosworth W, et al. Childhood tuberculosis in the Bronx, New York. Lancet 1994;343:1482–1485. Reinhard C, Paul WS, McAuley JB. Epidemiology of pediatric tuberculosis in Chicago, 1974–1994: a continuing public health problem. Am J Med Sci 1997;313:336–340. Chaulk CP, Khoo L, Matuszak DL, et al. Case characteristics and trends in pediatric tuberculosis: Maryland 1986–1993. Public Health Reports 1997;112:146–152. Schaaf HS, Gie RP, Beyers N, et al. Tuberculosis in infants less than 3 months of age. Arch Dis Child 1993;69:371–374. Mukadi Y, Wiktor S, Coulibaly I, et al. Impact of HIV infection on development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cote d’Ivoire. AIDS 1997;11:1151–1158. Palme I, Gudetta B, Bruchfeld J, et al. Impact of immunodeficiency virus 1 infection on clinical presentation, treatment and survival in a cohort of Ethiopian children with tuberculosis. Pediatr Infect Dis J 2002;21:1053–1061. Chintu C, Mudenda V, Lucas S. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002;360:985–990. Drobac PC, Mukhergee JS, Joseph KJ, et al. Community-based therapy for children with multidrugresistant tuberculosis. Pediatrics 2006;117:2002–2009. Schaaf HS, Shean K, Donald PR. Culture-confirmed multidrug-resistant tuberculosis in children: diagnostic delay, clinical features, response to treatment and outcome. Arch Dis Child 2003;88:1106–1111. Te Water Naude JM, Donald PR, Hussey GD, et al. Twice weekly vs. daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 2000;19:405–410. Jeena PM, Pillay P, Pillay T, Coovadia HM. Impact of HIV-1 co-infection on presentation and hospitalrelated mortality in children with culture proven pulmonary tuberculosis in Durban, South Africa. Int J Tuberc Lung Dis 2002;6:672–678. Bong C-N, Chen SCC, Jong Y-J, et al. Outcomes of HIV infected children with tuberculosis who are started on antiretroviral therapy in Malawi. Int J Tuberc Lung Dis 2007;11:534–538. World Health Organization. Guidance for National Tuberculosis Programs on the Management of Childhood Tuberculosis. WHO/HTM/TB/2006.371. Geneva: World Health Organization, 2006.
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SECTION 2 CHAPTER
6
BASIC SCIENCE
The genus Mycobacterium and the Mycobacterium tuberculosis complex John M Grange
THE MYCOBACTERIA AND THE TUBERCLE BACILLUS – AN HISTORICAL INTRODUCTION On the evening of 24 March 1882, Robert Koch astounded the audience at a meeting of the Berlin Physiological Society with a presentation of his meticulous work that had led to the discovery of the cause of TB. So thorough was Koch’s technique that his discovery was soon ratified by other bacteriologists and his opponents who postulated a constitutional or hereditary cause of TB were silenced.1 Koch (Fig. 6.1) referred to the causative agent of TB simply as the Tuberkelbazillus; the binomial term Mycobacterium tuberculosis was introduced by Lehmann and Neumann in the first edition of their Atlas of Bacteriology published in 1891. The name Mycobacterium – fungus bacterium – alludes to the mold-like pellicle produced by members of this genus on the surfaces of liquid media. At that time, the only other known member of this genus was the leprosy bacillus – Mycobacterium leprae – which was included as it shared the characteristic acid-fast staining property with the tubercle bacillus. The leprosy bacillus, which has never been cultivated in vitro, was first observed microscopically in the tissues of leprosy patients by the Norwegian physician Gerhard Armauer Hansen in 1874, preceding Koch’s discovery of the tubercle bacillus by 8 years.2 In 1898, small differences between tubercle bacilli isolated from humans and cattle were observed.3 Strains isolated from cattle were termed bovine tubercle bacilli but the specific name Mycobacterium bovis was not formally introduced until 1970. Other acid-fast bacilli were isolated in the late nineteenth and early twentieth centuries, some from granulomatous lesions in mammals, birds, and coldblooded animals and some from environmental sources such as grass and compost. In the early nineteenth century, four types of ‘tubercle bacilli’ were recognized – human, bovine, avian, and ‘cold-blooded’. These correspond, respectively, to M. tuberculosis, M. bovis, Mycobacterium avium, and a group of rapidly growing mycobacteria including Mycobacterium fortuitum (previously Mycobacterium ranae) and Mycobacterium chelonae isolated, respectively, from frogs and turtles. The exact relationship between mycobacteria other than typical tubercle (MOTT) bacilli as they were once referred to and the typical tubercle bacilli was a source of considerable confusion. As a result of some flawed experiments it was claimed that the various types of tubercle bacilli were the result of adaptation in different hosts. Thus it was erroneously claimed that M. tuberculosis changed into M. avium if injected into birds. In view of its clinical
44
importance, M. tuberculosis was selected to be the ‘type species’ of the genus Mycobacterium and all other species were referred to as ‘atypical mycobacteria’, a term in common use until recently. In 1939 the Dutch microbiologist den Dooren de Jong had the inspiration to realize that the environmental mycobacteria were the typical ones and that by evolving, or more likely devolving, to obligate pathogenicity, M. tuberculosis was an atypical exception.4 Indeed, she termed the tubercle bacillus ‘the wayward son of honourable parents’. Notwithstanding, the ‘tuberculocentric’ attitude is still propagated by the use of the term ‘non-tuberculous mycobacteria’ (NTM) to describe the environmental mycobacteria. During the first half of the twentieth century, many species names were given to mycobacteria isolated from human and animal lesions and from the environment and 128 names were listed in the 1966 edition of Index Bergeyana. In practice, it was so difficult to assign any isolate apart from the major pathogens to one of the many names that they became generally known as the ‘anonymous mycobacteria’. Order replaced chaos in the 1950s when Ernest Runyon observed that mycobacteria isolated from human clinical material could be divided into four groups according to their pigmentation and rate of growth on culture media (Table 6.1).5 The slow growers were divisible into those that formed a pigment, usually bright yellow, only on or after exposure to light (photochromogens), those forming pigments in the dark (scotochromogens), and those with no pigment (non-chromogens). The rapid growers that Runyon studied were isolated from clinical specimens and were all non-chromogens but environmental isolates are often photochromogens or scotochromogens. Runyon’s pioneering work led to a resurgence of interest in the classification of mycobacteria and eventually to the establishment of the International Working Group on Mycobacterial Taxonomy (IWGMT), which undertook detailed studies of collections of organisms in Runyon’s four groups, principally by the use of Adansonian taxonomy.6,7 In this system, a large number of characteristics, notably metabolism of a range of substrates including carbohydrates, amides, and organic acids, as well as physiological characteristics such as growth at various temperatures, were used to develop trees of relatedness according to similarity, with selected degrees of relatedness delineating genera, species, and subspecific variants. The IWGMT studies also delineated reliable tests for the routine laboratory identification of mycobacteria. Although the work of the IWGMT revolutionized the classification of the mycobacteria and their laboratory identification, one
CHAPTER
The genus Mycobacterium and the Mycobacterium tuberculosis complex
6
epidemiological purposes and their susceptibility to some of the anti-TB drugs to be determined with a minimum of delay.9 Furthermore, complete sequencing of the major pathogens in the genus is proving a great help in the determination of the mechanisms of virulence and pathogenicity which could lead to the rational development of novel vaccines and therapeutic agents. Of particular interest, and not without relevance to disease control, are modern insights into the evolutionary diversification of the species within the group causing human TB, the M. tuberculosis complex, as described below.
CLASSIFICATION OF THE GENUS MYCOBACTERIUM
Fig. 6.1 Robert Koch (1845–1910), the discoverer of the tubercle bacillus.
Table 6.1 Runyon’s four groups of mycobacteria Group
Pigmentation
Growth rate
Examples
I II
Photochromogens Scotochromogens
Slow Slow
III
Non-chromogens
Slow
IV
Rapid growers
Rapida
M. M. M. M. M. M. M.
kansasii, M. marinum scrofulaceum, gordonae avium, malmoense fortuitum, chelonae
a
Defined as visible growth on solid culture media within 1 week on subculture.
problem remained. Until 1980, by international convention, the oldest known name for a given species had priority over later names and there were several examples of well-recognized species being shown to be identical to older and more obscure ones, the name of which then became the official one. Understandably, this led to confusion, particularly among clinicians, and it was therefore decided to produce Approved Lists of Bacterial Names, which were published in 1980 and which are now the sole historical source of reference.8 The approved list of mycobacteria contained 41 species but it was not long before some workers, upset that their species had been omitted, reintroduced them and an increasing number of new species were described. By 2006, the number of new species had grown to over 100, principally as a result of the introduction of molecular methods for identification. In recent years, the application of molecular technology has revolutionized bacteriological studies on TB and other mycobacterial diseases. Not only do new techniques hold out great hope for rapid, sensitive, and specific diagnostic tests but they enable clinical isolates of the M. tuberculosis complex to be typed for
The genus Mycobacterium is divisible into two main groups – slow growers and rapid growers, which on genomic and antigenic analysis are distinct subgenera,10 with the rapid growers being closely related to the genus Nocardia. The species within these two broad divisions were originally determined by Adansonian taxonomy as described above, but determination of differences in highly conserved regions of the genome is now accepted as the ‘gold standard’ for speciation. In particular, analysis of the DNA coding for 16S and 23S ribosomal RNA (‘ribotyping’) has been used for this purpose.10,11 In most cases, results obtained by classical methods and by ribotyping coincide closely but an over-reliance on the latter has led to splitting, confusing from the clinical standpoint, of some rapidly growing pathogenic strains into separate species. Thus M. fortuitum and Mycobacterium peregrinum are now officially separate species rather than variants of the former. Likewise, M. chelonae is now divided into M. chelonae and Mycobacterium abscessus. It should be noted that there are no absolute criteria for speciation of mycobacteria and the current nomenclature is not entirely logical. Thus, the members of the M. tuberculosis complex are divided into seven named species as described below because the very small genomic difference between them (less than 0.1% difference) is not reflected in the very great differences in their significance for human and animal health. By contrast, members of the M. avium complex which were once accorded separate species status are now subspecies, even though they also differ considerably in respect to their host ranges and nature of the disease they cause. Doubtless, despite advances in techniques for characterizing bacteria at the genomic level, taxonomists will always remain either ‘lumpers’ or ‘splitters’ and it is worth bearing in mind the words of the English empiricist philosopher John Locke (1632–1704), ‘The boundaries of the species, whereby men sort them, are made by men.’ One of the clearest systems for division of the genus Mycobacterium into subgenera and species is based on the distribution of soluble cytoplasmic antigens determined by immunodiffusion in gel, as described below.
THE ECOLOGY OF MYCOBACTERIA The genus is divided into obligate pathogens (the M. tuberculosis complex and M. leprae) and the many species that live freely in the environment and are therefore often termed environmental mycobacteria. Some of the latter, as described in Chapter 7, are able to cause disease in susceptible humans and animals. The environmental mycobacteria are found principally in wet environments including marshes, lakes, and rivers. A particularly
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high concentration has been found in sphagnum marshes, including some strains that could not be cultivated in vitro but could be propagated in mouse footpads.12 Some species such as Mycobacterium marinum and Mycobacterium gordonae (previously known as Mycobacterium aquae or the tap-water scotochromogen) appear to prefer water while others, including Mycobacterium terrae, prefer soil. Mycobacteria have been found at a high density in the biofilm on the inner surfaces of domestic and industrial water pipes.13 The chlorination of water may aid the proliferation of mycobacteria in these biofilms by inhibiting the growth of other bacteria that compete for this ecological niche.14 As a result of their lipid-rich, water-repellent cell walls, mycobacteria are hydrophobic and thus easily enter aerosols generated by showers, spas, and whirlpool baths and may thus be inhaled. Indeed, use of aerosol-generating bathing facilities is a risk factor for the development of pulmonary disease due to M. avium, a condition sometimes referred to as ‘hot tub lung’.15 Being distributed widely in nature, including piped water supplies, contamination of the human body, especially the mouth, pharynx, and external genitalia, by environmental mycobacteria readily occurs. Accordingly, they are frequently cultivated from sputum and urine samples and, as described in Chapter 18, care must be taken in determining the clinical significance of such isolated mycobacteria. ‘Pseudo-epidemics’ of disease due to environmental mycobacteria in care facilities have been traced to the collection of specimens into unsterile containers, and in faults in equipment for cleaning endoscopes.16,17 Disease may also follow traumatic inoculation of environmental mycobacteria into the skin.18 Two named mycobacterial skin diseases, Buruli ulcer due to M. ulcerans and swimming pool granuloma due to M. marinum, are associated with traumatic inoculation, and post-injection abscesses due to rapidly growing mycobacteria including the aptly named M. abscessus and the closely related M. chelonae have been reported. Indeed, injected suspensions of viable M. chelonae, originally isolated from a turtle, were used for the immunotherapy of TB in the early twentieth century and the patients accepted the abscesses as an indication that the therapeutic agent was working! Exposure of the human population to environmental mycobacteria may be sufficient to have measurable effects on the immune system. Thus, in some regions, such ‘immunologically effective contact’ has been sufficient to induce low levels of tuberculin reactivity due to antigens shared with M. tuberculosis.19 In some regions, exposure appears to induce some degree of protective immunity against TB but in others it may interfere with the protection conferred by Bacillus Calmette–Gue´rin (BCG) vaccination by the mechanisms described in Chapter 74. Such environmental sensitization may, at least in part, explain the considerable regional variation in the protective efficacy of BCG vaccination.20,21 Some environmental mycobacteria, including members of the M. avium complex, are able to replicate within various protozoans and also to survive within amoebic cysts under conditions of environmental stress. It has been postulated that such intracellular replication may, by analogy with Legionella pneumophila, have played a central role in the evolution of mycobacteria as intracellular pathogens.22 Furthermore, a relationship between mycobacteria and protozoa may explain some enigmatic features of M. leprae, an obligate pathogen with a degenerate genome which does not grow on any known culture medium in vitro. With very rare exceptions M. leprae only causes disease in humans and it appears, from skeletal evidence, only to have done so for the past 3,000 years, a very
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short time in evolutionary history. Although assumed to be transmitted directly between humans, 50–70% of sporadic cases of leprosy in well-studied populations occur in those who have had no known contact with human source cases, suggesting an environmental source, possibly soil.23 Accordingly, it has been suggested that M. leprae could be an obligate endoparasite of a protozoan and that the human macrophage is an alternative unicellular host.24
GROWTH CHARACTERISTICS AND METABOLISM OF MYCOBACTERIA The mycobacteria are non-sporing and non-flagellate. Their cells are mostly straight or slightly curved rods although members of some species are coccoid. Some, notably Mycobacterium xenopi, M. marinum, and Mycobacterium kansasii, may be long and filamentous under some growth conditions and the latter two may contain lipid storage granules that give the cells a distinct beaded appearance (Fig. 6.2). Branching of cells may be seen in older cultures and colonies of some species, including M. xenopi, may bear small arial hyphae. The morphology of mycobacteria in clinical specimens is very variable and is affected by prior antimicrobial therapy. Thus, reports of microscopical examinations should merely state that acid-fast bacilli are present. Identification at the species level requires the application of cultural or molecular methods. Mycobacteria are Gram positive, although they are poorly stained by this method. They are acid-fast, retaining the color of arylmethane dyes when treated with a dilute mineral acid. Thus the term acid-fast bacilli (AFB) is often used as a synonym for mycobacteria. They also retain the colour on treatment with acid and alcohol and are thus sometimes termed acid-alcohol-fast bacilli (AAFB). Contrary to a widespread view, the addition of alcohol does not enable members of the M. tuberculosis complex to be differentiated from environmental mycobacteria; it merely reduces the risk of staining artefacts. Acid-fastness is not unique to the mycobacteria – bacterial spores and members of the genus Nocardia are acid-fast to varying degrees. The acid-fast staining technique in regular use today bears the names of Ziehl and Neelsen although these workers merely modified a technique first described by Paul Ehrlich, who used it to detect tubercle bacilli in human sputum, including his own! In the classical Ziehl–Neelsen (ZN) technique
Fig. 6.2 Mycobacterium kansasii in sputum stained by the Ziehl–Neelsen method, showing elongated cells with a distinct banded or beaded appearance.
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Fig. 6.3 Acid-fast bacilli in sputum demonstrated by (A) Ziehl–Neelsen staining and light microscopy and (B) auramine staining and fluorescence microscopy. Courtesy of Dr. P. D. O. Davies.
specimens are stained with hot carbol fuchsin, decolourized with a dilute mineral acid in water or alcohol, and counterstained with a green or blue dye so that mycobacteria appear as red organisms against the counterstained background (Fig. 6.3). Fluorescent methods, based on the same principle of acid-fastness, are also available and enable more specimens to be examined in a given time as they can be scanned at a low magnification. Full technical details for the microscopical detection of mycobacteria and the organization of laboratory services are given elsewhere.25 As mentioned earlier, mycobacteria are, with the exception of a few non-cultivable species, divisible into slow and rapid growers. The latter are defined as those giving visible growth on solid media within 1 week on subculture. Most mycobacteria, both slow and rapid growers, have simple nutritional requirements and are able to utilize a range of sugars and organic acids as carbon sources and various amides and amino acids as nitrogen sources. Most species are therefore able to grow on simple synthetic media. The most common medium for the cultivation of mycobacteria in clinical laboratories is Lo¨wensteinJensen (LJ) medium, containing glycerol, mineral salts, and whole eggs which, in addition to being a source of nutrients, enable the medium to be solidified by heating at 80–85 C, a process termed inspissation. This medium is suitable for the cultivation of most mycobacterial species encountered in clinical practice with the notable exception of M. bovis. There are defects in several genes of M. bovis involved in carbohydrate metabolism, including those responsible for the phosphorylation of glucose and the formation of pyruvate.26 Growth of this species is therefore feeble on media containing glycerol, resulting in small, flat ‘dysgonic’ colonies, unlike the heaped-up ‘eugonic’ colonies of M. tuberculosis, likened to small cauliflowers or breadcrumbs, on such media. Growth of M. bovis is enhanced by replacing glycerol with sodium pyruvate. For research purposes mycobacteria may be grown on simple egg-free media solidified with agar.25 Various simple liquid media are also used for the cultivation of mycobacteria, especially in the automated culture systems described in Chapter 23. Mycobacteria are aerobic, although a few species, notably M. bovis, grow better under conditions of low oxygen concentration. Simple media contain sufficient iron and trace elements to sustain growth
although, as suggested by the name, Mycobacterium haemophilum requires media supplemented with blood or other substrates rich in iron for growth. Some members of the M. avium complex are deficient in mycobactin, a lipid required for acquisition of iron, and this must be added to the medium for the cultivation of these organisms (p. 49).
ANTIGENIC STRUCTURE OF MYCOBACTERIA Mycobacterial antigens are divisible into three main groups – actively secreted, cell wall-bound, and cytoplasmic. The first two are those initially encountered by the immune system and are thus likely to play a role in the induction of protective defence mechanisms and in pathogenicity. The nomenclature and classification of mycobacterial antigens is confusing. Some, especially the various polysaccharide antigens, are known by their chemical names, such as lipoarabinomannan, phenolic glycolipid, and trehalose dimycolate. Protein antigens are defined by their size in kilodaltons, their N-terminal amino acid sequencing, and their mass spectroscopic patterns.27 Numerous soluble and cell-bound mycobacterial antigens have been described but only a few have been well characterized functionally. Some have been utilized for the development of various diagnostic tests based on antibody or cell-mediated host immune responses. Around 200 antigenic culture filtrate proteins (CFPs) are demonstrable in two-dimensional immunoelectrophoresis in gel.27 Double immunodiffusion in gel reveals around 15 soluble antigens in each species which form the basis of a taxonomic system particularly developed by Stanford and Grange in the early 1970s.28 In this system, soluble antigens are divisible into those shared by all mycobacteria and variably by related genera (group I), those restricted to slowly growing species (group II), those found in rapidly growing species and shared with nocardiae (group III), and those unique to each species (group IV). A very few species, notably M. leprae, do not have antigens that distinguish slowly growing from rapidly growing species, as shown in Table 6.2. In some species, variation among the group IV antigens corresponds with recognized variants within them. Thus, the avium, intracellulare, brunense, paratuberculosis, and lepraemurium
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Mycosides
Table 6.2 Distribution of soluble antigens in the genus Mycobacterium Antigen group
Distribution
I
All mycobacteria and sharing of some with related genera Slowly growing mycobacteria Rapidly growing mycobacteria and the genus Nocardia Restricted to individual mycobacterial species and showing some intraspecific variation
II III IV
Trehalose dimycolates and sulpholipids Lipoarabinomannan Cell wall Mycolic acid Arabinogalactan Peptidoglycan Cell membrane
M. avium avium Bacterial cell, with nuclear body and lipid inclusions
M. avium brunense M. avium intracellulare M. avium lepraemurium M. avian paratuberculosis
v
v
Fig. 6.4 Variation in species-specific antigens in the M. avium complex demonstrable by immunodiffusion-in-gel.
subspecies of M. avium differ in their group IV antigenic structure (Fig. 6.4). Speciation by analysis of soluble cytoplasmic antigens should not be confused with the typing of smooth and emulsifiable mycobacteria by agglutination serology. This is based on differences in cell surface mycoside antigens and divides those species to which it can be applied into many variants. Before the advent of nucleic acid-based technology, agglutination typing was widely used to subdivide the M. avium complex for epidemiological purposes.29 A panel of antisera divides smooth isolates of M. avium subsp. avium into three types and M. avium subsp. intracellulare into 24 types, although some strains are untypable. Many of the CFPs are liberated into the medium by cell leakage or autolysis but a few have been shown to be actively secreted and may be involved in virulence and induction of immune responses. These include the 6-kDa early secreted antigenic target (ESAT-6) and the antigen 85 (Ag85) complex, which are described elsewhere in this chapter. In addition, by destroying toxic reactive oxygen intermediates produced within phagocytic cells, catalase-peroxidase and superoxide dismutase contribute to intracellular survival but it is not clear whether these enzymes are actively secreted by M. tuberculosis.30
MACROMOLECULAR STRUCTURE OF MYCOBACTERIA In common with other bacteria, the mycobacteria have a cell membrane consisting of two phospholipid layers. The bacterial cell membrane is, like the mammalian mitochondria, associated with various enzymes involved in energy production. The pigments responsible for the yellow color of some strains of mycobacteria are found within the bilayer. The outstanding characteristic feature of the mycobacteria, one that is responsible for acid-fastness, their slow rate of growth, and some aspects of their pathogenicity, is their very complex and
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Fig. 6.5 A diagrammatic representation of the mycobacterial cell wall.
lipid-rich cell wall external to the cell membrane (Fig. 6.5).31 The innermost layer is, in common with most other bacteria, a net-like macromolecule, peptidoglycan or murein, consisting of long polysaccharide chains cross-linked by short peptides consisting of four amino acids.32 This layer gives the bacterial cells their shape and rigidity. External to the murein layer is another macromolecule – arabinogalactan – a branched polysaccharide consisting of arabinose and galactose.32 Attached to this layer are the mycolic acids – long chain fatty acids that give the cell wall its thickness and acid-fast staining properties. These molecules have a long chain, containing 50–56 carbon atoms, and a shorter side chain with 22–26 carbon atoms. Similar but smaller mycolic acids are found in related genera such as Nocardia and Corynebacterium. In their basic structure the mycolic acids are aliphatic chains terminating in the acidic -COOH group but they may contain unsaturated bonds, oxygen-containing groups, methyl side chains, and cyclopropane rings. The latter contribute to the structural integrity of the cell wall and, by protecting against toxic oxygen derivatives such as hydrogen peroxide, they play a role in pathogenicity although the details are far from clear and observations are contradictory.33 The synthesis of mycolic acids is a complex one requiring multidomain fatty acid synthase (FAS) enzymes and additional enzymes involved in the synthesis of the cyclopropane rings and other components. The synthetic processes and the genes and enzymes involved have been well characterized and reviewed in detail.34 The processes by which the newly synthesized mycolic acids are transported to, and positioned in, the cell wall and attached to the arabinogalactan in the cell wall is less well understood. The final steps in the cell wall require the activity of a group of proteins termed the antigen 85 (Ag85) complex composed, in M. tuberculosis, of three structurally related proteins Ag85A, B, and C, which are among the predominant secreted proteins of this species.35 Mycolic acid synthesis is the target of the anti-TB agents isoniazid and ethionamide and a full elucidation of such synthesis may pave the way to the development of new therapeutic agents. The mycolic acids form the inner of two principal layers of lipids in the cell wall and the outer layer is formed by a related class of cell wall lipids, the acylated trehaloses, which contains two groups,
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The genus Mycobacterium and the Mycobacterium tuberculosis complex
Fig. 6.6 Fluorescent stained microcolonies of M. tuberculosis showing ‘serpentine cording’.
trehalose dimycolates and sulpholipids. The trehalose dimycolates were formerly termed ‘cord factors’ as they were thought to be responsible for the characteristic ‘serpentine cord’ arrangement of cells of M. tuberculosis in micro-colonies (Fig. 6.6). They were also thought to be major determinants of virulence of M. tuberculosis and although this is controversial there is now evidence that they are powerful inducers of several cytokines including tumor necrosis factor and that they have a number of effects, some beneficial but mostly harmful, on the host–pathogen relationship.36 In particular, trehalose dimycolates containing cyclopropane rings play a role in pathogenicity by adversely influencing early interactions of the infecting organism with the innate immune system.37 The cell wall content of the strongly acidic sulpholipids varies among the pathogenic members of the M. tuberculosis complex and their relevance to pathogenicity is uncertain. One of the most biologically important molecules in the mycobacterial cell wall is lipoarabinomannan (LAM), which is a branched molecule composed of the carbohydrates arabinose and mannan and anchored by a phospholipid to the cell membrane.38 LAM stretches from the cell membrane up to the surface of the cell wall and may be an important structural component, possibly acting as an anchor for several cell wall components. LAM is a dominant mycobacterial antigen and, as described in Chapters 8 and 23, plays an important role in determining the nature of the host immune response.39 In particular it is an adjuvant that plays a part in determining the pattern and regulation of the immune response by interacting with Toll-like receptors on antigen-presenting cells.40 Although it is widely accepted that the immune responses in TB are principally cell-mediated, there is evidence that antibodies, especially those against LAM, induced by BCG vaccination enhances innate and acquired immune responses to mycobacteria possibly by enhancing phagosome–lysosome fusion and intracellular killing of the pathogen.41 Two types have been described – AraLAM and ManLAM – in which the branches are capped with, respectively, arabinose and mannan. The ManLAM variant, found in the M. tuberculosis complex, has been shown to enhance entry of the bacilli into macrophages and survival within these cells.42 The outermost layer of the mycobacterial cell wall contains complex molecules termed mycosides.43 Most mycosides contain lipids (mycoserosic acids), carbohydrates, and peptides and are
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termed peptidoglycolipids and members of a related class, the phenolic glycolipids or phenol-phthiocerol dimycoserosates, lack the peptide component. The mycosides are responsible for a number of biological activities including determination of colony morphology and, in the case of strains forming smooth colonies, agglutination serotypes and they are also receptor sites for the attachment of some bacteriophages. They appear as ribbon-like structures under the electron microscope and they may be abundant enough in the cell wall to form pseudo-capsules. Smooth-to-rough mutational variation of the colony morphology, observed in many mycobacterial species, is associated with a loss of some mycosides from the cell surface. Mycosides contain a wide range of antigenic sugars, some of them being unusual ones, which form the basis of the agglutination serotypes, principally of M. avium. Phenolic glycolipids have been detected in many mycobacteria and large amounts of an apparently unique one, phenolic glycolipid-I (PGL-I), is found in the cell walls of M. leprae and has been used as an antigen in serological studies of leprosy.44,45 Intriguingly, non-cultivable mycobacteria isolated from sphagnum marshes by passage in mouse footpads contain PGL-1, suggesting that these might be an ancestral form of M. leprae.12 Another phenolic glycolipid has been found in strains of M. tuberculosis principally isolated in South India and of a distinct phage type (type I, p. 53) and, as these strains are attenuated in guinea pigs, it has been named the ‘attenuation indicator lipid’ but its link to attenuation is almost certainly coincidental.46 By contrast, certain phenolic glycolipids may contribute to virulence as one from strains of M. tuberculosis of particularly high virulence has been shown to inhibit innate immune responses.47 The complex mycobacterial cell wall forms a permeability barrier and is, for example, 100–1000 times less permeable to hydrophilic molecules than Escherichia coli. Permeability is facilitated by channel-forming protein structures termed porins, of which there are at least two types in M. tuberculosis.48 Some forms of pyrazinamide resistance are due to mutational changes in porin structure.49 A further functionally important class of cell wall lipids are the mycobactins, which are iron-chelating agents involved in the transport of iron across the cell wall and its subsequent storage.50 These lipids, which show considerable structural variation between species, are synthesized by almost all mycobacteria. Exceptions are M. avium paratuberculosis, M. avium sylvaticum, and some other members of the M. avium complex which produce little or no mycobactin. The in vitro cultivation of these organisms therefore requires the addition of mycobactin extracted from other mycobacteria to the culture medium. A group of 10 genes involved in mycobactin production and iron transport have been identified in M. tuberculosis and one of these is truncated in M. avium paratuberculosis, suggesting but not proving that this is responsible for the defect in mycobactin production in this species.51
DEFINITION OF THE M. TUBERCULOSIS COMPLEX The various so-called species that cause TB in humans and other mammals are grouped within the M. tuberculosis complex. Some, but not all, have been given separate species status, despite the fact that they are genetically very closely related. The use of separate species names has been justified on historical grounds and because,
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Table 6.3 Members of the M. tuberculosis complex with specific names Species
Principal host
M. M. M. M. M. M. M.
Human Cattle, deer, elk, bison, badger, opossum Goats Human Vole Human Seal
tuberculosis bovis caprae africanum microti canetti pinnipedii
although genetically very closely related, they differ considerably in their natural host ranges and, accordingly, their importance in respect to public and veterinary health. The named species and their principal host ranges are listed in Table 6.3. The human tubercle bacillus, M. tuberculosis, is not homogeneous. One of the first major variants in this species to be described was one common in South India and among those migrating from that region to other countries. This variant, termed the Asian or South Indian type, differs from other strains in being susceptible in vitro to the isoniazid analogue thiophen-2-carboxylic acid hydrazide (TCH), being attenuated in the guinea pig, having the so-called attenuation indicator lipid (see above) in its cell wall and being of bacteriophage type I.46 In the United Kingdom this type is much more common among immigrants of Indian subcontinent ethnic origin than among the indigenous population but, although the former have a relatively higher incidence of non-pulmonary TB, there is no relationship between the type of disease and the causative strain.52 More recently, a number of different genotypes, lineages or clades within the M. tuberculosis complex have been determined by DNA analysis as described below (p. 55). Another, though rare, variant of M. tuberculosis produces smooth colonies on egg-based solid media rather than the usual rough bread crumbs-like colonies. Originally termed the Canetti type, it is now often referred to as M. canetti.53 There is evidence, discussed later, that it is closely related to the supposed ancestral or progenitor type from which other members of the M. tuberculosis complex have devolved. Intraspecific variation has also been demonstrated in M. bovis, of which one of the generally accepted defining characteristics is resistance to the anti-TB agent pyrazinamide. In recent years, a few isolates of M. bovis from animals, principally goats, and also from humans in Spain and Germany have been found to be sensitive to this agent. Most of these strains differ in genomic structure from M. bovis and have been given the separate species name M. caprae.54 A very few strains of M. bovis that do not fit into the species M. caprae are also sensitive to pyrazinamide. Somewhat surprisingly, a study of strains of M. bovis isolated between 1999 to 2001 from 166 patients living in Germany showed that one-third were M. caprae, with the highest concentration (80%) being isolated in South Germany.55 This high incidence appears unique to Germany and it is possible that a new genotype is emerging in that country but, as the patients were mostly elderly and in the same age range as those from whom typical M. bovis was isolated, reactivation of old infections, acquired before the effective control of bovine TB, is a more likely explanation. Bacillus Calmette-Gue´rin (BCG) was derived from a tubercle bacillus, isolated by Nocard in the late nineteenth century from a
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case of bovine mastitis and termed Lait Nocard, by a total of 230 subcultivations on potato slices dipped in bile over a 13-year period, between 1908 and 1921. Initially, three lines of BCG maintained on different media were distributed by the Institute Pasteur to laboratories world-wide but after 1932 only one line, maintained on an antigen-free medium, was continued. The earliest daughter strains, all obtained before 1932, include the Brazilian, Japanese, Romanian, Russian, and Swedish. These differ from the other daughter strains in having two copies of the insertion sequence IS6110 (previously termed IS986), rather than only one, in the presence of methoxy groups in the cell wall mycolic acids and in actively secreting large amounts of the antigenic protein MPB70.56 In these respects, the earlier daughter strains more closely resemble M. bovis but, as the original strain from which BCG was derived was lost, it is not possible to determine the exact pathways by which the variants arose. As there have been no field studies in which BCG daughter strains of the two types have been directly compared, and as the protective efficacy of BCG varies greatly from region to region, the relative ability of the two genotypes to induce protective immunity is unknown. Strains of BCG also differ from M. bovis in being aerobic rather than microaerophilic and in utilizing glycerol as a carbon source. As in the case of the above variations, it is not clear how or when these metabolic differences occurred, or whether the original Lait Nocard strain had these properties. It seems, however, highly likely that the original strain was a typical M. bovis as genomic analysis of BCG shows it to be very closely related to a group of strains of M. bovis recently isolated in France.57 Mycobacterium africanum is the name given to a rather heterogeneous group of strains isolated from humans in equatorial Africa and in migrants from that region to other countries. Superficially, strains of this species appear to bridge the phenetic gap between M. tuberculosis and M. bovis and they are divided into type I which is found principally in West Africa and resembles M. bovis and type II which is of East African origin and has features in common with M. tuberculosis.58 When first encountered in the United Kingdom, type I strains were termed the ‘Afro-Asian bovine type’. Mycobacterium microti is a rarely encountered species originally isolated from the vole, Microtus agrestis. In humans it has the same level of virulence as BCG vaccine and it was used as a vaccine together with the latter in extensive clinical trials organized by the British Medical Research Council in which the two were found to afford the same level of protection against TB.59 It is highly likely that, if BCG had not been developed and was already in world-wide use, M. microti would have become the standard anti-TB vaccine. Mycobacterium pinnepedii is the name given to a group of tubercle bacilli isolated from tuberculous lesions in various species of seals and sea lions, captive and free, in Australia, New Zealand, and South America, and in an Australian seal trainer.60 A further case occurred in a captive seal, and in a tapir in an adjacent enclosure, in a zoo in Great Britain. Experimentally, M. pinnipedii causes disease in rabbits and guinea pigs. Genomic differences, revealed particularly by spoligotyping (p. 52), show that strains in this species form a cluster clearly different from those of other members of the M. tuberculosis complex. Doubtless, these named species do not cover the entire range of variation within the M. tuberculosis complex. Strains with characteristic differentiating features have been isolated from the rock hyrax or dassie, oryx, water buffaloes, and cats.
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The genus Mycobacterium and the Mycobacterium tuberculosis complex
THE GENOME OF M. TUBERCULOSIS AND OTHER MYCOBACTERIA The entire genome of M. tuberculosis H37Rv, a widely used reference strain, was completely sequenced in 1998.61 This analysis showed that the genome of this strain contained 4,411,529 base pairs (bp) and around 4,000 genes. This genome is larger than that of many bacteria, though not as large as that of E. coli. It has a high guanine + cytosine content (65.6%) and this is uniform throughout the genome, suggesting that it has evolved with little or no incorporation of DNA from other bacterial genera (Fig. 6.7). In contrast to other bacteria, many of the genes of M. tuberculosis are involved in synthesis and metabolism of lipids. Indeed every known lipid biosynthetic system, including those in plants and animals, as well as some unique ones, are found in mycobacteria and M. tuberculosis contains around 250 enzymes involved in lipid metabolism, compared to a mere 50 in E. coli. Mycobacteria are unique among the bacteria in possessing the enzyme fatty acid synthase I (FASI), which is also found in many eukaryotic cells, as well as fatty acid synthase II (FASII), which is found in most other prokaryotes and plants.62 Much of this metabolic capability enables the mycobacteria to synthesize their very complex lipid-rich cell walls. Another unusual feature of the mycobacterial genome is the large number of genes, over 4% of the total, containing polymorphic GCrepetitive sequence (PGRS) and coding for two unrelated families, PE and PPE, of acidic, glycine-rich proteins.61 The function of these proteins is unknown but, as many of them are found in the cell membrane and cell wall, they may mediate antigenic variation and thereby affect virulence and pathogenicity.62,63 At least one PE protein of M. tuberculosis binds to fibronectin and may therefore be of relevance to pathogenicity by facilitating adhesion to tissues and entry into host cells.64
Fig. 6.7 A diagrammatic representation of the genome of M. tuberculosis H37Rv. From Cole et al.61
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The genome of the strain of M. bovis selected for sequencing, a strain isolated in 1997 from a cow with pulmonary TB lesions, shows over 99.95% similarity with that of M. tuberculosis although, with 4,345,492 bp, the former is slightly smaller.26 The genome of M. bovis differs from that of M. tuberculosis by genetic deletion – it has no unique genes although there are several differences in gene expression and regulation between the two species. Most of the differences between the two species are in genes encoding cell wall lipids and secreted antigenic proteins. There are several differences in the cell wall PE proteins described earlier and it is possible that these may determine the differences in mammalian host ranges of M. bovis and M. tuberculosis.64 In addition, as discussed earlier, there are defects in several genes of M. bovis involved in carbohydrate metabolism. Being genetically highly conserved, many of the differences between strains within the M. tuberculosis complex involve just single nucleotides, the so-called single nucleotide polymorphisms (SNPs).66 A total of 1,075 SNP differences have been found between M. tuberculosis H37Rv and a clinical isolate CDC1551 and 2,437 between H37Rv and the fully sequenced strain of M. bovis described earlier. These differences are small considering that there are over 4 million bp in the genomes of members of the M. tuberculosis complex. In addition to single nucleotide polymorphisms, there are some interstrain differences involving several sequential nucleotides.67 These, the large-sequence polymorphisms (LSPs), are much less common than the SNPs and include around 20 so-called regions of difference (RDs), which, as described later, have been used to establish the evolutionary relatedness of strains within the M. tuberculosis complex. In common with all forms of life, the mycobacterial genome contains small nucleotides, up to 6 bp in length, termed microsatellites. By insertion or deletion, these cause reversible frame shift mutations at a relatively high frequency and it has been postulated that this imparts a ‘plasticity’ to the genome facilitating, by phenotypic variation, adaptation of pathogens to different hosts.68 In addition to the above genetic differences, the mycobacterial genome contains a number of repetitive genetic elements that have been utilized in the development of typing schemes for epidemiological purposes. These include various classes of mobile genetic elements (‘jumping genes’) which contribute to genetic diversity and evolution. One of these classes contains the so-called insertion sequences (IS) and 56 different ones, belonging to various families, have been detected in the genome of M. tuberculosis strain H37Rv. Several copies of one of these, IS6110, are found in the genomes of almost all strains of M. tuberculosis and, as their numbers and positions show considerable interstrain variation, they have been utilized in a typing system known as restriction fragment length polymorphism (RFLP) typing. Strains usually contain from 1 to 25 copies although a few strains contain none. In general, strains of M. bovis contain fewer copies than M. tuberculosis – BCG daughter strains, for example, contain either 1 or 2 copies. It has been postulated that strains with high and low copy numbers of IS6110 reflect different evolutionary lineages. Repetitive elements useful for typing purposes also include a region of repeat sequences found in all bacteria and termed ‘clustered regularly interspaced short palindromic repeats’ (CRISPA). The function of the CRISPAs is unknown but they have structural similarities with the centromeres of eukaryotic chromosomes and may therefore be involved in the initiation and regulation of replication of the bacterial genome. The CRISPA
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in the M. tuberculosis complex is structurally unique and is termed the direct repeat (DR) locus and consists of repetitive 36-bp units of DNA separated by non-repetitive 34- to 41-bp spacer oligonucleotides which can be amplified by PCR employing just one pair of primers. Variation in the patterns of the latter, of which there are thousands of possible combinations, in the M. tuberculosis complex, forms the basis of spacer oligonucleotide typing, or ‘spoligotyping’ for short.69 Spoligotyping has the great advantage over RFLP typing that it can be performed on PCR products, therefore avoiding the need for cultivation of the strains. Spoligotypes are more stable than RFLP types based on IS6110 variation and, as discussed later, the spoligotype of BCG has remained stable for around a century, despite multiple subcultivations and division into many daughter strains with differences detectable by RFLP typing. Other typing systems are available such as the VNTR (variable nucleotide tandem repeats), which, together with spoligotyping, provides a very discriminating system that may well replace the slower and technically more difficult RFLP typing system.70,71 Standardized methods for the typing systems currently in use and their various epidemiological uses are described in Chapter 4. The leprosy bacillus, M. leprae, has never been cultivated in vitro and was included in the genus Mycobacterium on account of its acidfast staining characteristics. Sequencing of the entire genome of M. leprae has confirmed that it is a mycobacterium.72 Its genome contains 3.27 million bp and is therefore only around threequarters the size of that of M. tuberculosis and less than half of its genome is composed of functional genes. Many of its genes are pseudogenes – non-functional counterparts of genes present in other mycobacteria – and this has deprived it of many crucial metabolic activities although it has retained the functional genes required for synthesis of its elaborate lipid-rich cell wall, and those enabling it to be a major human pathogen.73,74 The complete genome sequence of M. avium paratuberculosis has also been determined.51 This very slowly growing organism causes hypertrophic enteritis or Johne’s disease in cattle and other ruminants and there is also evidence, though controversial, that it is a cause of Crohn’s disease in humans. The complete sequencing of its genome should lead to the development of more efficient diagnostic tests, more rapid in vitro cultivation, and resolution over the controversy concerning its role as a human pathogen.
GENOMIC ASPECTS OF RESISTANCE TO ANTI-MYCOBACTERIAL AGENTS Mycobacteria, especially the slowly growing species including the M. tuberculosis complex, are naturally resistant to many of the classes of anti-bacterial agents used for treatment of other bacterial infections. On the other hand, certain distinctive metabolic processes, including those involved in the synthesis of the unique lipid-rich cell wall, are the targets of some agents used specifically for the treatment of TB, including three of the first-line drugs – isoniazid, ethambutol, and pyrazinamide. Advances in techniques for analyzing the genomic structure of mycobacteria has enabled the mode of action and the target molecule(s) of most of the anti-mycobacterial agents, and the genes involved, to be determined. These are summarized in Table 6.4. The same advances raise hopes for a rational development of additional agents active on other specific metabolic pathways and structures. Furthermore, determination of the mutation(s) in the
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Table 6.4 Targets of anti-mycobacterial agents and associated genetic loci Agent
Target molecule or function
Genes encoding targets or the site of resistancedetermining mutations
Isoniazid
Mycolic acid synthesis
Rifampicin
DNA-dependent RNA polymerase Cell membrane energy function Arabinogalactan synthesis Ribosomal protein S12 Mycolic acid synthesis
katG, inhA and its promoter region, oxyR-ahpC intergenic region rpoB
Pyrazinamide Ethambutol Streptomycin Ethionamide and prothionamide Capreomycin and viomycin Cycloserine Clofazimine p-aminosalicylic acid Dapsone
pncA embA, embB, embC
50S and 30S ribosomal subunit Peptidoglycan synthesis ? RNA polymerase Folic acid synthesis
rpsL ethA, inhA and its promoter region vicA (50S), vicB (30S) alrA Unknown Unknown
Folic acid synthesis
Unknown
relevant genes responsible for drug resistance is facilitating the development of rapid methods for detecting such resistance to several anti-TB agents.9,75 Various systems, including microarrays of oligonucleotides on chips for the detection of mutations determining resistance to rifampicin and isoniazid, are commercially available.76,77 The mode of action of rifampicin against mycobacteria is the same as in other bacterial genera and involves the prevention of synthesis of mRNA by inhibiting bacterial DNA-dependent RNA polymerase, thereby blocking the protein synthesis. Resistance is due to one of several tightly clustered single amino acid mutational changes in a short region of the rpoB gene, which encodes for the b subunit of the polymerase.78 Isoniazid is a pro-drug requiring oxidative activation by the mycobacterial catalase-peroxidase enzyme KatG, an enzyme involved in protection against oxidative stress. The most commonly reported mutations causing isoniazid resistance occur in the katG gene but mutations in the inhA locus or its promoter region and in the intergenic region of the oxyR-ahpC locus have also been associated with resistance. The inhA locus codes for a NADH-dependent enoyl-acyl carrier protein reductase which is involved in mycolic acid synthesis and is a target for isoniazid. The oxyR-ahpC locus is, like the katG locus, involved in protection against oxidative stress but the role of mutations in this locus in causing resistance to isoniazid is not clear. The relative frequency of these mutations in isoniazid-resistant strains varies from study to study and in different geographical regions and is, at least in part, related to the distribution of the genotypes of M. tuberculosis in given regions.79,80 Isoniazid (INH) is inactivated in vivo by acetylation and humans are divisible into rapid and slow inactivators.81 In addition, mycobacteria
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possess a polymorphic arylamine N-acetyltransferase (NAT) enzyme which, by local acetylation of INH, may contribute to resistance to this agent.82 NAT is essential for mycolic acid synthesis and mutants of BCG lacking this enzyme activity are more susceptible to killing by macrophages. Thus, although NAT is not a target for isoniazid, it could be a target for novel anti-TB agents. Pyrazinamide is an unusual drug as it has a powerful sterilizing activity against slowly replicating tubercle bacilli in acidic and anoxic or hypoxic inflammatory lesions.83 It is therefore most effective during the early stage of therapy before the inflammation has subsided. Pyrazinamide first requires conversion to the active metabolite pyrazinoic acid by mycobacterial pyrazinamidase enzymes encoded by the pncA gene and this enzymatic activity is not detectable in most pyrazinamide-resistant mutants of M. tuberculosis or in strains of M. bovis, which are naturally resistant to this agent. The mode of action of pyrazinoic acid is not fully understood but there is evidence that it disrupts bacterial membrane energetics and transport function. A wide range of mutations in the 600-bp pncA gene cause resistance to pyrazinamide and techniques for the detection of point mutations over a relatively large length of DNA are required for the molecular determination of resistance. One such technique is denaturing gradient gel electrophoresis, which has also been used to detect mutations in the rpoB gene causing rifampicin resistance, and a microarray for the detection of all known pncA mutations has been developed and evaluated.84,85 A few pyrazinamide-resistant strains, however, lack mutations in the pncA gene, indicating alternative mechanisms for resistance to this agent, including defects in transportation of the agent into the bacterial cell.49 Pyrazinamide also inhibits mycobacterial fatty acid synthase I and this activity may therefore contribute to its bactericidal property.62 Ethambutol inhibits the synthesis of the polysaccharide arabinogalactan, a macromolecule essential for the structural integrity of the mycobacterial cell wall, by inhibiting the enzyme arabinosyl transferase. Acquisition of resistance is a multistep process involving several genes in the embA, embB, and embC gene cluster (principally embB), which encode for this enzyme. One particular mutation in codon 306 of the embB gene is commonly associated with ethambutol resistance but it has been postulated that it does not cause classical resistance to this agent but predisposes the bacteria to develop resistance to a range of anti-TB agents, yielding strains which clustering studies indicate are readily transmissible.86 There is only a weak association between isoniazid and ethambutol although isoniazid-resistant strains with one particular mutation in the katG gene are more likely to acquire high-level resistance to ethambutol.87 Ethionamide and the closely related prothionamide are structurally related to isoniazid and have the same target molecule – the enoyl acyl carrier protein reductase involved in mycolic acid synthesis and encoded by the inhA locus.88 Also, in common with isoniazid, ethionamide, and prothionamide are pro-drugs requiring activation. An enzyme able to activate these drugs is encoded by the ethA locus but complete sequencing of this locus in ethionamide-resistant isolates revealed mutations in only about half of them, suggesting that other mechanisms of resistance occur.89 Mutations in the inhA locus or its promoter region are associated with resistance to ethionamide and prothionamide and explain the partial cross-resistance with isoniazid seen in some strains but, in contrast to isoniazid, mutants in the katG locus do not induce resistance to the former drugs.
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MYCOBACTERIOPHAGES, LYSOGENY, AND PHAGE TYPING Numerous bacteriophages able to infect, replicate in, and lyse a range of mycobacterial species, including members of the M. tuberculosis complex, have been isolated from environmental sources including soil and water. These have been detected by incubating environmental samples in liquid media inoculated with various strains of mycobacteria and then applying filtrates of the culture to lawns of the same strains and observing whether plaques due to cell lysis appear. In addition a few mycobacteria isolated from clinical and environmental material have been found to carry whole or defective phages.90 In some cases these phages integrate stably into the genome of the host mycobacterium and are transmitted to all progeny, a state termed lysogeny. In others, the relationship is a pseudolysogenic one, in which stable integration does not occur and the phages are therefore only transmitted to some of the progeny. Thus, if a phage enters the virulent cycle and lyses the host cell, surrounding phage-free cells in a bacterial lawn on a solid medium are infected and lysed, so that lytic plaques appear spontaneously. Lysis occurring in cultures of lysogenic and pseudolysogenic mycobacteria results in the liberation of cell contents including DNA and, when grown on solid media, there may be enough extracellular DNA to make the colonies very mucoid and sticky. Some lysogenic strains of environmental mycobacteria have anomalous properties, including changes in cell wall lipid structure, due to phage conversion but there is no evidence that lysogeny plays a role in mycobacterial virulence. Defective prophages have been indirectly detected in mycobacteria in recombination studies. Thus, infection of a strain by a single phage may result in the appearance of several morphologically different phage plaques on bacterial lawns, or phages with quite different electron microscopical appearances may be seen in culture filtrates. Infection of the H37Rv reference strain of M. tuberculosis with a phage (LEO) resulted in the appearance of three quite different types of lytic plaques on bacterial lawns, suggesting the presence in the strain of more than one defective phage, and genomic sequencing studies have confirmed that this strain contains two defective prophages.61,91 Although no whole phages have been isolated from M. tuberculosis, several phages from environmental sources have wide host ranges and are able to infect and lyse this species. These have been used to develop typing systems for M. tuberculosis although the number of clearly delineated types is small and for this reason, as well as technical ones, this typing method has been superseded by DNA fingerprinting. Three major phage types of M. tuberculosis have been delineated – A, B, and I – and these correlate with other major biological differences between the strains.46 Thus strains of type A have high contents of strongly acidic lipids and sulpholipids in their cell walls and those of type I are attenuated in the guinea pig and correspond to the variant of M. tuberculosis known as the Asian or South Indian type (p. 50). Phages containing the gene coding for firefly luciferase have been utilized in an ingenious technique for the rapid detection of viable M. tuberculosis. In the presence of the substrate luciferin, viable mycobacteria emit light which is detectable by a luminometer or a Polaroid photographic film as in a simple low-technology system termed the ‘Bronx box’.9,92 This system detects bacterial
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killing by anti-TB agents and provides a simple and inexpensive method for determining drug resistance.
PLASMIDS OR EPISOMES In addition to the circular genome, many bacteria contain smaller closed circles of DNA, termed plasmids or episomes. Plasmids bear a few genes which in most cases have no proven major function but in some bacterial genera plasmids accumulate genes determining resistance to antibacterial agents and can be transferred from one bacterial cell to another, a process termed infectious drug resistance. This phenomenon has not been demonstrated in the genus Mycobacterium and plasmids have not been detected in members of the M. tuberculosis complex or in M. leprae. They have been detected in some environmental mycobacteria including members of the M. avium complex in which they have been most intensively sought. As mycobacterial plasmids lack specific functional markers including determinants of drug resistance, most are very difficult to detect and isolate and, for this reason little is known of their effect, if any, on their host bacteria. A technique for the ‘rescue’ of mycobacterial plasmids has, however, been described and used to isolate four otherwise cryptic plasmids from M. avium.93 Further use of this technique may shed useful light on the properties of mycobacterial plasmids and their role, if any, in pathogenicity.
THE EVOLUTION AND DEVOLUTION OF THE M. TUBERCULOSIS COMPLEX It was, until recently, widely believed that TB first emerged in animals and that the original or ancestral member of the M. tuberculosis complex might well therefore have resembled M. bovis. It was also assumed that human TB, caused by M. tuberculosis, resulted from a species jump from animals, possibly when they were first domesticated, with a subsequent diminution of host range. Detailed genomic analysis strongly suggests a quite different scenario and it now seems likely that the ancestral member of the complex, ‘M. prototuberculosis’, arose around 3 million years ago and may have caused disease in the ancestors of modern humans.94 It has also been a general assumption that, in common with other forms of life, bacteria evolve and diversify by acquisition of new gene-coded functions and by transfer of genes from one species, or even one genus, to another. While undoubtedly horizontal gene transfer does occur in many species, it appears to be a rare occurrence in the mycobacteria. In 1973 it was postulated that variants within mycobacterial species are largely derived, directly or indirectly, from a common progenitor type with deletional mutation playing a key role.95 It required the development of techniques for DNA sequencing to confirm this postulate and to show that it applied to the M. tuberculosis complex. It has been shown that the present-day species within the M. tuberculosis complex differ from one another by their pattern of genomic deletions, particularly in the presence or absence of parts of the genome termed regions of difference.96 Fourteen such regions are present in M. tuberculosis H37Rv, the strain selected for sequencing of the entire genome, but absent from the Institute Pasteur strain of BCG. These, designated RD1 to RD14, vary in size from 2 to 12.7 kilobases (kb). Two RD regions, RD3 and RD11, contain, respectively, the defective prophages phiRv1
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and phiRv2. A further six regions are absent from strain H37Rv but present to a varying extent in other strains of M. tuberculosis. The loss of these from H37Rv may be due to the fact that this strain was isolated in 1905 and repeatedly subcultivated in vitro over a 35year period, and although it retained its virulence it could perhaps, by analogy with BCG, have undergone various genetic losses.97 The missing regions are designated RvD1 to RvD5 and TbD1 (M. tuberculosis specific deletion). Despite the name, the latter is deleted in many strains within the M. tuberculosis complex and is not deleted in all strains of M. tuberculosis. On the basis of the presence or absence of TbD1, strains of M. tuberculosis are divisible into ‘ancestral’ strains that posses this marker and ‘modern’ strains in which it is deleted.94,96 The latter group contains the strains, classified as described below, that appear to be associated with major contemporary epidemics while some strains in the Indo-Oceanic lineage described below belong to the ‘ancestral’ group. Almost all strains of M. microti and M. bovis possess the six regions deleted in H37Rv but they lack several of the other RDs, particularly RD7 to RD10. Mycobacterium microti also has a specific deletion termed RDmic. Most strains of M. africanum likewise possess the six regions deleted in H37Rv but lack some of the other RDs, notably RD9. Exceptions were two isolates from Uganda which possessed RD1 to 14 but lacked TbD1 and some of the other RvDs. As mentioned earlier, isolates of M. africanum from Uganda more closely resemble M. tuberculosis in their cultural characteristics than isolates from West Africa which have more in common with M. bovis. A PCR-based technique for the differentiation of the various species in the M. tuberculosis complex and for distinguishing them from the environmental mycobacteria on the basis of their RD profiles has been developed.98,99 The Canetti strains have almost all the RD and RvD markers as well as TbD1 and may therefore most closely resemble the postulated ancestral form of the M. tuberculosis complex. Thus a probable evolutionary scenario is that the Canetti strains separated from the common progenitor early on, followed later by the divergence of M. africanum, M. bovis, and M. microti. The common progenitor then underwent the loss of some of the RvD markers and, perhaps relatively recently, the loss of TbD1 to give the various ‘modern’ genotypes of M. tuberculosis. The devolution of M. prototuberculosis to the present-day species is shown diagrammatically in Fig. 6.8. Studies M. canetti
RDcan RD9
TBD1
RD7, 8, 10
M. tuberculosis ancestral M. tuberculosis modern M. africanum Type I M. africanum Type II
mic
RD
RD12, 13
M. microti seal
RD
RD4
M. pinnipedii M. caprae
RD1
M. bovis BCG
Fig. 6.8 Devolution of the M. tuberculosis complex from the putative common progenitor, showing the regions of difference (RDs) lost at the various devolutionary stages. The figure does not show the numerous single nucleotide changes. Adapted from Brosch et al., with simplification.96
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The genus Mycobacterium and the Mycobacterium tuberculosis complex
on ancient DNA of the M. tuberculosis complex are confirming and shedding further light on this devolutionary scenario.100 The presence or absence of certain RDs may affect virulence. Thus RD1, a 9.5-kb region, is present in M. bovis but absent from all daughter strains of BCG and also M. microti, which is of comparable low virulence for humans.101 As described below, RD1 contains genes relevant to virulence, including those coding for ESAT-6. In addition, the strains of M. tuberculosis that appear particularly virulent and are spreading world-wide are ‘modern’ strains that have lost TbD1. Spoligotyping has also shed light on the lines of diversification of the M. tuberculosis complex as there is evidence that the variations in the DR locus is the result of loss of various spacer oligonucleotides due to various mutational events, including disruption by the translocation of the insertion sequence IS6110 into the locus.102 Such variation occurs at a very slow rate and serves as an evolutionary ‘clock’. In this context, BCG daughter strains, although subcultivated repeatedly since the introduction of the vaccine in 1921, share the same spoligotype, which is identical to that of about a quarter of strains of M. bovis currently isolated between 1979 and 2000 from cattle in France, the country where the progenitor of BCG was isolated by Nocard in the late nineteenth century.57 Members of the M. tuberculosis complex have been divided into a number of groups, termed lineages, superfamilies, or clades, for epidemiological purposes. At the time of writing, the grouping and nomenclature of these lineages is confusing. Some workers identify the lineages on the basis of spoligotyping,103 some on single nucleotide polymorphisms,66 and some on large-sequence polymorphisms,104 and grouping by these methods does not completely coincide. While some workers are primarily interested in epidemiology others, as discussed earlier, are more concerned with the phylogenetic relationships between strains. There is no internationally recognized nomenclature of the lineages but published names include Beijing (or W/Beijing), Central Asian, East Asian (which includes the Beijing lineage), East African-Indian, West African 1 and 2 (including some strains of M. africanum), Indo-Oceanic, Haarlem, Euro-American, Latin American Mediterranean, Manu, S, T, and X. On the basis of spoligotyping, 62 lineages and sublineages in the M. tuberculosis complex have been defined, including 3 sublineages of M. bovis and 2 of M. pinnipedi.103 Doubtless, more lineages will be described and hopefully a clear and internationally agreed nomenclature will eventually be proposed. A minimal standard set of 16 single nucleotide polymorphisms that resolve M. tuberculosis into 6 lineages and distinguish these from M. bovis have been proposed, but these do not correlate exactly with the lineages defined by spoligotyping.66 There is evidence that lineages vary in virulence for humans and elicit different patterns of immune responses.105 Although other factors may be involved, the lineages vary in their ability to spread world-wide which may be expressed mathematically as their Spreading Index (SI).106 Lineages with a high SI are defined as ‘epidemic’ and include the Beijing lineage, which is now found in many parts of the world.107 The percentages of the major lineages in different geographical regions and maps of the distributions of six common lineages have been published.103 There is also evidence that lineages vary in the extent to which they lose virulence on mutating to drug or multidrug resistance.80 Members of the Beijing lineage appear to retain virulence on mutation to drug resistance and have been implicated in the
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epidemic spread of multidrug-resistant TB in some parts of the world.108
DETERMINANTS OF VIRULENCE AND PATHOGENICITY Numerous possible determinants of virulence of members of the M. tuberculosis complex, including secreted antigens and other molecules, cell surface components, enzymes involved in general cellular metabolism, and transcriptional regulators, have been described.30 Host–pathogen interactions appear to be multifactorial and involve the initial entry of the infecting organism into macrophages and other host cells and the subsequent determination of the host immune response, including the induction of responses that act in favour of the pathogen. There is evidence that most of the genes of M. tuberculosis are required for the maintenance of TB in the human population, although many may play only a minor role.109 Virulence of mycobacteria appears to be due much more to the immune interactions between the bacillus and the host rather than to any toxic properties of the bacilli. On the other hand, there is some evidence, discussed later, that a secreted antigen (ESAT-6) of M. tuberculosis may have a deleterious toxic effect on host cell membranes. An exceptional example of a toxin being involved in the pathogenesis of a mycobacterial disease is seen in the case of Buruli ulcer, caused by M. ulcerans. Gross tissue necrosis resulting in the characteristic large and deeply undermined skin ulcers in this disease is due largely if not entirely to a toxic substance termed mycolactone, which also has locally acting immunosuppressive properties.110 Three major problems have been encountered in studies on mycobacterial virulence. First, there are several stages in the course of TB – initial establishment of infection, a period of latency or dormancy, and post-primary disease due to either endogenous reactivation or exogenous reinfection. Secondly, virulence in experimental animal models does not correlate closely with that in humans and, thirdly, there are observations suggesting that mechanisms of virulence of M. tuberculosis may vary according to the genotypic lineages of the strains which may have diversified as adaptations to human populations of differing genetic constitution. Thus infection by a strain of M. tuberculosis may be more likely to proceed to overt TB in the human population to which it has adapted (sympatric hosts) than in a different population (allopatric hosts).104 This concept is supported by the demonstration that the lineages of M. tuberculosis differ considerably in the nature of the disease they cause, and the immune responses that they elicit, in the experimental mouse.111 Although the regional differences in the protective efficacy of BCG vaccination have generally been attributed to ecological factors, geographical differences in host–pathogen interactions may also be involved and require consideration in the development of novel vaccines.104 Although dissemination of disease from the site of infection, usually the lung, is affected by the host immune responses, bacterial factors are also involved. A study of patients infected with more than one strain of M. tuberculosis and in whom one strain was isolated from extrapulmonary sites and the other only from the lung showed that the former strains infected macrophages in vitro more efficiently than the latter and that they were more infectious in vivo in an experimental murine model.112
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These findings lead to the conclusion that TB is not a homogeneous disease. It is continuously changing and evolving as it spreads around the world and encounters different host populations including those containing many individuals with compromised immunity, as well as being subject to the various organizational and other factors that favour the selection of drug-resistant mutants. The Beijing lineage, which appears to be more virulent than other lineages even when multidrug resistant, is appearing in many countries and is a source of concern.107 In the words of Paracelsus, ‘There are never again the same causations; things are more virulent now as both the philosophies of heaven and the elements sufficiently prove.’ In primary human infection, the tubercle bacillus enters phagocytic cells, and possibly other cells, where it survives and replicates. Subsequently, if the primary infection is rendered quiescent by the host defence mechanisms, bacilli enter a state of poorly understood dormancy which, in humans, may continue for several years or decades until reactivation occurs. Such reactivation or exogenous reinfection results in post-primary tuberculosis which is characterized by gross tissue necrosis, which, by generating open pulmonary cavities, enables the organism to be transmitted from one host to another. Thus, the steps in pathogenicity are initial entry into cells, particularly macrophages, intracellular survival and replication, the establishment of the persister state, ‘awakening’ from the persister state, and subversion of the immune responses to induce the gross tissue necrosis seen in post-primary TB. These steps depend on quite different mechanisms of virulence which are therefore clearly multifactorial.
EARLY EVENTS The early events in the establishment of TB cannot be investigated in humans and are thus extrapolated from experimental animal studies and in vitro observations on the uptake of mycobacteria into macrophages. The first step in pathogenesis after initial infection is the entry of the mycobacterium into macrophages and, possibly, other cells. In common with other bacteria, phagocytosis of M. tuberculosis may involve complement activation and mannose binding. Within the macrophage, survival of the bacteria depends largely on their ability to inhibit phagosome maturation and to block phagosome– lysosome fusion.113 Mannose-capped lipoarabinomannan (ManLAM) of M. tuberculosis not only facilitates entry into macrophages by binding to mannose receptors but has these effects on phagosomal activity.42 Other poorly understood mechanisms also appear to be involved. Studies on M. marinum, the cause of swimming pool granuloma (Chapter 7), have led to the identification of two groups of genes termed mycobacterial-enhanced infection loci (mel ) 1 and 2.114 Genetic transfer of these loci to non-pathogenic mycobacteria showed that they enhanced both attachment to macrophages and intracellular survival. These loci contain 11 genes but the exact relevance of the various gene products to the observed effects is not clear. Although this study was conducted on M. marinum, the presence of both loci in M. tuberculosis but not in non-pathogens suggests a similar role in this species. Various glycine-rich fibronectin-binding mycobacterial proteins may also be involved in the establishment of infection by facilitating adherence to host tissues.63,65 Early secreted antigens have attracted attention as determinants of virulence and inducers of protective immunity. Particular attention has been focused on a group of secreted antigens coded for by
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the ESX-I locus in the RD1 region of the genome which is missing from BCG, M. microti, and other strains attenuated for humans. The ESX-1 locus codes for two antigens, ESAT-6 and CFP-10, and a protein, EspA, which is essential for the secretion of the two antigens.115 The function of ESAT-6 has not been fully determined but there is evidence that it may disrupt host cell membranes, resulting in lysis of infected cells, spread of infection from cell to cell, and possibly escape of intracellular pathogens from the phagosomes. Strains of M. tuberculosis vary in their ability to cause cytotoxicity and necrosis of murine macrophages in vitro and the extent of cytotoxicity correlates with other criteria of virulence.116 In addition, the early secreted antigens are potent inducers of protective immune responses by recruiting large numbers of the appropriate T cells. Thus, BCG complemented with RD1 (BCG::RD1) is more virulent than the parent BCG strain but also elicits a much more powerful immune response.117 A construct of BCG and RD1 possessing the immunogenicity but lacking virulence might prove to be a useful vaccine. Once engulfed by phagocytic cells, the next crucial step in pathogenesis is survival and replication of the mycobacterium within these cells. Various mechanisms enhancing survival of pathogenic mycobacteria within macrophages, including inhibition of the fusion of phagosomes and lysosomes, inhibition of the acidification of phagosomes, and resistance to killing by various reactive oxygen and nitrogen molecules, have been postulated.118 The exact mechanism of intracellular survival is poorly understood but one study based on gene transfer between M. tuberculosis and the nonpathogenic species M. smegmatis have led to the identification of a genetic locus termed the enhanced intracellular survival (eis) gene, which is present in members of the M. tuberculosis complex, including BCG, but not in M. smegmatis and 10 other non-pathogenic mycobacterial species.118 Preliminary evidence suggests that this gene codes for a 42-kDa protein situated on the surface of the mycobacterial cell and which might therefore modify the interactions between the bacterial and host cells. As mentioned earlier, the products of the mel1 and mel2 genetic loci also appear to affect intracellular survival.
PERSISTENCE, LATENCY, AND DORMANCY Very little is known about the morphological and physiological nature of tubercle bacilli in latent TB.119,120 Although animal models for studying latency have been developed, these appear rather artificial and therefore, perhaps, bear little relevance to human TB. In addition, it is possible that the bacilli persisting after the natural resolution of primary TB are different to those that persist after a course of treatment of post-primary disease and are responsible for early recurrence of the disease. One hypothesis is that persisting bacilli are truly dormant and are sequestered in dense, anoxic, scar tissue. In this context there is evidence that the establishment, and ‘awakening’ from the dormant state is controlled by genes transcribed in hypoxic environments.121 While some tubercle bacilli may adapt to a state of physiological dormancy in anoxic situations, this may not be the only mechanism of persistence. The problem with the dormancy hypothesis is that isoniazid is known to prevent reactivation of endogenous infection and that it only kills actively replicating tubercle bacilli. Thus an alternative explanation is that persisting bacilli exist in a more or less balanced cycle of replication and destruction by immune mechanisms. This
CHAPTER
The genus Mycobacterium and the Mycobacterium tuberculosis complex
would explain the association between a reactivation and immune compromise and the continuing production of gamma-interferon in those with latent TB.119 The morphological features of persisting mycobacteria remain a mystery. Although various forms have been described, including cell-wall-free forms and minute sporelike particles (Much’s granules), none have actually been clearly demonstrated. They may, however, be analogous to minute nonreplicating bacterial cells in the genera Rhodomicrobium and Rhodococcus that develop in response to adverse conditions.122 The situation of persisters within host cells and tissues is also uncertain. A common assumption is that they are within dense and anoxic fibrous or even calcified scar tissue, but the use of in situ PCR reveals that DNA supposedly specific to the M. tuberculosis complex is found throughout the lung in those with latent TB dying of other, mostly traumatic, causes.123 No acid-fast bacilli were seen at the sites of this DNA, suggesting that the persisters were cell-wall-free forms. In view of the rather puzzling observations to date, it has been postulated that the classical acid-fast rods seen in clinical specimens and in vitro cultures may just be one of a number of physiological and morphological variants of the mycobacteria.120
LATE EVENTS The principal difference between primary and post-primary TB is the extensive and excessive tissue necrosis in the latter, resulting in cavity formation in the lung and transmissibility of the infection. This process is principally determined by the nature of the host immune responses, particularly the action of interleukin-4 and other cytokines produced or induced by Th2 T cells as described in detail in Chapter 8 and 9. Pathogenic mycobacteria appear to drive detrimental Th2-mediated immune responses while some avirulent species including M. vaccae enhance protective Th1 responses and down-regulate Th2 responses and may therefore be useful immunotherapeutic agents for the treatment of TB and other conditions characterized by Th2-induced immunopathology.124
CONCLUSIONS Robert Koch discovered the cause of TB over 120 years ago but the application of this discovery to strategies for the diagnosis, prevention, and treatment of this and other mycobacterial diseases has been painfully slow. The fact that today the number of people contracting TB and dying of it each year are counted in millions is a sure indication that powerful new tools, or a much more
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determined deployment of existing tools, are required. Our principal diagnostic tool, tuberculin testing, was introduced in 1907, the only vaccine in present use was first used in 1921, and no drug superior to rifampicin has emerged since the late 1960s. There are signs, however, that we are on the verge of a scientific revolution. The past few years have seen enormous strides being taken in unravelling the hidden mysteries of the mycobacteria, the means by which they cause disease and the immune strategies which the infected host can utilize for protection. In addition, molecular techniques have led to the rapid detection and identification of mycobacteria in clinical specimens and, in the case of the M. tuberculosis complex, the rapid determination of patterns of drug susceptibility and resistance and the typing of strains for epidemiological purposes. Modern techniques have yielded specific antigens for use in diagnostic tests and for the unravelling of the complexities of the immune responses resulting in either protection or immunopathology. These developments have also raised the hopes of developing highly effective vaccines, including non-viable ones that could safely be given to those with HIV disease and other immunosuppressive conditions. The mammoth task of sequencing the entire genome, initially of M. tuberculosis and subsequently M. bovis, M. leprae, and M. avium paratuberculosis, has recently been completed successfully and is shedding enormous light on the structure and properties of these major pathogens, including the regulation of their metabolic activity which is likely to prove of enormous benefit in the rational development of novel anti-mycobacterial agents. The same work has also made it possible to determine the evolution of these pathogens which, in addition to being a most fascinating academic exercise, is revealing key aspects of host–pathogen interactions which may vary significantly across the globe. Never before in the very long history of TB and other mycobacterial disease, including leprosy, has the human race had such a wonderful opportunity to develop powerful tools for the final conquest of these afflictions. Whether the human race will grasp this opportunity to control one of the world’s principal preventable causes of suffering or will squander resources on weapons of mass destruction remains to be seen. It is perhaps worth reflecting on the words of the American public health worker John B. Huber, who a century ago, and well before the introduction of vaccines and anti-TB agents, wrote, ‘The tubercle bacillus is an index, by inversion, of the real progress of the human race. By it the claim of civilization to dominate human life may fairly be judged. Tuberculosis will decrease with the substantial advance of civilization, and the disease will as surely increase as civilization retrogrades.’125
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Other mycobacteria causing human disease Charles L Daley and Leonid Heifets
INTRODUCTION The non-tuberculous mycobacteria (NTM) comprise over 125 different species widely distributed throughout the environment, most of which have not been implicated as a cause of disease in humans.1 The NTM have been referred to as mycobacteria other than TB (MOTT), atypical mycobacteria, and environmental mycobacteria. Despite their frequent isolation in the environment and human specimens, the NTM were not widely recognized as a cause of human disease until the late 1950s. Since that time, the number of new species of NTM have grown dramatically primarily related to the availability of DNA sequencing, which has allowed identification of new species simply by detecting relatively small differences in DNA sequences. In addition to the proliferation of new species, the rate of disease related to NTM has also increased, overtaking the rate of TB in some areas. NTM have several features that distinguish them from organisms of the Mycobacterium tuberculosis complex, such as a wide range of pathogenicity and, unlike M. tuberculosis, they are not transmissible from human to human. Unfortunately, the pathogenic NTM are relatively drug resistant compared with M. tuberculosis and, thus, difficult to treat with high rates of treatment failure and recurrence. Because of our poor understanding of the transmission and pathogenesis of most NTM infections, we have little insight into how to prevent these infections and thus our public health strategy to control disease caused by these ubiquitous organisms is often lacking.
EPIDEMIOLOGY AND RISK FACTORS EPIDEMIOLOGY NTM are ubiquitous bacteria that have been isolated from soil and water sources, including both natural and treated water sources, from throughout the world. The source of infection appears to be through environmental exposure and transmission from human to human has not been described. Studies that address the epidemiology of NTM infections can be broadly divided into three types.2 Cutaneous delayed-type hypersensitivity to NTM antigens has been used to assess the frequency of infection with these organisms. Skin test studies have indicated that a substantial proportion of adults have had prior exposure to NTM. Between 1943 and 1959, 22,000 nursing students were tested with 5 tuberculin units of PPD-S.3 Students who did not react to 5 tuberculin units were retested with 250 units to detect reactivity to cross-reacting antigens. Sixty-five per cent of
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students who came from the southeast of the USA reacted to the higher dose of tuberculin compared with only 29% of those from other areas of the country. Skin test surveys of US Navy recruits in the 1960s demonstrated higher rates of reactivity in those from the southeast of the USA (56%) than in those from the northern states (15–25%), suggesting higher rates of infection.4 These surveys demonstrated the striking geographic differences in NTM infection. Another type of study utilizes consecutive isolates from a welldefined catchment area to estimate the frequency of infection but, because this approach lacks clinical information, it is unable to estimate the prevalence of disease. Survey data from state laboratories in the early 1980s estimated a prevalence of NTM infection of 1–2 cases per 100,000 population.5 A similar survey from 1993 to 1996 reported an annual case rate of 7–8 per 100,000, documenting an increase in isolation of NTM when compared with the previous survey.6 The most useful studies combine clinical and microbiological data to provide estimates of disease rates. The incidence of pulmonary NTM was studied prospectively in France between 2001 and 2003 at 32 sentinel surveillance sites: 262 patients met the American Thoracic Society (ATS) criteria for disease (see below).7Mycobacterium avium complex was the cause of disease in almost half of the patients, followed by Mycobacterium xenopi in 25%, Mycobacterium kansasii in 13% and rapidly growing mycobacteria in 10%. The overall incidence was estimated to be stable and approximately 0.72–0.74 per 100,000; however, the method for calculating the incidence rate probably underestimated the true incidence. Recent data support the view that the incidence of NTM infections is increasing.8 In a retrospective cohort review from 1997 to 2003 in Ontario, Canada, 222,247 pulmonary isolates from 10,231 patients were identified. The prevalence was 9.1/100,000 in 1997 and increased to 14.1/100,000 by 2003 (p < 0.0001) with an average annual increase of 8.4%. Increases were noted among M. avium complex, M. xenopi, rapidly growing mycobacteria and M. kansasii. Of note, the rate of TB declined 4.0% over the study period. Two hundred patients were evaluated in more detail and 33% fulfilled the clinical, radiological and bacteriological ATS criteria. The most common NTM pathogens vary geographically. Mycobacterium avium complex has been reported as the most common cause of NTM-related pulmonary disease in almost all studies.1 However, the next most common NTM that causes disease varies by location. For example, in the USA, it is M. kansasii, followed by Mycobacterium abscessus. In Canada, and some parts of Europe, M. xenopi is the second most common, whereas in northern Europe and Scandinavia, Mycobacterium malmoense is second.
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Mycobacterium marinum resides in both fresh and marine water environments, and infections are acquired by inoculation in these environments. Initial infections were reported from swimming pool exposures,9 although home aquariums have become increasingly implicated as the source of infection.10 The reported incidence of M. marinum infection is variable, ranging from 0.05 to 27 per 100,000 in adults in North Carolina, USA.11 Buruli ulcer, a skin disease caused by Mycobacterium ulcerans, was first described in central Africa during the late 1800s and early 1990s.12 The disease occurs primarily in humid rural tropical areas and predominantly affects children between 5 and 15 years of age although disease can occur at any age. Buruli ulcer is most common in some parts of Africa but it has also been reported in Papua New Guinea, French Guiana, Mexico and southeast Australia. Although the epidemiology is not well understood, the disease seems to occur in areas where water is standing or slow moving. Use of polymerase chain reaction (PCR) in West Africa has identified positive signals in the salivary glands of water bugs.13 The organism has now been cultured from these salivary glands.14
RISK FACTORS Recent skin testing data from Palm Beach, Florida, reported that 32.9% of 447 participants in a population-based random household survey had a positive reaction to M. avium sensitin.15 Independent predictors of a positive reaction included black race, birth outside the USA, and more than 6 years’ cumulative exposure to soil. Exposure to water, food and pets was not associated with skin test reactivity. However, the assessment of water exposure was crude and reactivity to M. avium sensitin may be associated with infection but not necessarily disease; thus the risk factors identified in this study may not be relevant to persons with disease. Patients who have pulmonary disease caused by NTM often have structural lung disease such as chronic obstructive pulmonary disease,1,16 bronchiectasis, cystic fibrosis (CF), pneumoconiosis, prior TB, alveolar proteinosis and chronic aspiration.17–20 In the study from France noted previously, over 50% of the patients who met ATS disease criteria (except for those with M. kansasii) had underlying predisposing factors such as pre-existing pulmonary or immune deficiency. There are reports of an association between abnormal CF genotypes21 and a1-antitrypsin phenotypes22,23 and NTM disease. Among 50 patients with bronchiectasis and pulmonary NTM infection, 20% were diagnosed with CF and 50% of the patients had a cystic fibrosis transmembrane conductance regulator (CFTR) mutation identified.21 Among 98 patients with bronchiectasis in the UK, 10 had NTM isolated from sputum specimens and CF was more likely in those with NTM than without.24 The incidence of NTM disease in gold miners in South Africa was reported to be 47.6 per 100,000 and that of M. kansasii, the most commonly isolated NTM, was 37.0/100,000, 34% of whom were human immunodeficiency virus (HIV)-infected.25 Patients who have abnormalities in the interferon-gamma (IFN-g) or interleukin-12 (IL-12) pathways are predisposed to severe NTM infections.26,27 In addition, patients receiving tumour necrosis factor (TNF) antagonist are also at increased risk of developing mycobacterial infections, particularly TB. HIV-infected patients who have advanced disease develop disseminated disease. Of note, many women with NTM infection have nodular bronchiectasis and similar body types: scoliosis, pectus excavatum, mitral valve prolapse and joint hypermobility.28 The reason for this association has not been definitively determined.
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BACTERIOLOGY ORGANISMS Mycobacteria and actinomycetes belong to the order of Actinomycetales. The taxonomy and nomenclature of the genus Mycobacterium (Mycobactericeae family) within this order has been addressed in special reviews.29–31 In order to improve the standardization of the naming of new species, the International Committee on Systematic Bacteriology of the International Union of Microbiological Societies provided recommendations on minimal standards for publications of new species.32 Currently, the definition of a new species is based on a molecular approach, which relies on the definition of species-specific nucleotide sequences, particularly within the hypervariable regions (termed A and B) of the 16S ribosomal DNA molecule. In 1998, there were already 71 validly described species of the Mycobacterium genus, selected from several hundred previously published and proposed names.29 Since 1998, more new species of mycobacteria have been reported.31 There are hundreds of mycobacterial species existing in the environment, but, so far, fewer than 80 of them have been found in diagnostic specimens from patients.33,34 Finding mycobacteria in a patient’s specimen leads to the question of whether the isolate is causing infection/disease in the patient. Isolation from blood or other sterile sites, along with a consistent clinical manifestation of the disease, is reasonable grounds for considering the NTM isolate as the causative agent. The decision on diagnosis is more complex in cases of suspected pulmonary disease. To exclude the transient occurrence of NTM in the patient’s respiratory specimen due to exposure to the bacteria, aerosolized from waters or soil, specific criteria have been recommended for the diagnosis of pulmonary disease caused by NTM (see below).1,35 Contrary to previous theories,19,36 it is now well established that so-called colonization with NTM without tissue invasion is likely a rare occurrence. NTM are typically divided into rapid- and slow-growing mycobacteria based on their ability to produce visible colonies on solid culture medium under optimal conditions in less or more than 7 days. Based on isolation from patients in whom the isolate was identified as a causative agent (sometimes only in a few cases), at least 39 organisms among slow-growing mycobacteria (listed in Table 7.1) are considered potential pathogens. In addition, other slow-growing mycobacteria not considered definitely ‘pathogenic’ for humans can be found in diagnostic specimens, some of them due to contamination from the environment or contact with animals or animal products: M. avium subsp. paratuberculosis (formerly Mycobacterium paratuberculosis), Mycobacterium gastri, Mycobacterium gordonae, Mycobacterium hiberniae, Mycobacterium nonchromogenicum, Mycobacterium terrae, Mycobacterium triviale, Mycobacterium lepraemurium and Mycobacterium microti. Some species among the rapid-growing mycobacteria are considered definite opportunistic pathogens for humans29 (upper part of Table 7.2). More recently this list has been expanded by adding more species occasionally isolated from patients’ specimens;31,33 however, their role in human pathology is not clear yet (lower part of Table 7.2).
ISOLATION OF MYCOBACTERIA The bacteriological diagnosis of NTM is based on isolation of these organisms from diagnostic specimens using standard mycobacteriology laboratories techniques. Frequency of isolation and semiquantitative assessment of the bacteriological load in the specimen
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Table 7.1 Slow-growing NTM and reported sites of infection Species
Infection sites Bacteraemia
M. arupense M. aviuma M asiaticum M. bohemicum M. branderi M. chemaera M. selatum M. conspicuum M. doricum M. florentinum M. genavense M. haemophilum M. heckeshornense M. heidelbergense M. intermedium M. interjectum M. intracellulare M. kansasii M. kubicae M. lacus M. lentiflavum M. malmoense M. marinum M. nebraskense M. parmense M. parascrofulaceum M. palustre M. saskatchewanse M. scrofulaceum M. selatum M. sherrissii M. shottsii M. shimodei M. simiae M. szulgai M. tusciae M. triplex M. ulcerans M. xenopi
þ
þ þ þ þ
þ þ
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Pulmonary
Skin
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þ þ þ þ þ þ þ þ
þ þ þ þ
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þ
þ
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CSF
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Bonesa bursitisa synovitis
Other
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þ þ
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Lymph nodes
þ þ
þ þ þ
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þ þ þ
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a
Subspecies: avium, colombiense, silvaticum, hominissuis, paratuberculosis. CSF, cerebrospinal fluid. References: Good and Snider,19 Goodfellow and Magee,29 Tortoli,31,33 Wallace et al.,35 Kent and Kubica.39, Woods and Washington.109
is necessary in cases when differentiation between invasive disease and colonization is an issue, as addressed below in cases of pulmonary NTM disease. A special issue is the bacteriological diagnosis of disseminated NTM disease, which is based on isolation of NTM from blood. The most convenient approach is to submit a blood sample collected in a sodium polyanetholesulphonate (SPS)-containing yellow-top vacutainer to the laboratory. Such a sample can be used for either culture isolation only and/or quantitation of the bacterial load in blood (quantitative culture) as a tool for monitoring the patient’s response to therapy.37,38 It is important that a properly processed specimen is inoculated into both liquid medium and agar plates rather than only on the Lo¨wenstein-Jensen slant, which is the least favourable for cultivation of NTM.
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MYCOBACTERIAL IDENTIFICATION Both rapid- and slow-growing NTM vary by their phenotypic characteristics such as optimal conditions for cultivation, appearance of the colonies on solid medium (pigmented and nonpigmented), enzymatic activity and tolerance to different reagents and antimicrobial agents. These features, described in a number of reviews and textbooks, are often used for so-called conventional methods (or ‘biochemical tests’) for identification of NTM among clinical and environmental isolates.37,39,40 Along with traditional techniques, the modern clinical laboratory includes a broad variety of rapid methods for mycobacterial speciation.41–50 These methods include nucleic acid probes, PCR
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Table 7.2 Rapid-growing NTM and reported sites of infection Species
M. M. M. M. M. M. M.
abscessus chelonae fortuitum a mucogenicum peregrinum porcinum senegalense
M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M. M.
alvei boenickei bollettii brumae canariasense confluentis cosmeticum elephantis goodii hassiacum holsaticum immunogenum mageritence novocastrense phocaicum septicum smegmatis thermoresistible wolinskyi
Infection sites Bacteraemia
Pulmonary
þ þ þ þ
þ þ þ þ þ
þ
Skin
þ
þ þ
þ þ þ þ
þ þ þ
þ
Wounds
þ
þ
Other
þ þ
þ þ
þ
þ þ
þ
þ þ
þ
þ
Bonesa bursitisa synovitis
þ þ
þ
þ
Soft tissue þ
þ
þ þ
þ
Lymph nodes
þ
þ þ þ þ þ
þ þ
a
Subspecies fortuitum and acetamydoliticum. References: Good and Snider,19 Goodfellow and Magee,29 Tortoli,31,33 Wallace et al.,35 Kent and Kubica,39 Woods and Washington.109
and other amplification methods, high-performance liquid chromatography (HPLC) and nucleic acid sequencing. The commercially available AccuProbe technology (Gen-Probe, San Diego, CA) is usually the preferred technique among the nucleic acid probes hybridization methods. It is currently recommended for identification of M. tuberculosis complex, M. avium complex (as well as M. avium and M. intracellulare separately), M. kansasii and M. gordonae. The method requires a substantial amount of bacterial harvest, and it takes at least 3 weeks for cultivation on agar medium or 10–12 days in a liquid medium to achieve sufficient growth for this test. Amplification of discrete fragments of bacterial DNA or RNA, by PCR or other techniques, made the nucleic acid probes hybridization technique highly sensitive and, thus, provided an opportunity to expedite the laboratory report by testing the patients’ raw specimens directly.51–55 The commercially available amplification techniques (for example, the Mycobacterium tuberculosis Direct (MTD) test from the Gen-Probe Company) are useful tools for rapid identification of M. tuberculosis complex and its differentiation from NTM. The subsequent identification among the NTM has been done in most clinical laboratories on the basis of the conventional methods mentioned earlier. One alternative to this approach is HPLC, which analyses the chromatographic profile of the mycolic acids extracted from the bacterial cell wall (Fig. 7.1). This method became highly sensitive after introduction of the fluorescent detection system incorporated into an automated HPLC
system.45,46,48,56 High sensitivity of the new HPLC system provides reliable results with a relatively small number of bacteria present in the sample. Testing a culture with HPLC at the minimal growth in a liquid medium may allow identification in a shorter period of time than with AccuProbe technology. One attraction of the modern HPLC technology is the opportunity for rapid and reliable identification of M. tuberculosis complex from cultures at their initial growth in liquid media. At least 63 chromatographic patterns, which represent 73 mycobacterial species, were recently reviewed.46,48 HPLC alone (performed with cultures submitted on various media) can rapidly identify M. tuberculosis complex, M. avium complex, M. gordonae, M. marinum, Mycobacterium simiae, M. xenopi, Mycobacterium asiaticum, M. malmoense, Mycobacterium scrofulaceum (from solid medium), Mycobacterium chelonae-abscessus group, Mycobacterium fortuitum-smegmatis group, Nocardia/Rhodococcus species, and genus Tsukamurella. A much broader range of species can be reliably identified by combining information from the HPLC test results with other data, such as growth requirements, growth rate, colonial morphology and pigmentation. Identification of mycobacteria by 16S ribosomal DNA sequencing is a new tool implemented in only a few clinical laboratories to date.43,47,49,50 This technique provides more accurate determination of the species, and it is especially useful in cases where any combination of the above-mentioned methods does not provide reliable identification of the mycobacterial species. The procedure includes disruption of the bacterial cells, followed by PCR using
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Auto-scaled chromatogram
800 700
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E4 3.202
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R-65 1.741
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Fig. 7.1 Mycolic acid peaks are depicted with the use of high-pressure liquid chromatography HPLC. The pattern represents the mycolic acid profile seen with M. avium complex. HPLC is unable to reliably differentiate M. avium from M. intracullulare.
primers 264 and 285 (complementary to the A and B regions) to amplify a 1-kb fragment of 16S ribosomal DNA. The species identification is based on a comparison between the sequences obtained and those in the libraries of already known species. The supplies for the test and the libraries are commercially available, for example the MicroSec 500 16S rDNA system from Applied Biosystems (Foster City, CA). Though this methodology requires further development and standardization, it can now be considered a useful
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supplement to the tools available in large mycobacteriology laboratories dealing with identification of NTM species. The algorithm combining various methods for mycobacterial identification should take into account both the need for rapid identification of M. tuberculosis and the optimal combination and costeffectiveness of all available methods. At National Jewish, the first step, the amplification assay (MTD test), is performed only when requested. Along with or without this procedure, the processed
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raw specimens, or cultures received from other laboratories, are inoculated into four units of medium, including agar plates and 7H12 broth (e.g. Bactec-460 or 960). Employment of the agar plates is essential for detection of mixed mycobacterial cultures, as well as for isolation of some NTM that either do not grow or grow poorly on Lo¨wenstein-Jensen and other egg-based media. The parallel (or next step) is the HPLC procedure. Either the next day (with the culture submitted from another laboratory) or within 8–12 days (at very early indications of growth in the broth culture), the HPLC report on identification of M. tuberculosis complex, M. avium complex and a number of other mycobacteria is issued. Additional testing using the Gen-Probe technique is required if differentiation between M. avium and M. intracellulare is requested, as well as when confirmation is needed for some other species (e.g. M. kansasii or M. gordonae). Additional tests are also required for differentiation between M. tuberculosis and Mycobacterium bovis (niacin production, nitrate reduction, pyrazinamidase, susceptibility to thiopene-2-carboxylic acid hydrazide (TCH)). The final step is the nucleic acid sequencing test (using MicroSec 500 16S rDNA system), sometimes in combination with conventional tests, to evaluate the isolates not identified through the previous steps or to resolve contradictory data from other tests.
DRUG SUSCEPTIBILITY TESTING Determination of drug susceptibility of NTM as a guiding tool for selection of appropriate antimicrobial therapy has less in common with TB (with only few exceptions, such as M. kansasii) than it has with infections caused by other Gram-positive bacteria. The most common methods for drug susceptibility testing of M. tuberculosis clinical isolates are qualitative tests using ‘critical concentrations’ of the drugs in question, which are reported as ‘susceptible’ or ‘resistant’. This approach was based on the fact that initial pre-treatment M. tuberculosis isolates that have never been exposed to TB drugs (often called ‘wild strains’) are very uniform in the degree of susceptibility to these agents, and any detectable change (decrease) in susceptibility would reflect development of resistance. The situation with NTM is different. First of all, there is a range of susceptibility/resistance to drugs considered for therapy against most NTM. Because of this, unlike in the case of TB, selection of drugs is often based on the correlation between the attainable drug serum concentrations and the degree of susceptibility of the patient’s isolate expressed quantitatively as the minimal inhibitory concentration (MIC) of the drug, determined in an in vitro laboratory test. Such a correlation is called ‘dual individualization’ if it is based on the data of both pharmacokinetics and pharmacodynamics determined for an individual patient.57-60,67 The specific technique for MIC determination and choice of drugs included in the test depends on the species of NTM. There is no uniform consensus on the preferred method or selection of drugs included, and there is a variety of opinion on the clinical predictability of these tests. With M. avium complex infection, a multicentre study using standardized methodology made it possible to express the level of susceptibility/resistance of the isolate to any drug in a quantitative manner as a broth-determined MIC.60 Most of the M. avium clinical isolates (but not all) from newly diagnosed patients are susceptible to clarithromycin and azithromycin, and the MIC determination in this case has shown a very clear predictability value of drug susceptibility testing.59,61,62 The situation with other available drugs is different. The isolates have shown a very broad range of susceptibility/resistance patterns, and from 30% to 75% of the isolates, depending on the drug, were resistant even in the
7
most favourable in vitro conditions, with MICs exceeding any possibility of being achieved in blood and tissues. It seems illogical (and to some extent even damaging) to administer such a drug to the patient unless data from clinical trials support its use. On the other hand, only a fraction of isolates (from 20% to 40%) were susceptible to the drug concentrations attainable in vivo, and there is a likelihood that under these conditions a drug may work in the patient. At the same time, a substantial proportion of isolates were in the ‘grey zone’ with MICs at an intermediate level, when the drug susceptibility test results may not have any value in directing the selection of the drugs for therapy. This variability of the M. avium isolates, along with improper MIC determination methods, has led some authors to conclude that there is a lack of correlation between the test results and the outcome of therapy.1 Drug susceptibility testing is probably a more important element in the management of patients who have already received treatment. It is especially important in cases when there is a need to diminish the toxicity of the regimen by removing from it those drugs to which the patient’s isolate is highly resistant. Though of limited value, as compared with TB, drug susceptibility testing has been found to be useful in a number of studies.63–65 In one study, patients whose isolates were susceptible to rifampicin and ethambutol had better outcomes, although the authors did not fully recognize the value of drug susceptibility testing in their conclusions.66 Pulmonary disease caused by M. kansasii has many features in common with TB, including a drug susceptibility pattern of wild strains isolated from patients who have not been treated with antimicrobial agents. Accordingly, there are two options for drug susceptibility of M. kansasii isolates: one is similar to that for M. tuberculosis (qualitative test with critical concentrations, for example, using proportion method); the other is determination of MICs in liquid medium. Unlike M. tuberculosis, most of the M. kansasii isolates are resistant to para-aminosalicylic acid (PAS), capreomycin, low concentrations of isoniazid (0.1–0.2 mg) and, as with any other NTM, pyrazinamide. Some strains are also resistant to low concentrations of aminoglycosides.67 Some authors suggest that drug susceptibility of the M. kansasii isolates can be limited to a test with rifampicin as the most essential element in the treatment of this infection.68 An alternative and perhaps better approach would be to perform drug susceptibility testing for all drugs with potential use against this infection from the very beginning. Testing against rifampicin only or other selected drugs is not likely to be cost-effective compared with a battery of drugs when using the agar proportion method. Unlike the case with other NTM, there are no arguments against the usefulness of such testing for the rapid-growing mycobacteria, though the predictability value of laboratory data for infections caused by organisms is not any clearer than in cases of infections by slow-growing mycobacteria, due to the lack of data from controlled clinical trials. The susceptibility test is an MIC determination procedure with a series of concentrations of a number of drugs incorporated into a microtitre plate. Because the test is performed simultaneously with the species identification procedures, results are available within 4–5 days. For these two reasons, the test is performed with all drugs incorporated into the plate, regardless of the possible usefulness of some of the results for treatment regimen selection. Therefore, recommendations on selective drug testing depending on the species identification may not be practical.69 There are various microtitre plates commercially available and a specific set of drugs to be tested can be ordered to accommodate testing either mycobacteria only or also Nocardia and other aerobic Actinomycetes species. For isolates identified as rapid-growing mycobacteria,
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inclusion of the following 14 drugs is recommended: amikacin, kanamycin, tobramycin, imipenem, doxycycline, clarithromycin, azithromycin, trimethoprim/sulfamethoxazole, augmentin, cefoxitin, ciprofloxacin, gatifloxacin, moxifloxacin, linezolid.
TRANSMISSION AND PATHOGENESIS The source of NTM infection appears to be through environmental exposure and transmission from human to human has not been described. Genotyping methods have demonstrated similar patterns between isolates cultured from patients and their environments.70–72 In most cases, the source of infection has been water, although soil has also been implicated.71 Once the organism enters the body, there are three possible fates for the organism: 1. the host can clear the organism; 2. the organism can ‘colonize’ the airways; or 3. the organism can cause infection and disease. Which of these three pathways is followed is determined by an interplay between the host and organism. The importance of host immunity has been demonstrated in individuals and families with mutations in the IFN-g/IL-12 pathway genes.26,27,73 These defects have led to disseminated mycobacterial infections. In a study from Japan, 170 patients with M. avium complex (MAC) lung infection were studied and, out of 622 siblings of these patients, three had MAC lung disease also.74 The authors concluded that the rate of infection among the siblings was higher than previously estimated among the general population. In patients with HIV infection, disseminated NTM infections typically occur only after the CD4 lymphocyte count falls below 50 cells/mL, suggesting that specific T-cell products or activities are required for mycobacterial resistance.1 MAC presumably enters the body through ingestion of contaminated food or liquid. There is a striking association between bronchiectasis, nodular pulmonary NTM infections and a particular body habitus, predominantly in postmenopausal women.28 In the latter instance, it remains to be seen whether these women have some sort of subtle immune deficiency that predisposes them to NTM pulmonary infections or whether their predispostion is related to ineffective mucociliary clearance or poor tracheobronchial secretion drainage. Unlike with M. tuberculosis, the NTM do not appear to live in a state of dormancy. Moreover, simply isolating NTM from a respiratory specimen does not mean that the patient has NTM-related disease. For years the term ‘colonization’ has been used to differentiate those who have a single or small number of positive cultures over time from those in whom progressive disease cannot be demonstrated. For example, Ahn and colleagues75 described 497 patients with pulmonary MAC and 226 patients with M. kansasii. Twenty-four per cent of the patients converted cultures to negative within 4 months with bronchial hygiene alone, while 74% converted cultures to negative on chemotherapy, 27 within 1 week. The authors concluded that many of these patients were unlikely to have disease related to these infections. However, with longer follow-up many patients demonstrate clinical and/or radiographic progression of disease, so it may be more appropriate to think of these patients as having indolent infection. Two additional observations suggest that colonization is uncommon. First, Prince and colleagues76 described 21 patients with pulmonary MAC who had no underlying lung disease, most of whom had non-cavitary disease that was slowly progressive. Subsequently, Erasmus and colleagues77 reported the findings on computed
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tomography (CT), demonstrating multiple small nodules and associated cylindrical bronchiectasis in these patients. Taken together, these studies suggest that some patients thought to have been colonized did in fact have evidence of disease on CT scans and demonstrated slow clinical and radiographic progression. Puncture of the skin is the usual mechanism of entry for cutaneous infections due to NTM. For M. marinum, the source of infection is usually contaminated water in a swimming pool or home aquarium or through puncture of the skin from a fish. The mechanism of entry for M. ulcerans is not so clear. As noted previously, the organism has been isolated from the salivary glands of water insects but a history of insect bite at the site of infection is seldom revealing.12 Whether other environmental exposures are important is not known but environmental studies are underway to attempt to better describe the transmission of this important pathogen. Once the organism enters the skin, it produces a polyketide called mycolactone that caused tissue necrosis, a hallmark of Buruli ulcer.78
CLINICAL PRESENTATION AND DIAGNOSIS CLINICAL PRESENTATION The most common clinical manifestation of NTM infection is chronic lung disease.1 However, lymphatic, skin/soft tissue, bone/joint involvement as well as disseminated disease are also important manifestations of infection. The propensity of a specific manifestation varies with the specific species and certain host factors. For example, HIVinfected patients typically present with disseminated disease, whereas persons with cystic fibrosis and elderly white females present with pulmonary disease. The rapid growers, while a common cause of lung disease, have a propensity for producing skin and soft-tissue infections.
Pulmonary disease Chronic pulmonary disease is the most common clinical presentation of NTM disease and usually presents with chronic cough, fatigue, malaise, dyspnoea, fever, haemoptysis, chest pain and weight loss. Physical examination may identify in postmenopausal women, and occasionally men, certain morphological characteristics that include thin body habitus, scoliosis, pectus excavatum and mitral valve prolapse. The radiographic features in patients with MAC pulmonary disease are typically divided into primarily fibrocavitary disease and nodular bronchiectatic disease. In patients with fibrocavitary disease, the radiographic abnormalities consist of upper lobe opacities with evidence of cavitation and volume loss. Classically, this pattern of disease was recognized in older men with underlying lung disease although women can also present with upper lobe cavitary disease (Fig. 7.2). Patients with predominantly non-cavitary nodular bronchiectatic disease have opacities in the mid- and lower lung fields (Fig. 7.3A). High-resolution computed tomography (HRCT) scans demonstrate bronchiectasis often in the middle lobe and lingula with evidence of small nodules, centrilobular in location and often described as ‘tree-in-bud’ (Fig 7.3B). Patients with M. kansasii infection usually present with upper lobe cavitary opacities and the cavities are typically thin walled (Fig. 7.4). The chest radiograph in patients with rapid-growing mycobacterial infections usually shows multilobar, patchy, reticulonodular or mixed interstitial alveolar opacities with an upper lobe predominance (Fig. 7.5A). Cavitation is reported to occur in 15%. HRCT will show bronchiectasis and small nodules similar to that of MAC (Fig. 7.5B).
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Fig. 7.2 A 65-year-old man with M. avium complex pulmonary infection. (A) Chest radiograph demonstrates bilateral upper lobe opacities with areas of cavitation. In addition there are nodular opacities noted in the middle and lower lobes. (B) Chest computed tomography of the same patient demonstrating bilateral large upper lobe cavities with bronchiectasis.
Fig. 7.3 A 78-year-old woman with M. avium complex pulmonary infection. (A) Chest radiograph demonstrates kyphoscoliosis with nodular opacities primarily in the middle lobe, lingula and lower lobes. (B) Chest computed tomography of the same patient with evidence of pectus excavatum, right middle lobe and lingular bronchiectasis and multilobar centrilobular nodules. The arrows are pointing at tree-in-bud opacities.
Mycobacterium xenopi is second to MAC as a cause of pulmonary disease in Canada and parts of Europe. Typically, patients with disease due to M. xenopi present with underlying chronic obstructive pulmonary disease and the radiographic appearance is similar to that seen in upper lobe cavitary MAC disease.
Lymphadenitis The most common form of NTM disease in children is cervical lymphadenitis.1 Mycobacterium avium is the most common aetiology accounting for 80% of culture-proven cases. Mycobacterium scrofulaceum is the second most common cause in the USA and Australia,
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Fig. 7.4 A 45-year-old woman with M. kansasii pulmonary infection. (A) The chest radiograph demonstrates upper lobe thin-walled cavities, typical of M. kansasii infection. (B) Chest computed tomography of the same patient shows one of the thin-walled cavities with adjacent bronchiectasis.
Fig. 7.5 A 65-year-old woman with M. abscessus pulmonary infection. (A) Chest radiograph demonstrating bilateral lower lobe and right middle lobe nodular opacities and bronchiectasis. (B) Chest computed tomography of the same patient shows atelectasis and bronchiectasis of the right middle lobe with nodular opacities in the right and left lower lobes.
whereas M. malmoense and Mycobacterium haemophilum are more common in Scandinavia, the United Kingdom and other areas of northern Europe. Mycobacterium tuberculosis is isolated in only approximately 10% of culture-proven mycobacterial cervical lymphadenitis in the USA but in adults 90% are due to TB.1 Infection usually involves the submandibular, submaxillary, cervical and preauricular lymph nodes in children between 1 and 5 years of age. The disease occurs insidiously and is rarely associated with systemic symptoms. Involvement of the lymph nodes is
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usually unilateral and non-tender. The lymph nodes may enlarge and eventually rupture producing sinus tracts just like tuberculous lymphadenitis.
Soft-tissue, skin and bone infection Although virtually any NTM can cause skin, soft-tissue, and bony infection, the most common species to do so are the rapid growers, M. marinum and M. ulcerans.79,80 Rapid growers often produce infections at the site of punctures or surgery and present with tender
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subcutaneous nodules. Mycobacterium marinum causes ‘swimming pool granuloma’ and ‘fish tank granuloma’. The lesions usually appear as papules on an extremity and eventually progress to shallow ulceration and scar formation. In cases of swimming pool granuloma the site of infection is typically the elbow or knee,10 whereas in fish tank granuloma the site of infection is usually the hands. The median incubation time from skin puncture to clinically evident lesion is 21 days but ranges from 5 to 270 days.81 Although most lesions are solitary they may spread and produce arthritis and tenosynovitis, particularly of the hand and wrist. Mycobacterium ulcerans causes indolent progressive ulceration of the skin and underlying tissues, producing scalloped edges called Buruli ulcers.82 The infection often starts as a painless, mobile nodule and in 90% of cases the lesions are on the limbs, with nearly 60% of all lesions on the lower extremities.
Disseminated infections Disseminated infections are most commonly associated with HIV infection and other forms of severe immunosuppression. Over 90% of reported disseminated infection in HIV-infected patients are due to MAC and almost all of these are due to M. avium.1 The next most common cause of disseminated NTM disease in HIV patients is M. kansasii but a number of other species have also been implicated. Interestingly, M. intracellulare and the rapid growers are uncommon causes of disseminated disease in HIVinfected patients. Most patients present with advanced HIV disease and complain of fever, night sweats and weight loss. Abdominal pain and diarrhoea may also be reported. In HIV-uninfected patients, fever of unknown origin is a common presentation. INVESTIGATIONS Pulmonary disease Patients suspected of having a pulmonary NTM infection should be evaluated with a chest radiograph and/or HRCT, particularly when there is no evidence of cavitation on the radiograph. If there is evidence of radiographic abnormalities consistent with an NTM infection, at least three sputum specimens should be obtained for acid-fast bacilli (AFB) examination and mycobacterial culture. Tuberculosis as well as other disorders should be excluded. In order to diagnose pulmonary NTM infection the clinician must weigh clinical, bacteriological and radiographic information (Table 7.3).1 NTM pulmonary infections should be suspected when a patient presents with a compatible clinical picture and has nodular or cavitary opacities on the chest radiograph or an HRCT scan that shows multifocal bronchiectasis with multiple small nodules. In addition to these clinical criteria, the patient should have at least two positive cultures from separate sputum specimens or a positive culture from at least one bronchial wash or lavage. A previous study by Tsukumura83 demonstrated that 98% of patients with two or more positive sputum cultures progressed without treatment. Additional diagnostic criteria include transbronchial or other lung biopsy with mycobacterial histopathological features and positive culture for NTM or biopsy showing mycobacterial histopathological features and one or more sputum or bronchial washings that are culture positive. In patients who do not meet the above definition for disease, close follow-up should occur since many of the patients will demonstrate progression over time. Lymphadenitis Diagnosis is usually made by fine needle aspiration or surgical excision of the involved lymph nodes. Only 50–82% of excised nodes will be culture positive.1
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Table 7.3 Clinical and microbiological criteria for diagnosing non-tuberculous mycobacterial lung disease Clinical (both required) 1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a HRCT scan that shows multifocal bronchiectasis with multiple small nodules and 2. Appropriate exclusion for other diagnoses Microbiological 1. Positive culture results from at least two separate expectorated sputum samples. If results are non-diagnostic, consider repeat sputum AFB smears and cultures or 2. Positive culture result from at least one bronchial wash or lavage or 3. Transbronchial or other lung biopsy with mycobacterial histopathological features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathological features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings culture positive for NTM AFB, acid-fast bacilli. Adapter from Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367–416. Official Journal of the American Thoracic Society. (c) American Thoracic Society.
Soft tissue Tissue biopsies that are cultured and examined histopathologically are the most sensitive way to diagnose infections due to rapid growers and M. marinum. Unfortunately, visualization of mycobacteria in the specimen is seen in only about 10% of cases and the yield of culture is not known since most cases that have been reported were culture confirmed.11,84 Buruli ulcer is usually diagnosed based on clinical findings although laboratory tests can be used to confirm the diagnosis. Direct smear examination performed on swabs from ulcers or smears from tissue biopsies is of low sensitivity (40%) and the sensitivity of cultures ranges from 20% to 60% with an incubation time of 6–8 weeks.82 Identification of M. ulcerans can be performed directly from clinical specimens or from culture media and the sensitivity of a PCR test is around 98%.12 Disseminated disease Diagnosis is usually through detection of the causative organism in the blood. In HIV-infected patients M. avium has been isolated in over 90% of cases.1
TREATMENT GENERAL PRINCIPLES OF TREATMENT There are several notable differences regarding the treatment of TB and that of infections caused by NTM. First, when a patient grows M. tuberculosis, treatment is always indicated assuming that the isolate was not due to laboratory cross-contamination. However, with NTM, isolation should not always lead to treatment. The decision to treat is based on the potential risks and benefits for the individual patient. Second, unlike with M. tuberculosis, in vitro susceptibility results for many NTM do not correlate well with clinical response to antimicrobial therapy; thus clinicians should use such data with a
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Table 7.4 Doses of drugs used to treat non-tuberculous mycobacterial infections in adults
Box 7.1 Controversies and unresolved questions in the management of Mycobacterium avium complex lung disease
Drug
Daily dose (max)
Three times/ week dose (max)
Isoniazid
5 mg/kg/day (300 mg)
Rifampicin
10 mg/kg/day (600 mg)
Rifabutin
5 mg/kg/day (300 mg)
Ethambutol
15–20 mg/kg/day (1.6 g)
Azithromycin
250 mg/day
Clarithromycin Doxycycline Trimethoprimsulfmethoxazole Ciprofloxacin Moxifloxacin Tobramycin Streptomycin
500–1000 mg/day 100 mg/day (100 mg) 160 mg trimethoprim/800 mg sulfmethoxazole twice daily 500–750 mg twice daily 400 mg/day (400 mg) 4–7 mg/kg/day 10–15 mg/kg/day (1 g)
Amikacin/ kanamycin Cefoxitin
10–15 mg/kg/day (1 g)
Imipenem
100–200 mg/kg (12 g/day) in divided doses 500–1000 mg 2 or 3 times/day
15 mg/kg/day (900 g) 10 mg/kg/day (600 g) 5 mg/kg/day (300 mg) 20–35 mg/kg/ day (2.5 g) 500–600 mg/ day 1000 mg/day — — — — — 15–20 mg/kg (1.5 g) 15–20 mg/kg (1.5 g) — —
clear understanding of the limitations. Third, while most patients with TB can be treated with a single four-drug regimen, the many species of NTM dictate different drugs and regimens (Table 7.4). Fourth, NTM infections usually require a duration of therapy longer than that with TB, partly because of the lack of potent bactericidal drugs and high levels of in vitro resistance. And, finally, surgical resection/excision is used more frequently in the management of NTM infection than with TB. Nevertheless, NTM like TB should be treated with more than one antimycobacterial drug in order to prevent the emergence of resistance. The role of in vitro susceptibility testing for managing patients with NTM disease remains controversial. In vitro susceptibility results and clinical outcome do not always correlate and this is particularly true of infections due to MAC, M. xenopi and M. simiae.1 On the other hand, there appears to be better correlation with M. marinum, M. kansasii and the rapid growers. Clarithromycin testing is currently recommended for new, previously untreated MAC isolates, those who fail macrolide-based treatment regimens or prophylaxis regimens.1 Previously untreated M. kansasii isolates should be tested in vitro against rifampicin. Isolates resistant to rifampicin should also be tested against rifabutin, ethambutol, isoniazid, clarithromycin, fluoroquinolones, amikacin and sulphonamides.
TREATMENT OF PULMONARY INFECTIONS Mycobacterium avium complex (Box 7.1) Untreated M. avium pulmonary disease is quite variable in its progression. In some patients progression can be seen over a matter of months and in others it may take years to demonstrate progressive disease. Prior to the availability of the newer macrolides, the long-term
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Usefulness of in vitro drug susceptibility results in management of patients. Which is the most effective macrolide? Which is the most effective rifamycin? Does addition of an aminoglycoside improve patient outcomes? Would two-, three- or four-drug regimen be most effective? What is the appropriate duration of therapy? What is the role of fluoroquinolones and other drugs in the management of patients?
treatment outcomes for patients treated with anti-TB regimens was approximately 50%.1 Small, non-comparative studies of azithromycin- and clarithromycin-containing regimens have been associated with higher bacteriological response rates but long-term follow-up is often lacking. Treatment responses are also variable with cures rates ranging from 60% to 85%.85–91 Genotyping data suggest that reinfection is common in women with nodular bronchiectasis so a patient in whom cure is achieved may become infected again.92 The ATS currently recommends that the treatment regimen be based on the presence or absence of cavitary disease and whether the patient has been treated previously (Table 7.5).1 For patients with non-cavitary nodular bronchiectasis disease a three-times-a-week regimen should be considered. In a recently published study examining the efficacy of inhaled IFN-g therapy for severe or previously treated MAC disease, the bacteriological response to three-times-aweek therapy was poor overall.90 Factors associated with a good bacteriological response were having non-cavitary disease, being AFB smear negative, no previous treatment for MAC lung disease, older age and longer duration of ethambutol use. For patients with noncavitary disease, 71% demonstrated improvement in culture results compared with 20% in those with cavitary disease. Because this study was stopped owing to lack of efficacy of the interferon, no long-term follow-up was available. Three-times-a-week dosing may be associated with less optic neuritis related to ethambutol: 8 of 139 patients with daily ethambutol therapy developed optic neuritis compared with 0 of 90 on intermittent therapy.93 For patients with cavitary and/or advanced disease and in those who have been treated previously, daily therapy is recommended.1 An aminoglycoside should be considered in these patients, at least for the first 2–3 months of therapy, although a recent study suggested that there was no long-term benefit to this practice. In a small randomized study, patients with pulmonary MAC were randomized to receive a standard three-drug treatment regimen with or without streptomycin.91 Although patients who received the aminoglycoside were shown to have a higher rate of sputum conversion at the end of treatment than those who did not receive the injectable agent, the sputum relapse rate and clinical improvement were no different between groups. Surgery should be considered in patients who have an underlying macrolide-resistant strain of MAC, have failed treatment or have primarily focal cavitary disease. Surgery should be performed by a surgical team experienced in managing these difficult cases.94–98
Mycobacterium kansasii Untreated M. kansasii is usually progressive much like TB. However, with appropriate treatment almost all patients respond well and both treatment failure and relapse are uncommon. Among 180 patients in three studies, the 4-month culture conversion rates were 100% and there was only one long-term relapse.99–101
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Table 7.5 Treatment of pulmonary disease due to Mycobacterium avium complex infections Type of disease
Regimen
Comment
Nodular/ bronchiectatic disease
Clarithromycin 1000 mg tiw or azithromycin 500–600 mg tiw Ethambutol 25 mg/kg tiw
When choosing a macrolide, the clinician should weigh such issues as drug tolerance and drug interactions. Intermittent ethambutol may be associated with a lower incidence of optic neuritis than with daily therapy. Rifampicin is recommended over rifabutin in these patients because it is better tolerated than rifabutin. When choosing a macrolide, the clinician should weigh such issues as drug tolerance and drug interactions.
Rifampicin 600 mg tiw Cavitary disease
Advance or previously treated
Clarithromycin 500–1000 mg/day or azithromycin 250–300 mg/day Ethambutol 15 mg/kg daily Rifampicin 450–600 mg daily Streptomycin or amikacin 15 mg/kg tiw Clarithromycin 500–1000 mg/day or azithromycin 250–300 mg/day Ethambutol 15 mg/kg daily Rifabutin 150–300 mg daily or rifampicin 450–600 mg daily Streptomycin or amikacin 15 mg/kg tiw
Rifampicin is recommended over rifabutin in these patients because it is better tolerated than rifabutin. The clinician should consider using an aminoglycoside in these patients. When choosing a macrolide, the clinician should weigh such issues as drug tolerance and drug interactions. Given this more difficult to treat scenario some experts feel that rifabutin may be worth using in place of rifampicin. The clinician should strongly consider using an aminoglycoside in these patients.
tiw, three times a week. Adapted from Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367–416.
Patients with lung disease due to M. kansasii should be treated with isoniazid, rifampicin and ethambutol.1 However, based on in vitro activity, the newer macrolides could probably be substituted for isoniazid. In one study no relapses were seen after 46 months of follow-up in patients who received clarithromycin, rifampicin and ethambutol.102 As with other pulmonary NTM infections, the treatment duration should include 12 months of negative sputum cultures. For patients whose isolate is resistant to the rifamycins, a three-drug regimen is recommended based on in vitro susceptibility data to clarithromycin or azithromycin, moxifloxacin, ethambutol, sulfamethoxazole or streptomycin.1 Surgical resection is seldom necessary in patients infected with M. kansasii.
Mycobacterium xenopi The optimal treatment regimen and duration of therapy is not known. In vitro susceptibility results may be difficult to interpret because the response of the organism does not always correlate. Most patients are treated with a typical anti-MAC regimen that includes a newer macrolide, ethambutol and rifampicin.1 Responses may be enhanced by the addition of a fluoroquinolone. The mortality rate with M. xenopi infection has been reported to be as high as 57% but this probably reflects the severity of the underlying lung disease.66 Rapid-growing mycobacteria The clinical course of untreated M. abscessus is generally slow and progressive but more rapidly progressive presentations have been described, particularly in patients with CF or oesophageal disorders associated with aspiration. Treatment outcomes with M. abscessus are generally poor in part because the organism is resistant to almost all of the standard anti-TB drugs. In vitro susceptibility testing is recommended for selection of a treatment regimen.1 Unfortunately, M. abscessus is susceptible to only a few antimicrobials including the macrolides, imipenem, cefoxitin, amikacin, tigecycline, and occasionally linezolid. Moreover, no antibiotic regimen has demonstrated long-term sputum conversion in patients with pulmonary disease. Current recommendations are to provide periodic drug administration of multidrug therapy including a macrolide and one
or more parenteral agents such as amikacin, cefoxitin or imipenem for 4–6 months to help control symptoms and prevent progression.1 For patients who are good candidates, surgical resection should be considered but only if done by an experienced surgeon and after a period of intensive antimicrobial therapy. Mycobacterium chelonae is typically susceptible to tobramycin, macrolides, linezolid, imipenem and amikacin and may demonstrate susceptibility to fluoroquinolones and doxycycline.1 Isolates are usually resistant to cefoxitin. Treatment should consist of at least two drugs to which there has been demonstrated in vitro drug susceptibility. The duration should be for at least 12 months of culture negativity. Mycobacterium fortuitum isolates are typically susceptible to newer macrolides, fluoroquinolones, doxycycline, minocycline, sulphonamides, cefoxitin and imipenem.1 Therapy should be with at least two agents with in vitro activity for at least 12 months of culture negativity.
TREATMENT OF LYMPHADENITIS Cervical lymphadenitis is usually caused by MAC or M. scrofulaceum infection.1 Surgical excision of the involved lymph nodes without chemotherapy is usually curative with success rates of approximately 95%. In patients who fail surgical excision a macrolide-based treatment regimen with or without repeat excision is usually successful.
TREATMENT OF SKIN, SOFT-TISSUE AND BONE/JOINT INFECTIONS For most patients with MAC infection of the skin and soft tissues, a combination of surgical excision plus multidrug chemotherapy is successful. The optimal duration of therapy is not known but should probably be 6–12 months.1 For serious infections caused by rapidgrowing mycobacteria, a newer macrolide should be combined with a parenteral medication (amikacin, cefoxitin or imipenem) or perhaps another oral agent with M. fortuitum.1 Therapy should continue for a minimum of 4 months for skin infections and at least 6 months for bone infections. Surgery is generally indicated for extensive
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disease and removal of foreign objects such as breast implants, percutaneous catheters and joint prostheses is necessary. Mycobacterium marinum isolates are usually susceptible to rifampicin, rifabutin and ethambutol with intermediate susceptibility to streptomycin and resistant to isoniazid and pyrazinamide.1 Isolates are susceptible to clarithromycin, azithromycin, sulphonamides and susceptible or intermediately susceptible to doxycycline and minocycline. Although some experts believe that M. marinum infections can be treated with a single drug, two active drugs seems more reasonable. The current recommendation is to give two active drugs for 1–2 months beyond resolution of the lesion or typically 3–4 months.1 In a study from France, 42 (93%) of 63 patients with localized disease who were treated for 3.5 months with two drugs (usually rifampicin and clarithromycin) resolved.103 For those with more invasive disease 13 (72%) resolved. In general, outcomes of treatment with clarithromycin and ethambutol or clarithromycin and rifampicin have been excellent. Surgical debridement should be reserved for extensive disease or infection involving closed spaces of the hand. The World Health Oraganization recommends a combination of rifampicin and streptomycin/amikacin for 8 weeks as a first-line treatment for all forms of active disease due to M. ulcerans.104 Among 224 patients diagnosed with Buruli ulcer in Benin who were treated with this regimen, 96% were considered treatment successes: 102 (47%) were treated with antibiotics only and 113 (53%) with a combination of antibiotics and surgical debridement.105 Chemotherapy alone was particularly effective in those with ulcers of less than 5 cm in diameter.
TREATMENT OF DISSEMINATED INFECTIONS Treatment of disseminated MAC infection in HIV-infected patients should include clarithromycin 500 mg twice daily, ethambutol 15 mg/kg daily with or without rifabutin 300 mg daily.1 Azithromycin 500 mg daily could be used as an alternative to clarithromycin. Treatment should be considered lifelong unless immune restoration is achieved by antiretroviral therapy. MAC
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treatment can be stopped for patients who are asymptomatic and have achieved a CD4 lymphocyte count of over 100 cells/mL for at least 12 months.106 Prophylaxis should be reintroduced if the count falls below 100 cells/mL. The treatment for disseminated disease due to M. kansasii is the same as that for pulmonary disease. Unlike with MAC, there is no known prophylactic regimen.
PREVENTION OF NTM INFECTIONS Preventive therapy for disseminated MAC is recommended for HIVinfected patients with fewer than 50 CD4 lymphocytes/mL.106 Azithromycin given as 1200 mg once weekly is the preferred agent.107 Alternative regimens include clarithromycin 500 mg twice daily or rifabutin 300 mg daily. Primary prophylaxis should be discontinued when patients have responded to antiretroviral therapy with an increase in CD4 cell count to more than 100 cells/mL for more than 3 months.106,108 Prophylaxis should be reintroduced if the cell count falls to less than 50–100 cells/mL. NTM infections in healthcare settings have been associated with contamination of water sources, biologicals and multidose vials used in post-surgical infections.1 In these settings, specific steps can be taken to prevent the use of tap water for washing wounds or equipment and use of multidose vials should be avoided for injections. Prevention of community-acquired pulmonary infections remains elusive. The organisms have been isolated in tap water and water distribution systems and some NTM, such as M. xenopi, M. simiae and M. avium, survive well at water temperatures over 40 C.1 Moreover, these organisms are resistant to our typical decontamination methods. Therefore it is not clear how to best decrease our environmental exposure. One practical approach for avoiding potentially contaminated aerosols would be to avoid indoor hot tubs or even showers. However, because these potential sources have not been implicated in most NTM infections, it is difficult to predict whether this approach would decrease the risk of NTM infections.
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Other mycobacteria causing human disease 25. Corbett EL, Blumberg L, Churchyard GJ, et al. Nontuberculous mycobacteria: defining dissease in a prospective cohort of South African miners. Am J Respir Crit Care Med 1999;160:15–21. 26. Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 2002;20:581–620. 27. Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev 2000;11:321–333. 28. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis. Thoracic anomalies associated with pulmonary disease caused by Mycobacterium avium complex. Am Rev Respir Dis 1991;144:914–916. 29. Goodfellow M, Magee JG. Taxonomy of mycobacteria. In: Gangadharam PRJ, Jenkins PA (eds). Mycobacteria I—Basic Aspects. New York: Chapman and Hall, 1998: 1–71. 30. Goodfellow M, Wayne LG. Taxonomy and nomenclature. In: Ratledge C, Stanford J (eds). The Biology of the Mycobacteria. London: Academic Press, 1982: 471–521. 31. Tortoli E. Impact of genotypic studies on mycobacterial taxonomy: the new mycobacteria of the 1990’s. Clin Microbiol Rev 2003;16:319–354. 32. Sneath PHA. International Code of Nomenclature of Bacteria. Washington, DC: American Society for Microbiology, 1992. 33. Tortoli E. The new mycobacteria: an update. FEMS Immunol Med Microbiol 2006;48:159–178. 34. Heifets L. Mycobacterial infections caused by nontuberculous mycobacteria. Semin Respir Crit Care Med 2004;25:283–295. 35. Wallace RJ Jr, Cook JL, Glassroth J, et al. American Thoracic Society Statement: Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997;156:S1–S25. 36. Wolinsky E. Nontuberculous mycobacteria and associated diseases. Am Rev Respir Dis 1979; 110:107–159. 37. Heifets LB. Quantitative cultures and drug susceiptibility testing of M. avium clinical isolates before and during the antimicrobial therapy (review). Res Microbiol 1994;145:188–196. 38. Sanchez T, Vanderkolk J, Seay S, et al. Quantitation of mycobacteria in blood specimens from patients with AIDS. Tuberc Lung Dis 1994;75:386–390. 39. Kent PT, Kubica GP. A Guide for the Level III Laboratory. In: Public Health Mycobacteriology. Atlanta: US Department of Health and Human Services, 1985. 40. Heifets LB, Jenkins PA. Speciation of mycobacteria in clinical laboratories. In: Gangadharam PRJ, Jenkins PA (eds). Mycobacteria 1—Basic Aspects. Philadelphia: WB Saunders, 1998: 308–350. 41. Rogall T, Flohr T, Bottger EC. Differentiation of Mycobacterium species by direct sequencing of amplified DNA. J Gen Microbiol 1990;136: 1915–1920. 42. Butler WR, Jost KC, Kilburn JO. Identification of mycobacteria by high-performance liquid chromatography. J Clin Microbiol 1991;29: 2468–2472. 43. Kirschner P, Springer B, Vogel U, et al. Genotypic identification of mycobacteria by nucleic acid sequence determination report of a two year experience in a clinical laboratory. J Clin Microbiol 1993;31:2882–2889. 44. Thibert L, Lapierre S. Routine application of highperformance liquid chromatography for identification of mycobacteria. J Clin Microbiol 1993;31:1759–1763. 45. Glickman SE, Kilburn SO, Butler WR. Rapid identification of mycolic acid patterns of mycobacteria by high-performance liquid chromatography using pattern recognition software and a Mycobacterium library. J Clin Microbiol 1994;32:740–749. 46. Roberts GD, Bottger EC, Stockman L. Methods for the rapid identification of mycobacterial species. In: Heifets LB (ed.). Clinical Mycobacteriology. Philadelphia: WB Saunders; 1996:603–639. 47. El Amin NM, Hanson HS, Pettersson B, et al. 16S rRNA gene sequence analysis vs. conventional methods. Scand J Infect Dis 2000;32:47–50.
48. Butler WR, Guthertz LS. Mycolic acid analysis by high-performance liquid chromatography for identification of Mycobacterium species. Clin Microbiol Rev 2001;14:704–726. 49. Claud JL, Neal J, Rosenberry R, et al. Identification of Mycobacterium spp. by using a commercial 16S ribosomal DNA sequencing kit and additional sequencing libraries. J Clin Microbiol 2002;40:400–406. 50. Hall L, Doerr KA, Wohlfiel SL, et al. Evaluation of the MicroSeq system for identification of mycobacteria by 16S ribosomal DNA sequencing and its integration into a routine clinical mycobacteriology laboratory. J Clin Microbiol 2003;41:1447–1453. 51. Eisenach KD, Sifford MC, Cave MD, et al. Detection of Mycobacterium tuberculosis in sputum samples using polymerase chain reaction. Am Rev Respir Dis 1991;144:1160–1163. 52. Forbes BA, Hicks KES. Direct detection of Mycobacterium tuberculosis in respiratory specimens in a clinical laboratory by polymerase chain reaction. J Clin Microbiol 1993;31:1688–1694. 53. Pfyffer GE, Kissling P, Wirth R, et al. Direct detection of Mycobacterium tuberculosis complex in respiratory specimens by a target-amplified test system. J Clin Microbiol 1994;32:918–923. 54. Shinnick TM, Jonas V. Molecular approach to the diagnosis of tuberculosis. In: Bloom BR (ed.). Tuberculosis: Pathogenesis, Protection, and Control. Washington, DC: ASM Press, 1994:517–530. 55. Desmond E, Loretz K. Use of the Gen-Probe amplified Mycobacterium tuberculosis Direct Test for early detection of Mycobacterium tuberculosis in BACTEC 12B medium. J Clin Microbiol 2001; 39:1993–1995. 56. Jost KC Jr, Dunbar DF, Barth SS, et al. Identification of Mycobacterium tuberculosis and M. avium complex directly from smear-positive sputum specimens and Bactec 12B cultures by high-performance liquid chromatography with fluorescence detection and computer-driven pattern recognition models. J Clin Microbiol 1995;33:1270–1277. 57. Heifets LB, Iseman MD. Choice of antimicrobial agents for M. avium disease based on quantitative tests of drug susceptibility. N Engl J Med 1990;323:419. 58. Heifets LB, Iseman MD. Individualized therapy vs. standard regimens in the therapy of M. avium infections (editorial). Am Rev Respir Dis 1991;144:1–2. 59. Heifets L. Susceptibility testing of Mycobacterium avium complex isolates. Antimicrob Agents Chemother 1996;40(8):1759–1767. 60. Siddiqi SH, Heifets LB, Cynamon MH. Rapid broth macrifilution method for determination of MICs for M. avium isolates. J Clin Microbiol 1993;31:2332–2338. 61. Heifets L, Mar N, Vanderkolk J. Mycobacterium avium strains resistant to clarithromycin and azithromycin. Antimicrob Agents Chemother 1993;37:2364–2370. 62. Craft JC, Notario GF, Grosset JH, et al. Clarithromycin resistance and susceptibility pattern in M. avium strains isolated during prophylaxis of disseminated infection in patients with AIDS. Clin Infect Dis 1998;2:430–434. 63. Davidson PT, Khanijo V, Goble M, et al. Treatment of disease due to Mycobacterium intracellulare. Rev Infect Dis 1981;3:1052–1059. 64. Horsburgh CR Jr, Mason UG, Heifets LB III, et al. Response to therapy of pulmonary Mycobacterium avium-intracellulare infection correlates with results of in vitro susceptibility testing. Am Rev Respir Dis 1987;135:418–421. 65. Tsukamura M. Evience that antituberculosis drugs are really effective in the treatment of pulmonary infection caused by M. avium complex. Am Rev Respir Dis 1988;137:144–148. 66. Research Committee of the British Thoracic Society. First randomized trial of treatments for pulmonary disease caused by Mycobacterium avium intracellulare, Mycobacterium malmoense, and Mycobacterium xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol. Thorax 2001;56:167–172. 67. Heifets LB. Drug Susceptibility in the Chemotherapy of Mycobacterial Infections. Boca Raton: CRC Press, 1991. 68. Griffith DE. Management of disease due to M. kansasii. In: Catanzaro A, Daley CL (eds). Lung Disease due to Nontuberculous Mycobacterial Infections. Philadelphia: WB Saunders, 2003: 613–625.
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69. Woods GL, Brown-Elliot BA, Desmond PE. Susceptibility testing of Mycobacteria, Nocardiae, and other aerobic actinomycetes; approved standard. In: National Committee for Clinical Laboratory Standards; 2003. 70. Marras TK, Wallace RJ Jr, Koth LL, et al. Hypersensitivity pneumonitis reaction to Mycobacterium avium in household water. Chest 2005;127:664–671. 71. De Groote MA, Pace NR, Fulton K, et al. Relationships between Mycobacterium isolates from patients with pulmonary mycobacterial infection and potting soils. Appl Environ Microbiol 2006;72 (12):7602–7606. 72. Falkinham JO. Nontuberculous mycobacteria in the environment. Clin Chest Med 2002;23:529–551. 73. Dorman SE, Picard C, Lammas D, et al. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet 2004;364(9451): 2113–2121. 74. Tanaka E, Kimoto T, Matsumoto H, et al. Familial pulmonary Mycobacterium avium complex disease. Am J Respir Crit Care Med 2000;161:1643–1647. 75. Ahn CH, McLarty JW, Ahn SS, et al. Diagnostic criteria for pulmonary disease caused by Mycobacterium kansasii and Mycobacterium intracellulare. Am Rev Respir Dis 1982;125:388–391. 76. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions [see comments]. N Engl J Med 1989;321:863. 77. Erasmus JJ, McAdams HP, Farrell MA, et al. Pulmonary nontuberculous mycobacterial infection: radiologic manifestations. Radiographics 1999;19(6): 1487–1505. 78. van der Werf TS, Stinear T, Stienstra Y, et al. Mycolactones and Mycobacterium ulcerans disease. Lancet 2003;362(9389):1062–1064. 79. Liao CH, Lai CC, Ding LW, et al. Skin and soft tissue infection caused by non-tuberculous mycobacteria. Int J Tuberc Lung Dis 2007;11(1):96–102. 80. Bartralot R, Garcia-Patos V, Sitjas D, et al. Clinical patterns of cutaneous nontuberculous mycobacterial infections. Br J Dermatol 2005;152(4):727–734. 81. Jernigan JA, Farr BM. Incubation period and sources of exposure for cutaneous Mycobacterium marinum infection: case report and review of the literature. Clin Infect Dis 2000;31(2):439–443. 82. Portaels F, Johnson P, Meyers WM. Buruli Ulcer. Diagnosis of Mycobacterium ulcerans Disease. Geneva: World Health Organization, 2001. 83. Tsukamura M. Diagnosis of disease caused by Mycobacterium avium complex. Chest 1991;99(3): 667–669. 84. Blackwell V. Mycobacterium marinum infections. Curr Opin Infect Dis 1999;12(3):181–184. 85. Wallace RJ Jr, Brown BA, Griffith DE, et al. Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50 patients. Am J Respir Crit Care Med 1996;153:1766–1772. 86. Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 2001;32:1547–1553. 87. Tanaka E, Kimoto T, Tsuyuguchi K, et al. Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med 1999;160:866–872. 88. Kobashi Y, Matsushima T. The effect of combined therapy according to the guidelines for the treatment of Mycobacterium avium complex pulmonary disease. Intern Med 2003;42(8):670–675. 89. Griffith DE, Brown BA, Cegielski P, et al. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis 2000;302:288–292. 90. Lam PK, Griffith DE, Aksamit TR, et al. Factors related to response to intermittent treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006;173(11):1283–1289. 91. Kobashi Y, Matsushima T, Oka M. A double-blind randomized study of aminoglycoside infusion with
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combined therapy for pulmonary Mycobacterium avium complex disease. Respir Med 2007;101(1):130–138. Wallace RJ Jr, Zhang Y, Brown-Elliot BA, et al. Repeat positive cultures in Mycobacterium intracellulare lung disease after macrolide therapy represent new infections in patients with nodular bronchiectasis. J Infect Dis 2002;186:266–273. Griffith DE, Brown-Elliott BA, Shepherd S, et al. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2005;172(2):250–253. Nelson KG, Griffith DE, Brown BA, et al. Results of operation in Mycobacterium avium-intracellulare lung disease. Ann Thorac Surg 1998;66:325–330. Pomerantz ML, Madsen L, Goble M, et al. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 1991;52:1108–1112. Shiraishi Y, Nakajima Y, Takasuna K, et al. Surgery for Mycobacterium avium complex lung disease in the clarithromycin era. Eur J Cardiothoracic Surg 2002; 21:314–318. Shiraishi Y, Fukushima K, Komatsu H, et al. Early pulmonary resection for localized Mycobacterium avium complex disease. Ann Thorac Surg 1998;66:183–186.
98. Pomerantz ML, Denton JR, Huitt GA, et al. Resection of the right middle lobe and lingula for mycobacterial infection. Ann Thorac Surg 1996; 62:990–993. 99. Pezzia W, Raleigh JW, Bailey MC, et al. Treatment of pulmonary disease due to Mycobacterium kansasii: recent experience with rifampin. Rev Infect Dis 1981; 3:1035–1039. 100. Ahn CH, Lowell JR, Ahn SA, et al. Chemotherapy for pulmonary disease due to Mycobacterium kansasii: efficacies of some individual drugs. Rev Infect Dis 1981;3:1028–1034. 101. Ahn CH, Lowell JR, Ahn SS, et al. Short-course chemotherapy for pulmonary disease caused by Mycobacterium kansasii. Am Rev Respir Dis 1983; 128:1048–1050. 102. Griffith DE, Brown-Elliot BA, Wallace RJ Jr. Thrice-weekly clarithromycin-containing regimen for treatment of Mycobacterium kansasii lung disease: results of a preliminary study. Clin Infect Dis 2003;37:1178–1182. 103. Aubry A, Chosidow O, Caumes E, et al. Sixty-three cases of Mycobacterium marinum infection: clinical features, treatment, and antibiotic susceptibility of causative isolates. Arch Intern Med 2002;162(15): 1746–1752.
104. World Health Organization. Provisional Guidance on the Role of Specific Antibiotics in the Management of Mycobacterium ulcerans Disease. Geneva: World Health Organization, 2004. 105. Chauty A, Ardant MF, Adeye A, et al. Promising clinical efficacy of the combination streptomycin— rifampin for the treatment of Buruli ulcer (Mycobacterium ulcerans disease). Antimicrob Agents Chemother 2007;51(11):4029–4035. 106. Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIVinfected persons. MMWR Morb Mortal Wkly Rep 2002;RR-8:1–52. 107. Oldfield EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebocontrolled multicenter trial. Clin Infect Dis 1998;26:611–619. 108. El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med 2000;342:1085–1092.
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The basic immunology of tuberculosis Brian S Eley and David W Beatty
INTRODUCTION The term Mycobacterium tuberculosis is used throughout this chapter to describe the M. tuberculosis complex group of organisms (M. tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti) as well as M. tuberculosis sensu stricto. Interaction between M. tuberculosis and host macrophages leads to the establishment of infection. This initial encounter typically occurs in the terminal respiratory structures such as the distal alveoli or alveolar sacs, following the inhalation of pathogenic organisms primarily contained in infected airborne droplets. After phagocytosis by macrophages and the initial innate immune responses, which include macrophage and dendritic cell activation, antigen processing and presentation, cell-surface expression of co-stimulatory molecules, cytokine and chemokine elaboration, and lymph node targeting, M. tuberculosisspecific adaptive cell-mediated immunity develops. The combined innate and adaptive immune responses enhance killing by macrophages and is usually successful in containing but not completely eliminating the pathogen. Containment or clinical latency and mycobacterial latency usually extend over the lifespan of the individual. The initial encounter with the innate immune system, directed primarily by macrophages and dendritic cells, may theoretically lead to immediate mycobacterial elimination, aborting the development of specific T-cell immunity. This is, however, not considered the usual path of infection. Instead the development of a primary TB complex at the initial site of infection and in the associated regional lymph nodes, during which specific immunity is optimized, precedes the containment of infection. Approximately 10% of infected individuals will progress to active TB over their lifespan but in those infected with human immunodeficiency virus (HIV) the risk for active TB disease, either localized or disseminated, rises to approximately 8–10% per annum. The risk of children progressing to active pulmonary and disseminated disease is much higher than that in adults. Children under the age of 1 year are at a much higher risk for disseminated disease. The elderly are also more susceptible to TB (Fig. 8.1). Following containment of infection, reactivation of disease may occur in settings in which M. tuberculosis-specific immunity is undermined. In high TB-endemic communities or geographical regions reinfection with a new M. tuberculosis strain may lead to the establishment or re-establishment of disease in individuals with compromised immunity.1 In this chapter we describe the key immunological responses to M. tuberculosis that help to clarify this pathogenesis framework.
PROTECTIVE IMMUNITY Development of protective immunity following infection by M. tuberculosis depends on the interaction between innate and adaptive immunity (Box 8.1). Innate immunity (or natural immunity), induced independently of prior contact with M. tuberculosis, is mediated mainly by macrophages and dendritic cells. Recent studies have shown that the innate immune system has a greater degree of specificity than previously appreciated. This system is governed by the interaction between pathogen-associated molecular patterns (PAMPs) and specific pattern recognition receptors (PRRs), which are expressed on macrophages and dendritic cells. Activation of innate immunity is a prerequisite for the induction of adaptive immunity.2 In contrast, adaptive immunity (known as specific immunity) develops after exposure to M. tuberculosis-specific antigens that have been processed by, and presented on, antigen-presenting cells, usually in association with major histocompatibility complex (MHC) class I and II or CD1 molecules and co-stimulatory molecules together with soluble cytokine signals. Adaptive immune responses are directed by antigen-specific T-cell subsets, notably in order of decreasing importance CD4þ ab T-lymphocytes, CD8þ ab T-lymphocytes, gd T-lymphocytes, and CD1-restricted ab T-lymphocytes.3 Granuloma formation and function, determined by the interplay between innate and cellular adaptive immunity, is central to the containment of infection and induction of mycobacterial latency. Granuloma formation is the most important immunopathological response following infection by M. tuberculosis. Natural killer (NK) cells and neutrophils are recruited and contribute to granuloma function.4 Although the role of humoral-mediated adaptive immunity in M. tuberculosis infection remains uncertain, there is sufficient experimental evidence to indicate that antibody-mediated immune reactions may modify the course of infection.5
PHAGOCYTOSIS BY MACROPHAGES Internalization of M. tuberculosis by macrophages is an important initial step in the establishment of infection. Phagocytosis is mediated via several receptors on the surface of the macrophages which bind either opsonized or non-opsonized organisms (Box 8.2).6 A classic example of uptake of opsonized bacteria involves complement receptors of which type 1 (CR1) binds to the complement components C3b and C4b but not C3bi, whereas types 3 and 4 (CR3 and CR4) bind C3bi. Mycobacterium tuberculosis
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Inhalation of M TB Primary complex (PPD+)
Immediate killing of M TB(PPD)
Localized disease (Primary TB)
Dissemination of M TB Acute disease (TBM, miliary TB) Containment (latency)
Reactivation or reinfection
Fig. 8.1 Key pathogenic steps following M. tuberculosis inhalation.
Box 8.1 Major components of protective immunity
Innate responses including antigen processing are directed by macrophages, dendritic cells, and NK cells. Adaptive immunity is directed by CD4þ, CD8þ, gd, and CD1-restricted T-lymphocytes. Microbial containment and elimination is determined by cooperation between innate and adaptive immunity. Granuloma function is pivotal for microbial containment.
Box 8.2 Macrophage receptors that promote the uptake of Mycobacterium tuberculosis
Complement receptors: CR3, CR4, CR1. Mannose receptors. Scavenger receptors. Surfactant protein A receptors. Fcg receptors.
is able to non-specifically and directly activate the alternative complement pathway leading to the generation of C3b and C3bi. Once bacteria are sufficiently coated with either or these molecules phagocytosis can proceed through CR1, CR3, and CR4 on macrophages. Mycobacteria may also recruit C2b directly to form a C3 convertase and generate C3b in the absence of early activation of the complement pathway, leading to predominately CR1-mediated uptake. Mycobacteria are able to bind directly or non-opsonically to CR3.7 This complement pathway-independent binding is achieved by direct interaction between the bacterial oligosaccharide lipoarabinomannan (LAM) or cell wall antigen 85C and specific CR3 domains. CR3 may also recognize LAM after forming a trimolecular complex with CD14 and Toll-like receptor 4. There is also evidence supporting non-opsonic uptake via CR4. CR3 is considered the major complement receptor involved in phagocytosis of mycobacteria. Using CR3-deficient macrophages derived from knockout
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mice, it has been established that CR3 mediates about 50% of non-opsonic binding and 60% of opsonized binding.8 A widely expressed receptor on the surface of the macrophage is the mannose receptor, which mediates non-opsonized phagocytosis. Entry of mycobacteria into the macrophage is mediated by direct interaction with mannosyl residues on LAM, other mannose-containing glycoconjugates, or adhesins including the 19-KkDa antigen of M. tuberculosis.9 Interferon-g (IFN-g) is able to down regulate the expression of macrophage-expressed mannose receptors. It is possible that these receptors play an important phagocytic role during early infection before granuloma formation has occurred. Several other surface-expressed receptors promote the phagocytosis of mycobacteria including scavenger receptors which bind polyanionic surface molecules, surfactant protein A receptors that facilitate phagocytosis of organisms opsonized with surfactant A or mannose-binding protein, and CD14 and Fcg receptors.7,9 Following receptor binding, cytoskeletal activation precipitates internalization and subsequent events including phagosome–lysosome fusion, antigen processing and presentation, cytokine upregulation, and intracellular killing via several mechanisms. Macrophages may also function as vectors for translocating mycobacteria across pulmonary epithelial barriers. There is some evidence that the nature of the receptor interaction influences subsequent immunological events.6
DENDRITIC CELLS Dendritic cells (DCs) are a system of cells that have the specialized function of presenting antigens to T-lymphocytes and are considered the most important antigen-presenting cell population. They are located throughout the body in mucosal tissues and are regarded as important immunological sensors. They detect pathogens, internalize and process pathogen antigens, and relay the information to lymphocytes, thereby inducing specific adaptive immune responses. The early interaction between DCs and M. tuberculosis occurs in the respiratory mucosa. Dendritic cells are able to internalize pathogens by several routes including endocytosis, phagocytosis, and macropinocytosis. Two specific surface-expressed receptors play a role in phagocytosis of M. tuberculosis – DC-specific intracellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), a C-type lectin, and the mannose receptor. Experimental evidence has shown that DC-SIGN is the major DC receptor for M. tuberculosis. The mannose receptor plays a minor role. DC-SIGN binds strongly to the mannose-capped cell wall component ManLAM of M. tuberculosis.10 Once phagocytosed, antigen processing and presentation proceeds, and the DCs undergo maturation, resulting in the expression of high levels of MHC molecules and the upregulation of co-stimulatory molecules such as CD80 and CD86, which are subsequently expressed on the surface of DCs. Activated DCs acquire migratory capacities, allowing them to exit the respiratory mucosa and enter regional lymph nodes where they can present antigens to naı¨ve T-lymphocytes. Dendritic cells are thus able to modulate the immune response through antigen presentation with consequent T-lymphocyte activation, as well as through cytokine elaboration resulting in the polarization of T-lymphocytes towards either Th1 or Th2 phenotypes. During the course of TB T-lymphocytes are predominantly directed towards a Th1 response. Therefore DCs link the innate and adaptive immune responses to infection by M. tuberculosis.11
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The basic immunology of tuberculosis
THE ROLE OF TOLL-LIKE RECEPTORS Toll-like receptors (TLRs) are an important family of specific PRRs, which serve to link microbial recognition to the activation of antigen-presenting cells (macrophages and dendritic cells) involved in T-lymphocyte activation and induction of adaptive immunity. They are a structurally conserved family of transmembrane glycoproteins which are homologous with the Toll proteins of fruit flies (Drosophila) in which they are essential for establishing dorsoventral polarity during embryogenesis and for innate immune responses against fungal infection. To date at least 13 mammalian TLRs have been identified, and the first to be characterized, TLR4, was cloned in 1997.12 In humans, signalling through the TLRs is important in inducing dendritic cell and macrophage activation and function, and facilitating adaptive immunity. The innate immune system uses a set of PRRs to identify conserved PAMPs on molecules such as lipopolysaccharide (LPS), peptidoglycan, mannan, hypomethylated CpG DNA motifs, and double-strand RNA. These molecular signatures, although present in a wide range of pathogens, are rarely found in the host, permitting discrimination between foreign pathogens and ‘self’ molecular signatures. Ligation of PRRs by microbial products leads to the activation of signalling cascades critical for the induction of an immune response to a specific microbial challenge.2,13 Signalling through TLRs induces maturation of DCs. Mature DCs up regulate surface expression of MHC class II and co-stimulatory molecules, elaborate cytokines, and migrate to peripheral lymph nodes where they induce the maturation of antigen-specific naı¨ve T-lymphocytes. Although components of the various TLR signalling pathways are shared, there are considerable differences. The extracellular domains of TLRs are important for pathogen recognition: they contain between 24 and 29 leucine-rich repeat sequences and form horseshoe-shaped structures which are involved with pathogen recognition. Leucine-rich repeat domains of different TLRs recognize structurally unrelated ligands. The cytoplasmic domains of all TLRs are homologous with the signalling domain of the interleukin (IL)-1 receptor and is currently referred to as the Toll/IL-1 receptor (TIR) domain. After ligand binding, TLRs form dimers and undergo conformational change, which permits the interaction of the cytoplasmic TIR domain with downstream adaptor molecules, myeloid differential primary-response protein 88 (My D88), TIR-domain-containing adaptor protein (TIRAP), TIR-domaincontaining adaptor protein inducing interferon (IFN)-b (TRIF), and TRIF-related adaptor molecule (TRAM). These adaptor proteins initiate complex molecular cascades leading to the activation of NF-kB and/or IFN-regulatory factor-3 transcription factors. These transcription factors translocate from the cytoplasm to the nucleus where they induce gene upregulation leading to DC maturation and cytokine elaboration (Fig. 8.2).2,14 Several M. tuberculosis-specific ligand–receptor interactions have been identified. The 19-kDa lipoprotein induces activation of TLR2. A soluble fraction of M. tuberculosis which contains mannosylated phosphatidylinositol (PIM) activates macrophages and DCs via TLR2 and TLR6. Viable and killed mycobacteria may signal via TLR2 and TLR4. Proinflammatory signals are up regulated by TLR2 and TLR4 after being bound to heat shock protein (HSP) 65 and HSP70, respectively. Furthermore, other TLRs may be involved in the regulation of the immune response to infection by M. tuberculosis. There is, for example, evidence to suggest that mannose-capped lipoarabinomannan
Transmembrane toll-like receptor
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M. tuberculosis ligand Plasma membrane Cytosol
My D88-independent signalling
My D88-dependent signalling
IRF-3 activation
NF-KB activation
Upregulation of gene expression
Effector functions
Fig. 8.2 Schematic representation of Toll-like receptor signalling pathways.
signals through a TLR other than TLR2 or TLR4. Signalling utilizes both My D88-dependent and -independent pathways. Although details of the specific TLR pathways activated by M. tuberculosis and its components are still being elucidated and remain the subject of contention, many immune functions have been identified. These include maturation of DCs, proinflammatory cytokine elaboration, maturation of Th1-biased T-lymphocytes, upregulation of macrophage phagocytosis, macrophage apoptosis, and induction of inducible nitric oxide synthetase (iNOS), resulting in the production of NO, a molecule with direct antimicrobial activity (Fig. 8.2).15
PHAGOSOMAL MATURATION AND ANTIGEN PROCESSING Receptor engagement leads to the internalization of microbes or pathogen-derived soluble proteins by macrophages and DCs. Following the degradation of the internalized material, a wide range of processed M. tuberculosis-derived antigens are presented to T-lymphocytes through several antigen-presenting molecules, notably MHC class I, MHC class II, or CD1 molecules. Dendritic cells and macrophages are mainly responsible for proteolytic processing and antigen presentation (Table 8.1).16,17 A phagosome is a vesicle that forms by invagination of the plasma membrane with its associated lipids and proteins during phagocytosis of microbes or microbial proteins. Antigen processing occurs after internalized phagosomes mature within macrophages and DCs (Fig. 8.3), a process involving a complex series of sequential fusion interactions with components of the endocytic pathway. These interactions cause major changes to the composition and function of the original phagosome. Progressive transfer of endosomal or lysosomal membrane and luminal constituents to phagosomes occurs during these fusion events. The endocytic pathway is organized as a continuum of organelles, progressing from early endosomes through late endosomes to lysosomes. Phagosomal maturation is a rapid process, which requires Ca2þ ions to activate calmodulin and the calmodulin-dependent protein kinase, CaMKII. Calcium is
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Table 8.1 The antigen-presenting functions of MHC class and CD1 molecules MHC class I
MHC class II
CD1a, CD1b, CD1c (group 1 molecules)
CD1d (group 2 molecule)
Genomic locus
MHC locus (chromosome 6)
MHC locus (chromosome 6)
CD1 locus (chromosome 1)
CD1 locus (chromosome 1)
Antigens presented
Endogenous/ exogenous peptides
Exogenous peptides
Endogenous/exogenous glycolipids
Endogenous/exogenous glycolipids
T-lymphocyte subsets primed
CD8þ TCRab
CD4þ TCRab
CD4–CD8– TCRab, CD4þ TCRab, CD8þ TCRab, TCRgd
CD4–CD8– TCRab, diverse TCRab, TCRa NK cells
Major T-lymphocyte functions
Cytotoxicity
Th1/Th2 cytokine productions
Th1/cytotoxicity
Th0/cytotoxicity?
Adapted from Gumperz and Brenner.27
Plasma membrane
Rab 5
Microbial contents
Rab 5
Early endosome
Endoplasmic reticulum pH: ~6.0
Early phagosome Rab 7
Rab 5
Late endosome pH: 5.5 6.0
Late phagosome
Lysosome pH: 4.5 5.5
Phagolysosome
Fig. 8.3 Simplified representation of Export of peptideMHC I complexes to the plasma membrane after cross-presentation
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Export of peptideMHC II complexes to plasma membrane surface
phagolysosome formation (adapted from Koul A, Herget T, Klebl B, et al. Interplay between mycobacteria and host signaling pathways. Nat Rev Microbiol 2004;2:189–202.)
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derived from endoplasmic reticulum stores and via open plasmalemmal channels. Phagosomal maturation also involves the acquisition of vacuolar-proton ATPase (V-ATPase), which catalyses the progressive acidification of phagosomes during maturation.18–20 Rab proteins are small GTPases or GTP-binding proteins that control the integrity of intracellular organelles, direct membrane trafficking and protein sorting, and play an important role in the maturation of the phagosome. The newly formed phagosomes acquire Rab5 either from the surrounding plasma membrane or by fusion with early endosomes. Rab5 controls the fusion of phagosomes with the early or sorting endosomes, where the phagocytosed material and receptors are sorted for degradation and/or recycling. Rab5 together with activated CaMKII recruits phosphatidylinositol-3-kinase (PI3K) to the early endosome, where it generates phosphatylinositol3-phosphate (PI3P) which then initiates the recruitment of early endosomal autoantigen 1 (EEA1) from endosomes. EEA1 is regarded as a ‘Rab5 effector’ that triggers the fusion of phagosomes with late endosomes, thereby facilitating Rab conversion, i.e. rapid acquisition of Rab7 and Rab9 from late endosomes with the simultaneous loss of Rab5.18,19 Rab7 is important in the regulation of late endosomal trafficking. It regulates the transition from early to late endosomes and controls the fusion of late phagosomes with lysosomes to form phagolysosomes. Phagolysosomes possess several degradative properties due to a low pH, between 4.5 and 5.5, generated by the vacuolar ATPase, hydrolytic enzymes such as cathepsin D, defensins, other bactericidal peptides, and the ability to generate oxidative compounds. Once phagolysosomes form, degradation of the internalized material by the hydrolytic enzymes can proceed. The processed antigens can be cycled to the cell surface bound to MHC class II molecules for antigen presentation as described below.19 Although TLRs are not involved in the uptake and internalization of microbes, they play a role in regulating phagosomal maturation and antigen processing. During phagocytosis, surfaceexpressed TLRs including TLR2 and TLR4 are recruited to the phagosome and become activated by microbial constituents. Phagosome maturation may then be influenced through My D88 and mitogen-associated protein kinase (MAPK) p38 activation. Although the detailed molecular mechanisms of TLR regulation are currently unknown, possible functions of MAPK p38 include the assembly of V-ATPase and regulation of Rab5 function. Furthermore, TLRs may be responsible for increasing the rate of movement of phagosomes along the endocytic pathway. Other receptor–microbe interactions may be involved in phagosome maturation.20,21
ANTIGEN PRESENTATION MHC CLASS II PRESENTATION A wide repertoire of clones of M. tuberculosis-specific CD4þ Tlymphocytes that play a dominant role in the protective immune response against TB has been identified. The maturation of these clones is induced by a broad spectrum of processed mycobacterial antigens. Many immunodominant antigens including ESAT-6, CFP-10, the 19- and 38-kDa lipoproteins, and several mycolyl transferases have been identified. CD4þ T-lymphocytes recognize epitope configurations on processed mycobacterial peptide fragments when presented by MHC class II molecules in association
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with co-stimulatory molecules. In this way exogenously derived antigens internalized through the endocytic pathway are presented by MHC class II molecules. Signalling through TLRs plays a role in improving the efficiency with which phagolysosomes execute their antigen-presenting function. The environment of the phagolysosome is important for antigen processing as well as for the modification of the MHC class II-associated invariant chain.16,22 Newly synthesized a- and b-chains of MHC class II molecules form a complex with an invariant chain in the endoplasmic reticulum. The cytoplasmic domain of the invariant chain contains a targeting signal that directs the MHC class II complexes to the endocytic pathway. These complexes enter the endocytic pathway and, within the hydrolytic environment of the late phagosomes and phagolysosomes, the invariant chain is proteolytically degraded so that an N-terminal fragment, the MHC class II-associated invariant chain derived peptide (CLIP), remains. This fragment occupies the peptide groove of MHC class II molecules. Within phagolysosomes, CLIP is exchanged for processed antigenic peptides. This pivotal antigenprocessing step is catalysed by the MHC-encoded molecules, HLA-H2-DM and HLA-DO. Toll-like receptors trigger the processing of the invariant chain after interaction with microbial constituents within phagolysosomes. The exact mechanisms by which this occurs have, however, yet to be defined. Once peptide–MHC class II complexes have formed, they are transported to the plasma membrane and presented to CD4þ T-lymphocytes in association with TLR-induced co-stimulatory molecules.20,23 During antigen presentation, signalling through the CD4þ cell receptor is necessary for the consequent maturation and activation of naı¨ve CD4þ T-lymphocytes. Mice with genes deleted for either the CD4 receptor or MHC class II molecules are extremely susceptible to disease after infection by M. tuberculosis, affirming the importance of CD4þ T-lymphocytes in protection. Cytokines such as IFN-g regulate cell-surface expression of MHC and co-stimulatory molecules, thereby influencing antigen presentation (Table 8.1).
MHC CLASS I ANTIGEN PRESENTATION MHC class I processing and the consequent induction of CD8þ T-lymphocyte-specific responses was first recognized in viral infections. In this setting newly synthesized viral proteins undergo posttranslational modification within the endoplasmic reticulum before being exported to the cytosol where they may be processed by proteosomes, resulting in the generation of antigenic peptides. Antigenic peptides are then transported back to the endoplasmic reticulum and undergo further trimming before associating with MHC class I molecules to form complexes. MHC class I complexes, formed in the endoplasmic reticulum, consist of a heavy chain and a light chain (or b2-microglobulin) together with peptide bound to the antigen groove of the MHC class I molecule. MHC class I complexes are exported to the plasma membrane surface via the Golgi apparatus where they are able to prime CD8þ T-lymphocytes.24 Specific CD8þ T-lymphocytes recognize mycobacterial peptides in association with MHC class I molecules. Mycobacteria located within macrophages are confined to the phagosomal compartment and their antigens are separated from the classical MHC class I presentation pathway. However, Mycobacterium tuberculosis antigens do gain access to the MHC class I presentation pathway although until recently the routes of entry have been difficult to define.25
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Box 8.3 The pathways by which segregated antigens gain access to the MHC class I processing and presentation
Cross-presentation: There is evidence that the endoplasmic reticulum membrane and its constituents, including the machinery for MHC class I presentation, are recruited to the early phagosome. The endoplamic reticulum-derived protein sec 61 allows bacterial proteins to shuttle from the phagosome to the cytosol for processing by proteasomes. Thereafter processed antigens are transported back to the phagosome where they are assembled on MHC class I molecules before being transported to the plasma membrane via the Golgi apparatus (Fig. 8.3). Cross-priming: Although M. tuberculosis located within the phagosome is relatively segregated from the cytosol, it is, by inducing apoptosis of the macrophage, able to release antigen-containing blebs into the microevironment. These antigens are then endocytosed by non-infected DCs, enter the phagosomal compartment, and are subsequently directed to the MHC class I presentation pathway for processing and presentation via the lysosome-to-cytosol pathway, which is present in DCs but not macrophages. Antigens may escape from phagosomes within macrophages, enter the cytosol, and be processed in a proteosome-dependent manner, gaining access to the classical MHC class I pathway (Table 8.1).25,26
The pathways by which segregated antigens gain access to the MHC class I processing and presentation are shown in Box 8.3.
MACROPHAGE AND DENDRITIC CELL CYTOKINE PRODUCTION The cytokine network and its interactions are complex in the setting of infection by M. tuberculosis. Conventional understanding supports a pivotal role for cytokines in the overall immune response to TB. Although cytokines are produced by a wide variety of cells, primed lymphocytes are the major producers, particularly two sub populations of CD4þ T-lymphocytes – the T-helper type 1 (Th1) cells that produce IL-2, IFN-g, lymphotoxin-a, and other proinflammatory cytokines, and the T-helper type 2 (Th2) cells that produce IL-4, IL-5, IL-10, IL-13, and other anti-inflammatory cytokines. During TB CD4þ T-lymphocyte production is biased towards a Th1, or proinflammatory, response that supports the killing of intracellular pathogens.30 There is, however, evidence to suggest that strains or genotypes of M. tuberculosis vary in the profile of cytokines that they induce and that the ability to control infection may be due in part to the induced profile.31 Cytokines produced by the major antigen-presenting cells (APCs), the macrophages and dendritic cells, have important regulatory functions during infection by M. tuberculosis. They help regulate the overall immune response, initiate APC activation, direct the CD4þ T-lymphocytes towards a Th1 profile, activate NK cells, stimulate and augment IFN-g production, direct antigeninduced cytotoxicity, and facilitate granuloma formation and function (Fig. 8.4).6 A few important cytokines elaborated by APCs during infection by M. tuberculosis are briefly discussed below.
CD1 PRESENTATION The CD1 family consists of antigen-presenting molecules encoded by genes outside the MHC. They have specific roles in the presentation of lipids, glycolipids, and lipopeptides to T-lymphocytes, and therefore play a major role in presenting M. tuberculosis cell wall-associated lipid antigens to naı¨ve T-lymphocytes. CD1 molecules resemble MHC class I molecules structurally, consisting of a transmembrane heavy chain that associates with b2-microglobulin.27 Signalling through TLRs induces the upregulation of CD1 expression, thereby facilitating lipid antigen presentation. There are currently five known CD1 isoforms: CD1a, CD1b, CD1c, and CD1d are involved in antigen presentation on cell surfaces, and CD1e facilitates the processing of complex glycolipids within the endocytic pathway.28,29 CD1 molecules are assembled within the endoplasmic reticulum and present antigens to several different T-lymphocyte subsets, including CD4–CD8–TCRab T-lymphocytes (double-negative T-lymphocytes) and CD8þ T-lymphocytes (Table 8.1).27 CD1 molecules function at different stages within the endocytic pathway. CD1a is present in early recycling endosomes where they load antigens in the absence of chaperone molecules. CD1b and CD1d molecules target endosomes and lysosomes, whereas CD1c is found throughout the endocytic pathway and is able to present antigens independent of lysosomal acidification. CD1c controls the induction of gd cells. CD1d is the only antigen-presenting molecule known to activate NK cells, thus recruiting these cells to the specific immune response. Mycobacterium tuberculosis-specific CD1-restricted T-lymphocyte clones mediate cellular cytotoxicity and/or are biased towards secreting Th1 cytokines. Although lipid presentation is a relatively novel concept, evidence suggests that CD1 presentation is important for the overall cellular adaptive response to infection by M. tuberculosis.16,29
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IL-12P70 AND RELATED CYTOKINES IL-12p70 Interleukin-12p70 (IL-12), a heterodimer composed of p40 and p35 subunits, is produced mainly by macrophages and DCs. Its early production by these cells is important for the induction of NK cells, the elaboration of IFN-g, and, subsequently, the activation, differentiation, and proliferation of M. tuberculosis-specific Th1 cells. It also induces IFN-g production by Th1 cells. It forms a link between the innate and adaptive responses and binds to the IL-12 receptor, consisting of two subunits, IL-12Rb1 and IL-12Rb2, expressed on Th1 and NK cells. In addition, IL-12 augments cytotoxicity of CD8þ T-lymphocytes and NK cells by inducing the transcription of genes encoding perforin and granzymes and by up regulating the expression of adhesion molecules. It also enhances antigen presentation by macrophages and DCs.32,33 IL-18 Several cytokines with IL-12-like function have been identified, including IL-18, IL-23, and IL-27. They are also produced by APCs, and complement the function of IL-12. Interleukin-18 is synthesized as an inactive precursor which undergoes proteolytic cleavage by caspase-1 before being secreted. It enhances CD8þ T-lymphocyte and NK cell cytotoxicity, and induces IFN-g production by NK cells together with IL-12 during the early stages of Th1 development but, alone, does not appear to induce IFN-g secretion. Instead it acts synergistically with IL-12 to augment IFN-g production. Interleukin-12 up regulates the expression of the IL-18 receptor, which is necessary for the functioning of IL-18.34 A newly identified proinflammatory cytokine, IL-32,
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Th2 cytokine expression IL-4, IL-10, TGFb, IL-27
M. tuberculosis
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Stimulation of T cells and NK cells IL-12, IL-15, IL-18, IL-23, IL-27
Acute phase response: IL-6 Macrophage of dendritic cell
IFNg
Autoinduction: TNFa, IL-1b, IFNg
Leukocyte chemotaxis: IL-8, MCP-1, MIP-1a, RANTES
Fig. 8.4 Major functions of macrophages and dendritic cells in containing M. tuberculosis infections (adapted from Van Crevel R, Ottenhoff THM, van der Meer JWM. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev 2002;15:294–309.)
is induced during infection by M. tuberculosis in an IL-18-dependent manner and it may also induce the production of tumour necrosis factor-a (TNF-a).35
IL-23 Interleukin-23 consists of a p19 subunit that associates with the IL-12p40 subunit. It interacts with a receptor complex, which is composed of the IL-12Rb1 subunit and an IL-23R subunit that shares homology with the IL-12b2 subunit. Along with IL-12, IL-23 plays an important bridging role between the innate and adaptive immune responses. It induces the production of IFN-g from activated or memory CD4þ T-lymphocytes but not from naı¨ve lymphocytes. In contrast IL-12 promotes IFN-g production from both naı¨ve and memory subsets. Interleukin-23 also stimulates the proliferation of memory T-lymphocytes but not naı¨ve T-lymphocytes, and it enhances the elaboration of IL-17 primarily from gd T-lymphocytes.33,36 This IL-17 cell lineage is believed to have developed separately but in parallel with specialized Th1 and Th2 effectors that address intracellular pathogens and parasitic infections, respectively. Interleukin-17 receptors are expressed on a broad range of cell types. Upon ligation, IL-17 induces production of several cytokines including granulocyte colony-stimulating factor, IL-1, IL-6, IL-8, and TNF-a and may therefore mediate anti-TB activity through increased phagocytosis and proinflammatory actions. Interleukin-17 does not appear to play a role in the formation or maintenance of the granuloma.37,38 IL-27 Interleukin-27 is also required for the development of Th1 responses during infection by M. tuberculosis. It induces proliferation of naı¨ve T-lymphocytes, secretion of IFN-g by naı¨ve T-lymphocytes, and the production of IFN-g by NK cells in association with IL-12 or IL-18. It may therefore act in the early stages of the immune response.39 Studies on mice in which the gene encoding WSX-1, a type 1 cytokine receptor, was deleted showed that IL-27 is able to exert a paradoxical anti-inflammatory function in the setting of
Granuloma development
Initiation of adaptive immunity MCH, CD1, co-stimulatory molecules, Th1 cytokines
Containment or elimination of M. tuberculosis
Antigen-specific T-cell response: IFNg, LTa3, TNFa, perforin, granulysin
M. tuberculosis infection. By signalling through WSX-1, to which it binds with high-affinity, IL-27 was shown to attenuate the magnitude of the Th1 response and hence may control potentially pathological sequelae arising from the chronic inflammatory state induced by infection by M. tuberculosis.39,40
TUMOUR NECROSIS FACTOR-a Tumour necrosis factor-a, a proinflammatory cytokine that belongs to the TNF cytokine family, is produced mainly by DCs and macrophages. It exists in soluble and transmembrane isoforms which, respectively, activate the TNF type 1 and type 2 receptors. During infection by M. tuberculosis, soluble TNF-a regulates the immune response and consequent immunopathology. The importance of TNF-a in human infection has been confirmed in patients with chronic inflammatory conditions such as rheumatoid arthritis, where the administration of anti-TNF-a monoclonal antibodies significantly increases the risk of reactivation TB.41,42 Specific actions of TNF-a include the promotion of apoptosis of macrophages infected with M. tuberculosis, thereby contributing to the clearance of the infection, induction of DC maturation, and migration to regional lymph nodes. This facilitates antigen presentation, T-lymphocyte priming within lymph nodes, upregulation of expression of endothelial adhesion molecules, and chemokine elaboration and chemokine receptor expression, thus promoting the recruitment of APCs and T-lymphocytes to the infection site. Gramuloma formation and function, which leads to the control and containment of the infection and mycobacterial dormancy, is dependent on TNF-a production. In mice, TNF-a in combination with IFN-g plays a key role in mycobacterial killing within macrophages by stimulating the production of reactive nitrogen intermediates. In human infection, this does not appear to be a function of TNF-a. Circulating TNF-a is considered responsible for the cachexia that accompanies TB.42,43
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In addition to TNF-a, there are several other cytokines elaborated primarily by APCs that drive the proinflammatory response to TB including IL-1b and IL-6.
INTERLEUKIN-4 AND OTHER ANTI-INFLAMMATORY CYTOKINES Several cytokines, including transforming growth factor (TGF)-b, IL-4, IL-10, and IL-13, elaborated during infection by M. tuberculosis, exert anti-inflammatory effects.6 Interleukin-4 is produced by various cells including CD4þ T-lymphocytes, CD8þ T-lymphocytes, NK cells and APCs. Interleukin-4 levels are higher in patients with TB who reside close to the equator than in those in Europe. The exact regulatory role of IL-4 has not been completely elucidated. During the early stages of M. tuberculosis infection, IL-4 may be involved in driving the Th1 response; during the later stages of infection it probably down regulates Th1 responses, and may be associated with progressive disease and TNF-a-associated immunopathology. Interleukin-4 knockout mice are able to control M. tuberculosis infection as well as wild-type mice but they experience less TNF-a-mediated toxicity and pulmonary fibrosis, implying that IL-4 is involved in these effects.44,45
THE ACTIVATION OF T-LYMPHOCYTES Activation of CD4þ and CD8þ T-lymphocytes are antigen-specific events resulting from the interaction between DCs and naı¨ve T-lymphocytes. Activation primarily occurs within regional lymph nodes following the migration of DCs from the site of infection. Each T-lymphocyte expresses a unique T-cell receptor (TCR) which recognizes antigenic peptides in association with MHC class molecules. Each TCR consist of two transmembrane subunits, a and b. The hypervariable region of each subunit is formed by random genetic rearrangement of the V, D, and J functional segments. Genetic rearrangement is the major mechanism responsible for generating receptor diversity and it confers on each TCR a unique antigen recognition site, which is formed by the hypervariable regions of the two subunits. Binding of the TCR to peptide-bound MHCs with high affinity induces signalling downstream of the receptor, resulting in a range of cellular responses including proliferation, differentiation, elaboration of cytokines, induction of a memory response, and, in CD8þ T-lymphocytes, cytotoxicity.46,47 Several signals are required for T-lymphocyte activation. Following antigen ligation the cytoplasmic domains of TCR subunits associate non-covalently with downstream molecules, activating the signalling cascade. Surface-expressed co-receptors are important for signalling. The CD4 co-receptor expressed on CD4þ T-lymphocytes and the CD8 co-receptor expressed on CD8þ T-lymphocytes bind to the non-variable portion of the MHC class II and class I molecules, respectively.46 Co-stimulation is provided by two T-lymphocyte expressed receptors, CD28 and CTLA-4 (CD152), which bind to either CD80 or CD86 expressed on APCs. CD28 is constituently expressed while CTLA-4 is rapidly up regulated on the surface of T-lymphocytes following T-cell activation. Additional co-stimulation pathways including the B7-H1/B7-DC/PD-1 and B7-H2/ICOS pathway have been identified. Stimulation of ICOS on T-lymphocytes augments proliferation and Th1 and Th2 cytokine production. Polarization of T-lymphocytes into various phenotypes such as Th1, Th2, and Th17, and regulatory T-cell (Tr) subsets, requires additional signals provided by the
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existing cytokine milieu and, through co-signalling via dendritic cell subsets, NK cells and other cellular elements of the innate immune system. During infection by M. tuberculosis IL-12 and related cytokines appear to play an important role in directing a predominantly Th1 response.48
T-LYMPHOCYTE AND NK CELL FUNCTIONS Following priming, specific T-lymphocyte subsets play important roles, determined by their modified gene expression, following infection by M. tuberculosis. Activated T-lymphocytes express chemokine receptors which allow them to migrate to the site of infection where they participate in the immune response.
CD4þ T-LYMPHOCYTES The pivotal role of CD4þ T-lymphocytes has been clearly demonstrated in the setting of HIV infection in which CD4þ T-lymphocyte dysfunction and attrition significantly predisposes both adults and children to an increased risk of TB. Th1 cells elaborate several cytokines including IFN-g, IL-2, and lymphotoxin-a, which is a member of the TNF family of cytokines. These cytokines are instrumental in optimizing macrophage killing, augmenting macrophage TNF-a production, suppressing Th2 cytokine elaboration, and influencing cytotoxic responses by CD8þ T-lymphocytes, NK cells, and other CD1-restricted T-lymphocytes. Th1 cells and their cytokines play an important role in granuloma formation and organization.49
CD8þ T-LYMPHOCYTES Activated CD8þ T-lymphocytes lyse M. tuberculosis-infected macrophages by two major mechanisms. First, cytolysis via the granule exocytosis pathway depends on perforin, a pore-forming protein, which is synthesized and stored in cytotoxic secretory granules within CD8þ T-lymphocytes. Antigen-specific CD8þ T-lymphocytes form an immunological synapse with M. tuberculosis-infected macrophages. The lymphocytes then discharge the contents of their secretory granules, including perforin and granzymes A and B, into the synapse. Perforin induces the formation of pores within the plasma membrane of the macrophages, permitting entry of granzymes A and B which initiate caspase-dependent and -independent apoptosis leading to rapid cell death of targeted macrophages. Secondly, caspasedependent apoptosis follows upregulation of Fas-ligand expression on CD8þ T-lymphocytes and consequent signalling via Fas (CD95) expressed on target macrophages. In addition, activated CD8þ T-lymphocytes produce granulysin which is capable of exerting direct microbicidal activity against M. tuberculosis and, in the presence of perforin, kills intracellular bacilli. CD8þ T-lymphoctyes elaborate IFN-g and TNF-a, which are important in influencing macrophage effector responses.50
CD1-RESTRICTED T-LYMPHOCYTES CD1-restricted T-lymphocytes fulfil helper and effector functions, and interact with other cell types including macrophages and dendritic cells. In TB most activated CD1-restricted clones respond to many lipid antigens (Table 8.2). The effector CD1-restricted cells are of the Th1 type and they produce IFN-g and TNF-a and lyse M. tuberculosis-infected macrophages in a similar manner to lysis by
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Table 8.2 The survival of M. tuberculosis within macrophages is dependent upon several strategies Inhibition of macrophage activation ManLAM prevents the activation of mitogen-activated protein kinase, thereby inhibiting synthesis of TNF-a, chemokines, and the respiratory burst. Prevention of phagosome maturation Recruitment of the host protein, coronin 1, or tryptophan–aspartatecontaining coat protein (TACO) blocks the fusion of phagosome and lysosome. Mycobacterial cell wall components, e.g. ManLAM, inhibit phagosome– lysosome fusion. Mycobacterial kinase G blocks lysosomal delivery. Mycobacterial inhibition of Ca2þ-mediated signalling, generation of phosphatidylinositol-3-kinase, and the retention of Rab5 prevents phagosome maturation. Inhibition of MHC class II processing and presentation 19-kDa lipoprotein inhibits class II processing and presentation. Resistance against mycobacterial destruction Rearrangement of the cytoskeleton prevents the concentration of nitric oxide within phagolysosomes, thereby reducing its destructive effects. Nitric oxide damage is countered by the mycobacterial proteosome. Formation of anti-oxidant complexes prevent oxidant damage.
CD8þ T-lymphocytes. CD1-restricted CD4þ and CD8þ lymphocytes both elaborate granulysin and therefore exhibit direct microbiocidal activity.29
gd T-LYMPHOCYTE SUBSET The gd T-lymphocyte subset exhibits features of both innate and adaptive immunity.51 The majority of circulating gd T-lymphocytes express TCRs comprising Vg2 and Vd2 segments and are referred to as Vg2Vd2þ T-lymphocytes.52 gd T-lymphocytes recognize classical type I and II MHC molecules and non-classical molecules such as CD1 and MHC class 1b. Chemokine-receptor-mediated trafficking allows activated cells to migrate to the site of infection. Their functions include elaboration of Th1 cytokines, chemokines, perforin, and granulysin. Activated gd T-lymphocytes are capable of functioning as APCs. They express TLRs, transiently express CCR7 (a lymph node-honing chemokine receptor), up regulate surface expression of MHC class II and co-stimulatory molecules, and facilitate the proliferation of CD4þ ab T-lymphocytes.52 They also induce CD8þ ab T-lymphocytes to proliferate and differentiate into cytotoxic T-lymphocytes and they regulate macrophage and DC function through cytokine-mediated cross-talk.51
NATURAL KILLER (NK) CELLS Natural killer cells are, in common with all T-lymphocytes, derived from precursor CD34þ CD7þ cells. In general, NK cells do not require antigen-specific recognition to kill target cells but they do, however, recognize MHC class I molecules through surface receptors that deliver inhibitory rather than activating signals. A subset of NK cells, the NK T-lymphocytes (NKT cells), express the common NK cell marker, CD161, but are activated by processed lipid antigens presented in association with CD1d molecules, and therefore respond in an antigen-specific manner.27 In response to infection NK cells elaborate cytokines, particularly IFN-g, that are critical for early macrophage activation, mediate
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cytotoxicity primarily through the granule exocytic mechanism, and appear to maintain M. tuberculosis-specific CD8þ T-lymphocyte cytotoxic function by producing IFN-g, which induces macrophages to produce IL-15 and IL-18.53
INTERFERON-g Interferon-g, a homodimer produced by CD4þ, CD8þ, and gd T-lymphocytes and NK cells, is an important mediator of macrophage activation and effector function. Its importance in the immune response against mycobacteria has been confirmed by the demonstration of increased susceptibility, disease severity, and poor outcome in individuals with genetic or acquired defects/deficiencies of IFN-g, IFN-g receptor subunits, and the STAT-1 protein, all components of the IFN-g cytokine pathway.54 The IFN-g receptor complex expressed on a variety of cell types consists of IFN-gR1 and IFN-gR2 subunits. Ligand binding to the functional receptor complex usually involves the interaction of one IFN-g dimer and two IFN-g receptors. Upon binding of the IFN-g dimer to the extracellular domains of adjacent receptors, association of downstream signalling molecules leads to the activation of the Janus kinase (JAK)/signal inducer and activation of transcription1 (STAT-1) signalling cascade and consequent upregulation of IFN-g-inducible gene expression. Interferon-g induces the production of multiple proteins involved in the MHC class I and II antigen-presenting pathways, apoptotic mechanisms, nitric oxide production, and leucocyte trafficking, thus having important regulatory functions.55
CHEMOKINES, ADHESION MOLECULES AND CELLULAR MIGRATION Chemokines and their complementary chemokine receptors, as well as adhesion molecules including vascular addresins and lymphocyte- and macrophage-associated integrins, play a major role in regulating the trafficking of the cellular elements of the immune response during infection by M. tuberculosis, as well as influencing granuloma formation and organization. The inflammatory milieu that develops at the site of infection includes microbial products and a variety of cytokines, and is responsible for inducing the expression of chemokines, their receptors, and adhesion molecules.56,57 The chemokines are small molecules that mediate both constitutive and induced cell recruitment. They are grouped into several structurally defined families, including CXC, CC, C, and CX3C. Specific chemokines are able to bind more than one chemokine receptor and most receptors bind several different chemokines. Extensive chemokine expression is induced in infection by M. tuberculosis. Knockout mice experiments have established the importance of chemokines in directing the immune response to TB.57,58 Chemokines contribute to trafficking of cells, involving rolling, adhesion, and migration across endothelial barriers, by binding to G-protein-coupled transmembrane receptors, which result in actin-dependent effects such as membrane ruffling, pseudopod formation, and adhesion complex assemblage. Constitutive recruitment is responsible for the continual accumulation of naı¨ve and memory T cells in secondary lymphoid tissue including lymph nodes. Induced recruitment directs activated regulatory lymphocytes
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and effector cells including macrophages, NK cells, and CD8þ T-lymphocytes to the site of infection. Different chemokines and chemokine receptors are involved in constitutive and induced recruitment.49,57,58
MICROBIAL ELIMINATION The mechanisms by which M. tuberculosis is killed during human infection are only partly understood (Box 8.4). Macrophage effector functions augmented by the adaptive immune responses are believed to play a central role in eliminating the microbe. A key factor in the success of M. tuberculosis is its ability, through several mechanisms (Table 8.2), to survive within macrophages by obstructing macrophage activation, phagolysosomal formation, and antigen processing.59 The immune system must overcome this parasitic tendency and cross-talk, largely directed by antigen-specific cellular elements of adaptive immunity, is able to circumvent phagosomal maturational arrest through an as-yet incompletely characterized mechanism, thereby facilitating microbial killing.60 Resistance to killing of M. tuberculosis is overcome by specific induction of the production of LRG-47, a 47 kDa guanosine triphosphatase (p47 GTPase) protein.60 This is one of at least six proteins belonging to the newly identified IFN-g-inducible p47 GTPase family of proteins widely expressed in nature and important for resisting microbial infection by both plants and animals. In the absence of infection, macrophage mRNA levels of p47 genes are extremely low, but upon encountering bacteria there is a rapid and dramatic increase in p47 GTPase expression.61 IFN-g induces p47 GTPase production through the adaptor protein STAT-1, which binds directly to the genes encoding p47 GTPase proteins, thereby increasing specific mRNA production. LRG-47 is the only member of the p47 GTPases that participates in infection by M. tuberculosis in humans.60 Furthermore, experiments in LRG-47 knockout mice have shown increased susceptibility to mycobacterial infection.62 Toll-like receptor stimulation may also increase LRG-47 production through increased IFN-b production. LRG-47 is expressed mainly on endoplasmic reticulum and the Golgi apparatus, but is recruited directly to phagosomes containing M. tuberculosis where it assists in overcoming resistance to killing by facilitating phagosomal maturation. The hostile environment of the mature phagolysome, characterized by acidification and the processing of immature hydrolases, eliminates the contained mycobacteria. The mechanism by which LRG-47 facilitates maturation of phagosomes containing M. tuberculosis has not yet been elucidated.60,61
Box 8.4 Intracellular and extracellular mechanisms by which human M. tuberculosis infection is contained
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Acidified phagolysosome environment. Lysosomal hydrolases. Reactive nitrogen intermediates. Downregulation of macrophage transferrin receptors. Defensins. Indoleamine 2,3-dioxygenase-mediated containment. Macrophage apoptosis. Granulysin. The role of specific antibodies remains unknown.
IFN-g is important for inducing several macrophage antimycobacterial mechanisms. The generation of nitric oxide and related metabolites is catalysed by the IFN-g-inducible form of nitric oxide synthetase 2. Maximal induction of iNOS2 requires additional stimuli including TNF-a. Although the role of reactive nitrogen intermediates is controversial, evidence suggests that they do contribute to the elimination of M. tuberculosis and control of the infection in humans.55 Downregulation of transferrin receptor expression limits the availability of intracellular iron and therefore restricts M. tuberculosis metabolism and growth.63 Defensins are leucocytic antimicrobial peptides capable of killing a wide range of microorganisms. In mice, IFN-g induces the production of b-defensin 3, a homolog of the defensin b-2 lysin, which has been shown to be tuberculocidal.60 Furthermore, the production of indoleamine 2,3-dioxygenase enhances the anti-mycobacterial ability of macrophages and may be important in infection by M. tuberculosis.64 Apoptosis or programmed cell death is characterized by digestion of the genomic DNA of target cells by endonuclease and is mediated through cell signalling involving several ‘death’ receptors expressed on the surface of cells targeted for apoptosis. In the context of mycobacterial infection, apoptosis is a major effector mechanism by which antigen-specific T-lymphocytes and NK cells eliminate infected macrophages. Mycobacterial growth is restricted because apoptosis destroys the protected environment of the phagosome as a result of the dissolution of macrophage organelles. The released mycobacteria are taken up by uninfected macrophages or eliminated by the direct action of granulysin, thereby reducing mycobacterial load. Mycobacterium tuberculosis is a potent inducer of apoptosis, mainly mediated through the expression of TNF-a. Furthermore, the 19 kDa lipoprotein of this pathogen activates TLR2, leading to the induction of apoptosis. Fas ligandinduced apoptosis, mediated by T-lymphocytes and NK cells, results in the destruction of intracellular organelles, the uptake of apoptotic bodies by adjacent phagocytes, and the inhibition of mycobacterial spread and growth. Apoptosis occurs in granulomas and may therefore modulate cell turnover and limit the spread of infection.50
GRANULOMA FORMATION AND FUNCTION Granuloma formation correlates with the development of delayed hypersensitivity revealed by a positive tuberculin test, emergence of activated T-cell subsets, improved macrophage responsiveness in areas of localized infection, and improved phagocytosis and mycobacterial killing. The granuloma plays a pivotal role in orchestrating the interaction between immune cells leading to an effective response, inhibiting and killing M. tuberculosis, containing infection, preventing the spread of the organism, and localizing the inflammatory response and tissue damage.57 Granuloma formation may be divided into four phases: initiation, accumulation, effector, and resolution. Very little is known about the initiation phase, but macrophages migrate into the site of infection and initiate granuloma formation. Both initiation and accumulation phases involve cellular recruitment.65 Knockout mice experiments have established the importance of both TNFa and lymphotoxin-a in granuloma formation. These cytokines achieve their effect by regulating the expression of adhesion molecules and chemokine receptors, and establishing chemokine gradients.49,57 T-lymphocytes are involved in all four phases.65
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accumulate within granulomas and research in mice suggests that these may assist in down regulating the inflammatory responses.65,68
IMMUNE RESPONSES IN CHILDREN
Fig. 8.5 A mature, caseating tuberculous granuloma with an area of central necrosis surrounded by a typical cellular infiltrate.
A fully formed tuberculous granuloma consists of a central zone of caseating necrosis, surrounded by cellular infiltrate comprising activated macrophages (epithelioid cells), DCs, T-lymphocytes, Blymphocytes, and fibroblasts. Macrophages are centrally located and have the ability to differentiate into multinucleated giant cells. The outer layer of the human granuloma structurally resembles secondary lymphoid follicles and contains APCs, CD4þ T-lymphocytes, CD8þ T-lymphoctes, and B-lymphocytes where the host and pathogen probably interact (Fig. 8.5).4 T-lymphocyte proliferation is limited in granulomata. T-cell receptor diversity is determined by cellular migration and possibly T-lymphocyte priming, which is thought to occur in the outer layers of the granuloma.65 In productive granuloma without recognizable caseation very few cells show apoptotic features but large numbers of macrophages and lymphocytes undergoing apoptosis are seen within caseating granulomas.66 Granuloma formation is accompanied by a change in the mycobacterial gene expression pattern as the organisms adapt to the environment of the granuloma. Loss of acid-fastness during latency suggests that the cell wall structure of dormant M. tuberculosis is altered.67 The location of the latent organisms remains uncertain but one study indicates that they are present in tissue outside the areas of caseating necrosis.14 During the effector phase macrophage–lymphocyte cooperation plays a determining role in reducing the pathogen burden within granulomas. Resolution of granulomas involves immunomodulatory cytokines including TGF-b and IL-10. Interleukin-13 and TGF-b induce fibrosis, the final step in resolution. gd T-lymphocytes
REFERENCES 1. Warren R, Victor TC, Streicher EM, et al. Patients with active tuberculosis often have different strains in the same specimen. Am J Respir Crit Care Med 2004;169:610–614. 2. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4:498–511. 3. Kaufmann SHE. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 2001;1:20–30. 4. Ulrichs T, Kaufmann SHE. New insights into the function of granulomas in human tuberculosis. J Pathol 2006;208:261–269.
There are several immunocompromised states that predispose infected humans to active TB, including the relative immaturity and naivety of the immune system of very young children, waning immune competency in the elderly, primary immunodeficiency disorders, particularly genetic disorders of the IFN-g cytokine pathway, and secondary immunodeficiencies such as HIV infection. Young children, particularly those less than 1 year of age, are at a greater risk for developing TB than older children or adults and are at an increased risk for disseminated disease including tuberculous meningitis. These clinical vulnerabilities reflect the underlying immunological susceptibility of young children in whom both innate and adaptive responses are relatively weak. Evidence for impaired innate responses is mainly derived from animal studies and support suboptimal macrophage functionality. Dendritic cells play a critical role in regulating several immunological responses to infection by M. tuberculosis and deficiencies in their function have been demonstrated in both children and young animals. Studies in young children with congenital infections suggest that antigen-specific CD4þ T-lymphocyte responses are impaired, neonatal T-lymphocytes demonstrate reduced capacity to elaborate IFN-g and TNF-a, and following antigenic stimulation, cytokine production is biased towards a Th2 pattern. Furthermore, virus-specific CD8þ T-lymphocyte responses are suboptimal in young children.69,70
CONCLUSION The immune response following infection by M. tuberculosis is only partly understood. Recent progress has defined in great detail many intricate molecular events that underpin mycobacterial containment and clinical latency observed in the majority of individuals who encounter the organism. Key immunological processes include antigen recognition, adaptive immune responses, granuloma formation, microbial containment, and killing. Recent advances have, unfortunately, not been matched by improved therapeutic options. More attention should be given to translating fundamental immunological concepts into effective antimicrobial and immunomodulatory interventions so that therapy and preventive measures may be improved, particularly in resource-poor countries.
5. Glatman-Freedman A, Casadevall A. Serum therapy for tuberculosis revisited: Reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis. Clin Microbiol Rev 1998;11:514–532. 6. Van Crevel R, Ottenhoff THM, van der Meer JWM. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev 2002;15:294–309. 7. Ernst JD. Macrophage receptors for Mycobacterium tuberculosis. Infect Immun 1998;66:1277–1281. 8. Velasco-Vela´zquez MA, Barrera D, Gonza´lez-Arenas A, et al. Macrophage-Mycobacterium tuberculosis interactions: role of complement receptor 3. Microbial Pathogenesis 2003;35:125–131. 9. Ehlers MRW, Daffe´ M. Interactions between Mycobacterium tuberculosis and host cells: are
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mycobacterial sugars the key? Trends Microbiol 1998;6:328–335. Van Kooyk Y, Geijtenbeek TBH. DC-SIGN: Escape mechanisms for pathogens. Nat Rev Immunol 2003;3:697–709. Hope JC, Thom ML, McCormick PA, et al. Interaction of antigen presenting cells with mycobacteria. Vet Immunol Immunopathol 2004;100:187–195. Doherty TM, Arditi M. TB or not TB: that is the question - does TLR signalling hold the answer? J Clin Invest 2004;114:1699–1703. Barton GM, Medzhitov R. Control of adaptive immune responses by Toll-like receptors. Curr Opin Immunol 2002;14:380–383. Barton GM, Medzhitov R. Toll-like receptor signalling pathways. Science 2003;300:1524–1525.
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15. Krutzik SR, Modlin RL. The role of toll-like receptors in combating mycobacteria. Semin Immunol 2004;16:35–41. 16. Kaufmann SHE, Schaible U. Antigen presentation and recognition in bacterial infections. Curr Opin Immunol 2005;17:79–87. 17. Koul A, Herget T, Klebl B, et al. Interplay between mycobacteria and host signaling pathways. Nat Rev Microbiol 2004;2:189–202. 18. Russell DG. Mycobacterium tuberculosis: Here today, and here tomorrow. Nat Rev 2001;2:1–9. 19. Viera OV, Botelho RJ, Grinstein S. Phagosome maturation: aging gracefully. Biochem J 2002;366: 689–704. 20. Blander JM, Medzhitov R. On regulation of phagosome maturation and antigen presentation. Nat Immunol 2006;7:1029–1035. 21. Blander JM, Medzhitov R. Regulation of phagosome maturation by signals from toll-like receptors. Science 2004;304:1014–1018. 22. Broom WH, Canaday DH, Fulton SA, et al. Human immunity to M. tuberculosis: T cell subsets and antigen processing. Tuberculosis 2003;83:98–106. 23. Ramachandra L, Noss E, Boom WH, et al. Phagocytic processing of antigens for presentation by class II major histocompatibility complex molecules. Cell Microbiol 1999;1:205–214. 24. Flutter B, Gao B. MHC class I antigen presentation – recently trimmed and well presented. Cell Mol Immunol 2004;1:22–30. 25. Winau F, Kaufmann SHE, Schaible UE. Apoptosis paves the detour path for CD8 T cell activation against intracellular bacteria. Cell Microbiol 2004;6:599–607. 26. Lewinsohn DM, Grotzke JE, Heinzel AS, et al. Secreted proteins from Mycobacterium tuberculosis gain access to the cytosolic MHC class-I-antigenprocessing pathway. J Immunol 2006,177: 437–442. 27. Gumperz JE, Brenner MB. CD1-specific T cells in microbial immunity. Curr Opin Immunol 2001; 13:471–478. 28. De La Salle H, Mariotti S, Angenieux C, et al. Assistance of microbial glycolipid antigen processing by CD1e. Science 2005;310:1321–1324. 29. De Libero G, Mori L. Mechanisms of lipid-antigen generation and presentation to T cells. Trends Immunol 2006;27:485–492. 30. Spellberg B, Edwards JE. Type 1/Type 2 immunity in infectious diseases. Clin Infect Dis 2001;32:76–102. 31. Chaco´n-Salinas R, Serafin-Lo´pez J, Ramos-Paya´n R, et al. Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 2005;140:443–449. 32. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003;3:133–146. 33. Langrish CL, McKenzie BS, Wilson NJ, et al. IL-12 and IL-23: Master regulators of innate and adaptive immunity. Immunol Rev 2004;202:96–105. 34. Reddy P. Interleukin-18: recent advances. Curr Opin Hematol 2004;11:405–410.
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35. Netea MG, Azam T, Lewis EC, et al. Mycobacterium tuberculosis induces interleukin-32 production through a caspase-1/IL-18/interferon-g-dependent mechanism. Plos Med 2006;3:e277. URL: http:// www.plosmedicine.org 36. Happel KI, Lockhart EA, Mason CM, et al. Pulmonary interleukin-23 gene delivery increases local T-cell immunity and controls growth of Mycobacterium tuberculosis in the lungs. Infect Immun 2005;73:5782–5788. 37. Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 2002;71:1–8. 38. Lockhart E, Green AM, Flynn JL. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 2006;177:4662–4669. 39. Villarino AV, Hunter CA. Biology of recently discovered cytokines: discerning the pro- and anti-inflammatory properties of interleukin-27. Arthritis Res Ther 2004;6:225–233. 40. Ho¨lscher C, Ho¨lscher A, Ru¨ckerl D, et al. The IL-27 receptor chain WSW-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J Immunol 2005;174: 3534–3544. 41. Pfeffer K. Biological functions of tumour necrosis factor cytokines and their receptors. Cytokine Growth Factor Rev 2003;14:185–191. 42. Gardam MA, Keystone EC, Menzies R, et al. Antitumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3:148–155. 43. Stenger S. Immunological control of tuberculosis: role of tumour necrosis factor and more. Ann Rheum Dis 2005;64:24–28. 44. Rook GAW, Hernandez-Pando R, Dheda K, et al. IL-4 in tuberculosis: implications for vaccine design. Trends Immunol 2004;25:483–488. 45. Jung Y, LaCourse R, Ryan L, et al. Evidence inconsistent with a negative influence of T helper 2 cells on protection afforded by a dominant T helper 1 response against Mycobacterium tuberculosis lung infection in mice. Infect Immun 2002;70:6436–6443. 46. Choudhuri K, Kearney A, Bakker TR, et al. Immunology: How do T cells recognize antigen? Curr Biol 2005;15:R382–R385. 47. Van der Merwe PA, Davis SJ. Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 2003;21:659–684. 48. McGuirk P, Mills KHG. Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol 2002;23:450–455. 49. Peters W, Ernst JD. Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis. Microbes Infect 2003;5:151–158. 50. Grotzke JE, Lewinsohn DM. Role of CD8þ T lymphocytes in control of Mycobacterium tuberculosis infection. Microbes Infect 2005;7:776–788. 51. Brandes M, Willimann K, Moser B. Professional antigen presentation function by human gd T cells. Science 2005;309:264–268.
52. Chen ZW, Letvin NL. Vg2Vd2þ T cells and antimicrobial immune responses. Microbes Infect 2003; 5:491–498. 53. Vankayalapati R, Klucar P, Wizel B, et al. NK cells regulate CD8þ T cell effector function in response to an intracellular pathogen. J Immunol 2004;172;130–137. 54. Ottenhoff THM, Verreck FAW, Lichtenauer-Kaligis EGR, et al. Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet 2002;32:97–105. 55. Schroder K, Hertzog PJ, Ravasi T, et al. Interferon-g: an overview of signals, mechanisms and functions. J Leukoc Biol 2004;75:163–189. 56. Kerr JR. Cell adhesion molecules in the pathogenesis of and host defense against microbial infection. J Clin Pathol Mol Pathol 1999;52:220–230. 57. Algood HMS, Chan J, Flynn JL. Chemokines and tuberculosis. Cytokine Growth Factor Rev 2003;14: 467–477. 58. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000;18:217–242. 59. Vergne I, Chua J, Singh SB. Cell biology of Mycobacterium tuberculosis: phagosome. Annu Rev Cell Dev Biol 2004;20:367–394. 60. MacMicking JD, Taylor GA, McKinney JD. Immune control of tuberculosis by IFN-g-inducible LRG-47. Science 2003;302:654–659. 61. MacMicking JD. Immune control of phagosomal bacteria by p47 GTPases. Curr Opin Microbiol 2005;8:74–82. 62. Feng CG, Collazo-Custodio CM, Eckhaus M, et al. Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia. J Immunol 2004;172:1163–1168. 63. Olakanmi O, Schlesinger LS, Britigan BE. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J Leukoc Biol 2007;81:195–204. 64. Hayashi T, Rao SP, Takabayashi K, et al. Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase. Infect Immun 2001;69:6156–6164. 65. Co DO, Hogan LH, Il-Kim S, et al. T cell contributions to the different phases of granuloma formation. Immunol Lett 2004;92:135–142. 66. Fayyazi A, Eichmeyer B, Soruri A, et al. Apoptosis of macrophages and T cells in tuberculosis associated caseous necrosis. J Pathol 2000;191:417–425. 67. Seiler P, Ulrichs T, Bandermann S, et al. Cell-wall alterations as an attribute of Mycobacterium tuberculosis in latent infection. J Infect Dis 2003;188:1326–1331. 68. Ladel CH, Blum C, Dreher A, et al. Protective role of gamma/delta T cells and alpha/beta T cells in tuberculosis. Eur J Immunol 1995;25:2877–2881. 69. Lewinsohn DA, Gennaro ML, Scholvinck L, et al. Tuberculosis immunology in children: diagnostic and therapeutic challenges and opportunities. Int J Tuberc Lung Dis 2004;8:658–674. 70. Smith S, Jacobs RF, Wilson CB. Immunobiology of childhood tuberculosis: a window on the ontogeny of cellular immunity. J Pediatr 1997;131:16–26.
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9
Host susceptibility and resistance to Mycobacterium tuberculosis Genetic, neuroendocrine, and acquired factors Graham AW Rook and T Mark Doherty
INTRODUCTION Susceptibility to TB, like susceptibility to other infections, is controlled by genetic factors, as well as by environmental factors and interactions between the two. The role of host genetic variation in susceptibility to TB is evident from animal models of the disease, ethnic clustering of TB cases, and increased concordance rates for TB among monozygotic twins compared with dizygotic twins. However, for some of the genes discussed below there is striking disagreement between studies in different populations. It is important to bear in mind the fact that an association between protection/susceptibility and a particular allele can be misleading. The allele in question might not be the true disease susceptibility allele, and the pattern of linkage disequilibrium between the allele and the true disease-causing allele might be different in different populations. For instance, different studies give precisely reverse associations between single nucleotide polymorphisms (SNPs) of tumour necrosis factor-a (TNF-a) and susceptibility to TB, but there is strong linkage disequilibrium with HLA genes, so we do not discuss these TNF-a SNPs below. Finally, the relevance of a genetic variant often depends upon the environment in which the individual lives: gene–environment interactions. For instance one might guess that there will be polymorphisms relevant to people with simultaneous helminth infections, but irrelevant in people without such infections. Moreover the Mycobacterium tuberculosis strains are also variable. Humans and M. tuberculosis have co-evolved over thousands of years, so not all strains of M. tuberculosis are equivalent. Indeed, it has been suggested that different strains have tropisms for specific human populations so the relevance of a particular human polymorphism might be determined by interaction with polymorphisms in the bacteria that infect the population in question.1 In this chapter we deal first with genetic factors, and then with environmental ones, though, because of these interactions, there is inevitably some overlap. The basic immunology of TB and the impact of human immunodeficiency virus (HIV) are covered in their own chapters.
GENETIC FACTORS AND SUSCEPTIBILITY TO TUBERCULOSIS Both animal and human studies have identified cell-mediated immunity, particularly those pathways involving interferon (IFN)-g as
crucial to protection against M. tuberculosis. There are multiple factors that can influence this, but this topic is discussed in detail elsewhere in this volume. Here, the focus is not on immunology, but on those factors where genetic evidence for a role in immunity is known.
COMPONENTS OF THE Th1 PATHWAY IL-12 and IL-23 and their receptors Interleukin (IL)-12 consists of two subunits, p35 and p40, encoded by IL12A and IL12B respectively. IL-23 also uses the p40 subunit, but has a unique second subunit, p19. A child who was homozygous for a large loss-of-function deletion in IL12B suffered from infections caused by Bacillus Calmette–Gue´rin (BCG) and Salmonella enteritidis. Both IL-12 and IL-23 will have been non-functional in this child. Several other loss-of-function genotypes have been detected and patients with these variants also tend to suffer from mycobacterial infections.2,3 Polymorphisms that do not cause loss of function, but cause less extreme modulation of the expression of the p40, can affect susceptibility to TB, protection being associated with genotypes leading to high production and vice versa (Fig. 9.1).4 The IL-12 receptor has two subunits, IL-12Rb1 (shared with the IL-23 receptor) and IL-12Rb2. The second (non-shared) subunit of the IL-23 receptor is designated IL-23Rb3. Defects in the gene encoding IL-12Rb1 (IL12Rb1) are more common than defects in the cytokine itself. Since IL-12Rb1 also forms part of the IL-23 receptor, the defects again affect the function of both cytokines. Severe defects lead to Mendelian susceptibility to mycobacterial disease.5 More recently it has been noted that less severe polymorphisms that do not cause loss of function can also have significant effects on susceptibility, but this is not seen in all studies.6–8 Defects in IL12Rb2 have not been found, probably because this would leave signalling via IL-23 intact, and this activity may compensate adequately. IFN-g and IFN-gR Associations between TB and polymorphisms of IFN-g have been reported, but the most striking data come from the study of genetic variants of the IFN-g receptor (Fig. 9.1).9,10 This receptor has two chains, the ligand binding chain, IFN-gR1, and a second chain, IFN-gR2, encoded by IFNGR1 and IFNGR2, respectively. Complete absence of functional IFN-gR can result from recessive mutations (most often in IFNGR1), and leads to a severe defect.11
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M. tuberculosis CD8 MHC Class I MCH Class II
CD4+ Th1 IL-12R & IL-23R
Mac or DC IL-12 IL-23 IL-1 & IL-1RA
IFN-g IFN-g receptor STAT-1
Mac
Nucleus
Fig. 9.1 Pathways immediately relevant to the induction of interleukin (IL)-12/IL-23/interferon (IFN)-g-mediated immunity, in which it is claimed that there are polymorphisms relevant to susceptibility to TB.
There is striking susceptibility to progressive BCG infection and to non-tuberculous mycobacteria such as members of the Mycobacterium avium/intracellulare group, but not usually increased susceptibility to Salmonellae. Complete lack of IFN-gR1 has been seen in several TB patients.3 However there are other genetic defects leading to less severe syndromes, and there are conflicting data as to whether partial IFN-gR defects have any effect on susceptibility to, or severity of, TB.12,13 This raises fascinating issues. It might simply be that exposure to BCG or M. avium is much more frequent than exposure to M. tuberculosis. Alternatively, TB patients with such defects might die too quickly or they might not be investigated properly. However, the possibility remains that the IL-12/IL-23/IFN-g axis is less crucial for resistance to M. tuberculosis perhaps because it is able to block release of IL-12 and the response to IFN-g.14,15 In such a case, other pathways such as cytotoxicity or bactericidal peptides may play a larger role.16,17
STAT-1 STAT-1 encodes the signal-transducer and activator of transcription associated with signalling via the IFN-gR (Fig. 9.1). Partial deficiencies have been detected in kindreds with mycobacterial infections, and complete deficiency was found in two unrelated infants that had experienced disseminated BCG infection. While BCG could be successfully cleared by anti-mycobacterial therapy, these children eventually died from viral infections, perhaps because signalling via IFN-b and IFN-a was also impaired.18 Again it is not clear how crucial these pathways are for immunity to M. tuberculosis itself – the importance is inferred from susceptibility to more common mycobacteria. IL-1 Both IL-1b and its natural inhibitor, the IL-1 receptor antgonist (IL-1RA) are the products of polymorphic genes (Fig. 9.1). There are allelic variants that result in relatively higher or lower levels of production. The most proinflammatory haplotype (high IL-1b, low IL-1RA) was significantly associated with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis-sensitized control subjects or patients with other disease forms. In contrast, the high IL-1RA haplotype was associated with a reduced Mantoux response to purified protein derivative (PPD).19 The conclusion is that, while IL-1 polymorphisms may contribute to the pathogenesis of TB, they are not the major factor.19,20
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HLA MHC class II. The HLA class II molecules expressed by antigen-presenting cells present peptide antigens to CD4 T cells (Fig. 9.1). DQ and DR are two of five isotypes of HLA class II proteins; heterodimers composed of a and b chains, encoded by the highly polymorphic loci HLA-DQ and -DR, respectively. The HLA class II serotype, DR2, encoded by alleles DRB115 and DRB116, is associated with TB in several Indian populations, but no such association was found in studies in Poland or Cambodia.21 However, the DQB10503 HLA class II allele was associated with TB in Cambodia.22 Further work suggested that this association might be due to HLA alleles encoding an aspartic acid at codon 57 of the HLA-DQ b-chain. It was revealed that homozygosity for this SNP was strongly associated with progressive pulmonary TB.23 Moreover this variant was shown to bind a peptide from the central region of the M. tuberculosis-secreted protein ESAT-6 with low affinity and to stimulate less IFN-g production from CD4 T cells from TB patients than when this peptide was presented by an HLA-DQ-b allele encoding an alanine at codon 57.23 These observations appear important. In the Venda people in the Limpopo Province of South Africa, TB is significantly associated with HLA class II variants, common in Africa, and previously associated with resistance to malaria and hepatitis.21 Interestingly, most of the HLA-DQB1 alleles associated with TB in the Venda (alone or in haplotypes) matched alleles associated with progressive TB in Cambodia when present in homozygous form. All these alleles also encode Asp at position 57 of the HLA-DQ b-chain. Thus, although the associations of class II MHC alleles and SNPs with TB are different in different communities, there are some potentially important commonalities.21 MHC class I. There have been fewer studies of MHC class I, which presents antigens to CD8 T cells (Fig. 9.1), though recent work suggests that class 1 restricted CD8 T cells may be very important.16 A study in India suggested that HLA-B52 might be protective, while HLA-B51 was associated with susceptibility to pulmonary TB.24 CYTOKINES AND CHEMOKINES THAT MIGHT BE DETRIMENTAL TO IMMUNITY (FIG. 9.2) IFN-a/b In a mouse model, the virulence of a strain of M. tuberculosis was attributed to its tendency to drive production of IFN-a and -b rather than a Th1 response.25 It also emerged that IFN-a and -b inhibit the antimycobacterial effect of human macrophages and that hypervirulent Beijing strains of M. tuberculosis tend to up regulate IFN-a/b.26,27 However, a genetic variant that results in high levels of IFN-a/b was associated with susceptibility to sarcoidosis, but not to TB in a Japanese population.28 Th2-biasing chemokines (CCL2 and CCL18) and cytokines (IL-4) A polymorphism of the promoter region of the gene encoding CCL2 (also known as MCP-1) that results in excessive production of this chemokine is common in Mexico (50% of the population) and is strongly associated with TB both in Mexico and in Korea.29 This polymorphism might account for a significant fraction of susceptibility to TB in these communities, and has been described as the most substantial impact ever described of a human allele on adult TB at the population level.30 CCL2 drives recruitment of Th2 cells in the mouse and is associated with Th2 cytokines in man.31,32
CHAPTER
Host susceptibility and resistance to Mycobacterium tuberculosis Drive Th2 and / or Treg
M. tuberculosis
TGF-b IL-10 IL-4 Mac (or DC)
Tregs
different populations, but the associations with TB are inconsistent.44 Several studies have also looked at polymorphisms of TGF-b, but here too the results are variable, as discussed by Amirzargar et al.37
Th2
RECEPTORS FOR M. TUBERCULOSIS AND ITS COMPONENTS
Suppress anti-mycobacterial effects IFN-a/b CCL18 CCL2
9
Attract Th2 cells
Suppress IL-12
Fig. 9.2 Some relevant effects of cytokines and chemokines that might undermine the IL-12/IL-23/IFN-g pathway, and in which it is claimed that there are polymorphisms relevant to susceptibility to TB. All abbreviations are explained in the main text. Most of these mediators can be released by antigen-presenting cells and macrophages, in which case the response may be deviated towards Th2 or regulatory T cells. These T cells then become further sources of the potentially detrimental mediators. It is unlikely that any of these mediators is wholly detrimental, but they may become so when the balance of mediators is suboptimal. In particular, some regulatory cells probably play an essential role in controlling immunopathology.
The polymorphism described in Mexico and Korea is associated with asthma in Europe.33 Similarly, another Th2-associated chemokine, CCL18, might be associated with susceptibility to TB in Brazil.34 CCL18 also preferentially recruits Th2 cells and basophils, and is associated with asthma and atopic dermatitis.35,36 In conclusion part of the increased IL-4 that accompanies TB in developing countries might have a genetic basis. There is a single report that a C-T substitution in the promoter (590) of the gene encoding IL-4 is associated with protection from TB in an Iranian population.37 The significance of this is unclear. In an American population the 590 T allele was said to be associated with higher IL-4 and IgE, but in Taiwanese infants the 590 C allele was associated with higher IgE. At this stage all we can say is that it is interesting that a SNP likely to affect regulation of IL-4 might be relevant to TB. A splice variant of IL-4, designated IL-4d2, acts as an inhibitor of IL-4 and is increased in the unstimulated blood cells of individuals with stable latent TB.38 Interestingly there is, as one might expect, decreased allergic sensitization in these people with stable latent TB, possibly attributable to expression of this IL-4 antagonist.39 In sharp contrast, patients in whom TB progresses have increased expression of the agonist, IL-4, a corresponding increase in allergic sensitization, and reduced CMI responses.40–42
IL-10 and TGF-b These two cytokines are released by various regulatory cell types (described below), and can be present at high levels in progressive TB. Some authors have suggested that they are implicated in the failure of immunity to M. tuberculosis. In an African population, a variant of Slc11a1 (this gene is dicussed in detail later) associated with susceptibility to adult TB was found also to associate with higher release of IL-10 by macrophages in response to lipopolysaccharide (LPS).43 This suggested that the monocytes of people susceptible to TB might be inherently more prone to exaggerated IL-10 release, and raised the possibility that this is how SLC11A1 influences susceptibility to TB. Subsequently various polymorphisms of IL-10 have been studied in
M. tuberculosis interacts with numerous soluble molecules that modulate subsequent interactions with cells, and numerous receptors on human cells that influence immediate signalling to the cell, the initial cytokine response, and what happens to the organism after uptake (Fig. 9.3). In addition to antibody and complement, M. tuberculosis binds the surfactant proteins (SP-A and SP-D) and mannose-binding lectin (MBL) and dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), all of which are C-type lectins. M. tuberculosis also contains multiple ligands for Toll-like receptors. A number of these have genetic variants that influence susceptibility, confirming their importance.
Surfactant proteins A and D (SP-A, SP-D) Pulmonary surfactant and its components are essential for normal lung function but also play poorly defined roles in local host defence. Surfactant proteins are lectins, and bind to M. tuberculosis via carbohydrates in a saturatable and Ca2þ-dependent manner, and also bind to alveolar macrophages. SP-A enhances attachment of M. tuberculosis to alveolar macrophages, while SP-D agglutinates the organisms, though it is not clear whether (or if ) this helps the host or the organism.45 Two studies, one in a Mexican population and the other among Indians, suggested that some polymorphisms in these molecules are relevant to susceptibility to TB (Fig. 9.3).45,46 Mannose-binding lectin Mannose-binding lectin plays an important role in the early stages of primary infections and during the decay of maternal antibodies in infants. There are haplotypes resulting in low, intermediate, or high serum levels of MBL. It binds to mannose on the surface of M. tuberculosis and fixes complement, so high levels might cause
Mac (or DC)
M. tuberculosis
SP-A or SP-D
MBL NOD2
Modulate antimycobacterial function
SP110 Slc11a1
? DC-SIGN
TLR
Signals that regulate cellular functions
VDR
P2X7 purinergic receptor Vitamin D3
Nucleus
Fig. 9.3 Molecules that modulate the initial interaction between M. tuberculosis and the macrophage or dendritic cell (DC) are shown on the left. The diagram is not comprehensive, and shows only those factors in which it is reported that there are polymorphisms relevant to susceptibility to TB. By altering this initial interaction they also alter the signals that drive subsequent cellular functions. On the right are four other genetically variable molecules thought to modulate anti-mycobacterial functions. Vitamin D3, signalling via the vitamin D3 receptor (VDR), increases expression of anti-mycobacterial cathelicidins. TLR, Toll-like receptor.
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the organisms to be taken up via complement receptors (Fig. 9.3). On the other hand, when levels of MBL are low the mannose will bind to membrane mannose receptors, so uptake will be differently mediated.47 This might explain one study that has concluded that haplotypes resulting in low serum levels of MBL are protective though the reverse was found in a Chinese population.48,49
DC-SIGN DC-SIGN is another C-type lectin expressed mainly on the membranes of DC (Fig. 9.3). A recent study in a coloured population in South Africa suggested that two SNP variants (871G and 336A) confer protection against TB. Curiously, in the South African study, one of these (336A) was associated with increased expression of DC-SIGN, despite the fact that previous work had suggested that, by interacting with this receptor on DC, M. tuberculosis is able to pervert the immune response, and trigger release of IL-10.50 However, no significant association was found in a Colombian population.51 Toll-like receptors and NOD2 A polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with decreased TLR2 function. If TLR2 is important for triggering protective mechanisms such as the cathelicidin pathway, one might expect this polymorphism to be associated with susceptibility to TB.17 This was found to be the case, particularly in homozygotes.52 Another polymorphism (TLR2 Arg677Trp polymorphism, due to a C2029T nucleotide substitution) results in non-functional TLR2 and is associated with lepromatous leprosy.53 This substitution appeared to be a risk factor for TB in Tunisia.54 These findings are supported by a study of Toll–interleukin 1 receptor domain containing adaptor protein (TIRAP), an adaptor protein that mediates signals from Toll-like receptors activated by mycobacteria. The SNP C558T was associated with susceptibility to TB, particularly TB meningitis, and appeared to result in decreased signalling.55 Several components of M. tuberculosis signal via TLR2, but signalling via TLR4 is much weaker. The Asp299Gly polymorphism in human TLR4 is associated with in vivo hyporesponsiveness to LPS in Caucasians. However, no association with susceptibility to TB was found in the Gambia.56 The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and a polymorphism in this gene is associated with Crohn’s disease, for which some authors suspect a mycobacterial cause. However, no association was found with TB in a Gambian population.57 MACROPHAGE FUNCTION Vitamin D3 (calcitriol) In the 1940s attempts were made to treat TB with vitamin D3 (VitD3). When patients with skin TB (Lupus vulgaris, often due to Mycobacterium bovis) were treated with VitD3, the chronic non-healing granulomatous lesions often underwent necrosis followed by resolution.58 However, necrosis and liquefaction also occurred in deep lesions in the spine and lungs if these were present, so this therapy was discontinued, and the role of VitD3 remained uncertain.59 Circulating levels of VitD3 can be high in TB patients, because IFN-g causes upregulation of a 1-a-hydroxylase, which generates VitD3 from a circulating precursor, 25-hydroxyvitamin D3.60 A clue that this might be a protective mechanism came from the observation that notifications of TB peaked in the summer season in England and Wales, particularly among immigrants from the
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Indian subcontinent. The suggestion was that individuals with darker skins living in the UK became VitD3 deficient during the winter, leading to increased reactivation of TB, manifested clinically a few months later.61 This hypothesis assumed that VitD3 was beneficial. VitD3 was shown in 1986 to enhance the ability of human macrophages to control the growth of M. tuberculosis.62 This observation has been consolidated by the discovery that stimulation of macrophages or monocytes via TLR-2/TLR-1 heterodimers leads to upregulation not only of 1-a-hydroxylase but also of VitD3 receptors (VDR). Then VitD3 generated from 25-hydroxyvitamin D in the serum signalled via the specific VDR to induce the antimicrobial peptide cathelicidin and killing of intracellular M. tuberculosis.17 It was also noted that serum from African American individuals was less able to support this process, and this was attributed to the presence of lower levels of circulating 25-hydroxyvitamin D. This provides a potentially satisfying explanation for the apparent greater susceptibility of African Americans to TB. Further support has come from the study of genetic polymorphisms of the VDR. Homozygotes for a polymorphism at codon 352 were significantly underrepresented among individuals with TB.63 Numerous studies have revealed similar findings, but complete haplotypes tend to correlate with susceptibility or resistance to TB rather than individual polymorphisms.21 Thus it appears that the influence of polymorphisms on VDR activity is collective rather than individual. Haplotypes of VDR polymorphisms located in the promoter region, coding regions for ligand- or DNA-binding domains, and the 30 UTR, respectively, influence VDR expression, VDR transactivation activity, and mRNA stability, respectively, and collectively influence function. Protective haplotypes appear to represent more active forms of the receptor.21
Slc11a1 (formerly Nramp1) Solute carrier 11a1 (Slc11a1; formerly Nramp1; natural-resistanceassociated macrophage protein) is a proton/bivalent cation transporter that in phagocytosing macrophages is rapidly recruited to the membrane of late endosomes/lysosomes.64 Its relevance to immunity to TB was first observed in genetic studies of susceptible and resistant strains of mice where it was found to affect immunity to multiple different intracellular pathogens. Recent studies in mouse macrophages and in Dictyostelium amoebae suggest that Slc11a1 is involved in both influx and efflux of iron and other cations from late endosomes/lysosomes, the direction of transport depending upon other factors such as the pH and availability of ATP and the V-Hþ ATPase.64,65 The evidence suggests that, under physiological conditions of low intravacuolar pH, Slc11a1 transports bivalent cations into, rather than out of, late endosomes. So if Slc11a1 is involved in removing from the cell any iron taken up during phagocytosis, it might do so via a lysosomal secretory pathway, rather than by pumping iron out of the phagosome and into the cytoplasm. This means that, if M. tuberculosis is able to disturb maturation of the phagosome, regulation of intraphagosomal pH, and expression or function of V-Hþ ATPases, then it is possible that it can exploit Slc11a1 in order to scavenge iron by profiting from the increased iron in late endosomes. On the other hand Peracino et al.,65 working admittedly with Dictyostelium, suggest that if the organisms were in non-acidic, Slc11a1-positive vesicles in the post-lysosomal pathway, in the presence of abundant V-Hþ ATPase, the role of Slc11a1 might be phagosomal depletion of iron and other metal ions, which are essential for bacterial growth. However, a different view is that iron, whether moving into or out of the endosomes, is not the whole story. Slc11a1 is involved in cation fluxes that abrogate pathogen-induced blockage of phagosome maturation, and also, as mentioned earlier, seems to modulate IL-10 release.43 The truth is
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position 762 of the gene encoding the P2X7 receptor (P2RX7) in a Gambian population.69
that the role of Slc11a1 in human macrophages is not known, but it is clear that we should not be surprised that the interactions of polymorphisms of Slc11a1 with susceptibility to TB are remarkably complex. Bellamy and colleagues66 typed polymorphisms of Slc11a1 in a case–control study of TB in the Gambia, West Africa. Four polymorphisms were significantly associated with TB. Some subsequent studies have yielded similar results, but many have not.67 A metaanalysis suggests no associations with TB in subjects of European descent.67 However, a recent paper looked at associations with paediatric TB, and might have cast light on the discrepancies.68 In this paediatric study the direction of Slc11a1 allele association with TB was inverted compared with previous studies in adult pulmonary TB. Thus common Slc11a1 alleles associated with protection from adult TB emerged as risk factors for paediatric TB. The authors suggested that the common alleles are risk factors for TB with an early onset following exposure. Thus the discrepancies can be rationalized by suggesting that the common Slc11a1 alleles predispose to rapid progression, but, if that does not occur, are then associated with stable latency. In view of the complexity of the role of Slc11a1 in control of iron and of phagosome maturation and cytokine profiles, complexity at this level is not surprising.
Ipr1 and the putative human homologue, SP110 Studies in mice identified Ipr1 (intracellular pathogen resistance 1) as a gene responsible for innate resistance of macrophages to intracellular proliferation of M. tuberculosis. The closest human homologue of Ipr1 is SP110, though it has only 41% identity at the amino acid level. SP110 is induced by IFN-g and is a component of the nuclear body, a multi-protein complex thought to participate in gene regulation. Three polymorphisms of this gene were associated with disease in a population in the Gambia.70 However, large studies in Ghana and Russia failed to find associations.71,72
ENVIRONMENTAL FACTORS AND SUSCEPTIBILITY TO TUBERCULOSIS Inevitably some environmental factors (such as lack of sunlight leading to low VitD3) have been discussed above in relation to relevant polymorphisms and the varying results in different populations imply such interactions are the rule, rather than the exception. Here we discuss the major additional factors.
P2X7 purinergic receptor When extracellular ATP binds to the P2X7 purinergic receptor on macrophages, large membrane pores permeable to molecules of <0.9 kDa develop, resulting in macrophage death by a combination of apoptosis and osmotic lysis (apolysis). There is rapid simultaneous induction of killing of intracellular mycobacteria. A significant protective association against TB was found for a SNP at nucleotide
ADRENAL STEROIDS IN TUBERCULOSIS The effects of stress Psychological stress causes activation of the hypothalamus–pituitary– adrenal (HPA) axis, resulting in release of cortisol and other glucocorticoid hormones from the adrenal cortex (Fig. 9.4). Glucocorticoids bias
Stress BRAIN
Pituitary
Sympathetic efferents
Parasympathetic efferents (vagus nerve)
Noradrenaline adenosine
Acetylcholine
ACTH Adrenal cortex
Cortisone (inactive)
Biased towards Th2 and Treg
11-bhydroxysteroid dehydrogenase
Cortisol (active)
T-cells
Nucleus TNF-a Ø IL-12Ø IL-10 ¹ Microbicidal effectØ
Mac/DC
a7 nicotinic receptor
Nicotine from smoking
Fig. 9.4 Pathways from the central nervous system to the immune system activated by psychological stress. The pathways are also activated by feedback from inflammation signalled via sensory afferents, and by cytokines passing from the blood into the brain via the circumventricular organs. Cortisol is the most important in chronic stress, and, in animal models, stress-induced activation of TB can be mimicked by slow release glucocorticoid pellets. These pathways tend to alter the cytokine profile of macrophages and dendritic cells, in such a way that anti-mycobacterial mechanisms are likely to be compromised (this has been shown for cortisol) and the T-cell response deviated towards Th2 and regulatory cells. Nicotine, taken in when smoking, will suppress tumour necrosis factor (TNF) release, while leaving interleukin (IL)-10 release unaltered, by triggering the a7 nicotinic acetylcholine receptor.
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the response to type 2 cytokine production via effects on dendritic cells, which secrete less IL-12 and more IL-10 in their presence, and also directly down regulate the anti-mycobacterial effects of macrophages.73–76 Therefore reactivation of latent TB can be caused by glucocorticoid therapy or by activation of the HPA axis by stress. For example living in war zones or poverty are both associated with TB.77 The TB-promoting effects of stress have been demonstrated under more controlled conditions in mice as well as in cattle and cervids.78,79
The HPA axis and dysregulation of the cortisol–cortisone shuttle in human tuberculosis In TB patients who are rested and acclimatized to hospital and so are no longer stressed by their environment, the cortisol diurnal rhythm is normal and so are the responses of the adrenals to corticotropin-releasing hormone (CRH) and to very low doses (i.e. physiological) of ACTH.80,81 The total 24-hour cortisol output may be normal or modestly raised. However, there is a change in the pattern of metabolism of cortisol, indicating a large alteration in the equilibrium point of the cortisol–cortisone shuttle.80 A major mechanism for the regulation of local tissue cortisol levels is the interconversion of active cortisol (11-hydroxy) and inactive cortisone (11-keto) by 11b-hydroxysteroid dehydrogenases (11bHSD). Thus cortisol concentrations in different organs can be very different from the values found in the serum. Gas chromatography and mass spectrometry revealed a striking excess of metabolites of cortisol relative to metabolites of cortisone in 24-hour urine collections from TB patients.80 Subsequent analysis of alveolar lavage samples revealed that the site of abnormal conversion of inactive cortisone to active cortisol is the infected lung itself, probably because both TNF-a and IL-1b increase the expression levels and reductase activity of 11b-HSD-1.81,82 The result is a local increase in cortisol levels not apparent from measurements of serum cortisol. This cortisol excess would presumably cause a shift towards type 2 cytokine expression, deactivation of the anti-mycobacterial effects of macrophages, increased IL-10, and increased TGF-b, so it may contribute to the changes seen in the human disease. Another pathway that might be activated by stress involves downregulation of TNF-a with concomitant maintenance of IL-10 levels, due to an effect on macrophages of acetylcholine released from vagal efferents.83 This mechanism is discussed later in the context of the effects of smoking, which also act via this pathway. Dehydroepiandrosterone and its metabolites in tuberculosis The most abundant steroid secreted by the adrenal cortex in man is dehydroepiandrosterone. Secretion is greatly decreased in TB patients.80 While this is not disease-specific because a similar fall occurs in most illnesses, it might be important. In a mouse model of pulmonary TB, dehydroepiandrosterone and a derivative, androstenediol, were protective and partly therapeutic, but not a practical therapy for humans because they are converted in the gonads into sex steroids.84 A synthetic analogue, 16a-bromoepiandrosterone (HE-2000), which has the advantage that it cannot enter sex steroid pathways, was also both protective and therapeutic in this model, and is currently in human clinical trials.85 SMOKING Epidemiological evidence from the UK, China, India, and the USA, implicating smoking as a risk factor for TB, has been reviewed elsewhere.86 Where an association has been found there seems to be an increase in TB case rates by between two- and fourfold for those
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smoking in excess of 20 cigarettes a day, but in some environments it is difficult to control for other factors associated with smoking such as poverty, poor educational standards, and excessive alcohol consumption. The effect of smoking is likely to be due to suppression of TNF-a levels in the lungs. Acute effects of nicotine on the immune system are mediated via the HPA axis, but adrenalectomy does not eliminate the chronic effects. It was then noted that nicotine caused increased proliferation of Legionella within a macrophage line in vitro, presumably inhibiting activation via nicotinic acetylcholine receptors,. Acetylcholine released from cholinergic vagal efferents strongly inhibits release of TNF-a from tissue macrophages.83 The effect is so potent that mice with severed vagus nerves are much more susceptible to fatal LPS-induced shock, and die with exaggerated circulating levels of TNF-a.83 The animals can be protected by electrical stimulation of the peripheral end of the cut vagus, which reduces the circulating TNF-a levels that result from the LPS challenge.83 Macrophages express high levels of the a-7 subunit of the nicotinic acetylcholine receptor, and downregulation of TNF-a via the vagus is eliminated in a-7 knockout animals.87 The anti-inflammatory cytokine IL-10 is not inhibited by nicotine acting on nicotinic receptors, so smokers will have a high IL-10/ TNF-a ratio in their lungs. Thus smoking, like neutralizing antibodies to TNF, might be expected to encourage activation of TB.
POVERTY AND MALNUTRITION Malnutrition tends to occur together with poverty, stress, and smoking, so it is difficult to isolate the nutritional component. Similarly, malnutrition could follow rather than precede development of TB. However, malnutrition is thought to impair Th1 responses. A recent study compared the incidence of TB in individuals with and without coeliac disease, which is a disorder of the gut often associated with malnutrition. There was a marked increase in TB in those with this disorder.88 In Indonesia TB was associated with malnutrition and with diabetes mellitus.89 Much more work is needed to define the roles of overall protein or carbohydrate malnutrition, or of specific deficiencies such as vitamin A and zinc. Multiple deficiencies tend to occur in the same individuals.
INTERFERENCE BY EXPOSURE TO ENVIRONMENTAL MYCOBACTERIA AND HELMINTHES The mycobacteria include hundreds of saprophytic environmental species common in soil and untreated water. Therefore in developing countries, even healthy individuals not exposed to M. tuberculosis have a background response to mycobacteria that is cross-reactive with M. tuberculosis as a result of contact with environmental species. Skin-test studies with reagents prepared from these species show that in developing countries almost everyone is skin-test positive to many mycobacterial antigens, whereas in developed countries at higher latitudes this is increasingly unusual, presumably because of changes in lifestyle, and chlorination of water supplies.90 There is strong evidence that contact with environmental mycobacteria can induce a Th1 response and provide some protection from TB. This effect can sometimes mask the effects of BCG.91 However, contact with environmental mycobacteria is very variable in different environments, and can also drive Th2 responses and regulatory T cells.
Th2 RESPONSES The evidence that a Th2 response is detrimental in TB has been reviewed in detail, and Fig. 9.5 illustrates some of the mechanisms
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Alternative activation of macrophages
REGULATORY T CELLS
Transferrin receptors ¹
Intracellular iron¹
TNF-aØ
sTNFR¹
Apoptosis Ø
iNOSØ
Arginase ¹
RNI Ø
Regulatory T cells, of which many different types are being identified, are involved in the control of the strength, nature, and duration of the immune response. Thus they fill a necessary role as modulators of excessive inflammatory reactions. Since TB is largely a disease of immunopathology it is possible that a defect in regulatory pathways, whether caused by genes or environment, could lie behind the pathogenesis of TB. On the other hand excessive regulation that suppresses a key protective pathway may be a factor leading to susceptibility in some people. In short, TB might be accompanied by too little regulation leading to immunopathology, too much regulation leading to suppressed effector mechanisms, or the wrong type of regulation leading to inappropriate effector functions such as Th2. It is inevitable that some environmental mycobacteria prime regulatory T cells. In the case of Mycobacterium vaccae these regulatory cells switch off Th2 responses, which might be beneficial.95,96 However, it is likely that different environmental species prime different types of regulation. This issue has not yet been explored. TB is accompanied by IL-10-secreting T cells that might be Tr1 regulatory cells, TGF-bsecreting cells, which include T cells possibly corresponding to Th3 regulatory cells, CD4+ CD25+ Foxp3+ regulatory cells, Th1-like cells that secrete both IFN-g and IL-10, and CD8+ LAG-3+ cells driven by living mycobacteria in vitro.97–102 In conclusion, while the role of environmental organisms in priming different subsets of effector and regulatory T cells is almost entirely unexplored, it is likely to be a major area of work for the future.
Reduced microbial activity
Immunoregulation FOXP-3+
Treg ¹
T-cell function Ø
Immunopathology VCAM-1¹
Cell infiltration¹
IL-4/TNF synergy ¹
Toxicity TNF¹
b transcript of GC receptor ¹
Inflammation¹
Arginase ¹
Collagen¹
ornithine ¹
TGF-b ¹ LTBP Ø MMP-9 ¹
Activated TGF-b
Necrosis
Fibrosis
Fig. 9.5 Some of the ways in which excessive Th2 activity, particularly IL-4, is likely to be detrimental to immunity to TB. STNFR, soluble TNF receptors; iNOS, inducible nitric oxide synthase; VCAM-1, vascular cell adhesion molecule-1; GC, glucocorticoid; LTBP1, latent transforming growth factor-b binding protein-1; MMP-9, matrix metalloproteinase 9.
involved.40 The size of the background Th2 response is strikingly higher in countries close to the equator where BCG vaccination fails to protect adults from TB, and the Th2 response that accompanies the disease is similarly greatest in these areas.92 Genetic factors that might influence this were outlined earlier. The response induced by environmental mycobacteria in developing countries is not a ‘pure’ Th1 response. This was shown in blood samples from Malawians, in which PPD (antigens precipitated from M. tuberculosis culture supernatant) induced secretion of the Th2 cytokine IL-5, whereas little IL-5 was seen in samples from the UK run in parallel. BCG vaccination failed to down regulate this IL-5 response to M. tuberculosis in Malawians (Dockrell HM, Black GF, Weir RE, personal communication). The Th2 component of the response might be enhanced by the exposure of mother and child to helminthes, which commonly induce Th2 immune responses. BCG vaccination induced a Th2-biased response in babies that had been sensitized in utero to antigens of the Th2-inducing helminthes Wuchereria bancrofti or Schistosoma haematobium as a result of maternal infection.93 Helminthes also induce regulatory T cells, and the presence of helminthes will modulate not only the response of these babies to BCG but also their response to cross-reactive environmental mycobacteria. It is therefore inevitable that populations in developing countries have mixed Th1, Th2, and Treg responses to mycobacteria.94
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CONCLUDING REMARKS In this chapter we have discussed a selection of genetic and environmental factors that modulate susceptibility to TB. We have concentrated on those that cast light on pathogenesis. Perhaps the most useful thing to emerge from the genetics is the fact that defects in the IL-12/IL-23/IFN-g pathways seem more likely to cause increased susceptibility to infection with mycobacteria of low virulence than susceptibility to M. tuberculosis itself. This observation, together with the association of TB with factors such as SNPs of vitamin D receptors, might imply that the major effector mechanisms needed for control of M. tuberculosis are only partly linked to the standard Th1 pathway. The second major conclusion is that there is so much variation in the genetics of the organisms, the genetics of the populations they infect and the nature of the environments with which these genes interact that the pathogenesis of TB might be different in different parts of the world. If this is so we might need different vaccines, diagnostic reagents, and immunotherapies in different places. We clearly have much to learn, and current ideas about vaccine design might need to be modified as our knowledge increases.
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live Mycobacterium tuberculosis in pulmonary tuberculosis. FEMS Immunol Med Microbiol 2006;46:433–437. Soborg C, Madsen HO, Andersen AB, et al. Mannose-binding lectin polymorphisms in clinical tuberculosis. J Infect Dis 2003;188:777–782. Liu W, Zhang F, Xin ZT, et al. Sequence variations in the MBL gene and their relationship to pulmonary tuberculosis in the Chinese Han population. Int J Tuberc Lung Dis 2006;10: 1098–1103. Barreiro LB, Neyrolles O, Babb CL, et al. Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis. PLoS Med 2006;3:e20. Gomez LM, Anaya JM, Sierra-Filardi E, et al. Analysis of DC-SIGN (CD209) functional variants in patients with tuberculosis. Hum Immunol 2006;67:808–811. Ogus AC, Yoldas B, Ozdemir T, et al. The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 2004;23:219–223. Bochud PY, Hawn TR, Aderem A. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol 2003;170:3451–3454. Ben-Ali M, Barbouche MR, Bousnina S, et al. Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol 2004;11:625–626. Hawn TR, Dunstan SJ, Thwaites GE, et al. A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis 2006;194:1127–1134. Newport MJ, Allen A, Awomoyi AA, et al. The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis (Edinb) 2004;84:347–352. Stockton JC, Howson JM, Awomoyi AA, et al. Polymorphism in NOD2, Crohn’s disease, and susceptibility to pulmonary tuberculosis. FEMS Immunol Med Microbiol 2004;41:157–160. Macrae DE. Calciferol treatment of Lupus vulgaris. BMJ 1947;59:333–338. Brincourt J Le calcife´rol a-t-il une action lique´fiante sur le caseum? Poumon Coeur 1967;23:841–851. Cadranel J, Hance AJ, Milleron B, et al. Vitamin D metabolisim in tuberculosis. Production of 1,25 (OH)2 D3 by cells recovered by bronchoalveolar lavage, and the role of this metabolite in calcium homeostasis. Am Rev Respir Dis 1988;138:984–989. Davies PD. The role of vitamin D in tuberculosis. Am Rev Respir Dis 1989;139:1571. Rook GAW, Steele J, Fraher L, et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986;57:159–163. Bellamy R, Ruwende C, Corrah T, et al. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999;179:721–724. Mulero V, Searle S, Blackwell JM, et al. Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake. Biochem J 2002;363:89–94. Peracino B, Wagner C, Balest A, et al. Function and mechanism of action of Dictyostelium Nramp1 (Slc11a1) in bacterial infection. Traffic 2006;7:22–38. Bellamy R, Ruwende C, Corrah T, et al. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998;338:640–644. Li HT, Zhang TT, Zhou YQ, et al. SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis. Int J Tuberc Lung Dis 2006;10:3–12. Malik S, Abel L, Tooker H, et al. Alleles of the NRAMP1 gene are risk factors for pediatric
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tuberculosis disease. Proc Natl Acad Sci USA 2005;102:12183–12188. Li CM, Campbell SJ, Kumararatne DS, et al. Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population. J Infect Dis 2002;186:1458–1462. Tosh K, Campbell SJ, Fielding K, et al. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc Natl Acad Sci USA 2006; 103:10364–10368. Thye T, Browne EN, Chinbuah MA, et al. No associations of human pulmonary tuberculosis with Sp110 variants. J Med Genet 2006;43:e32. Szeszko JS, Healy B, Stevens H, et al. Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis. Hum Genet 2007;121: 155–160. Brinkmann V, Kristofic C. Regulation by corticosteroids of Th1 and Th2 cytokine production in human CD4+ effector T cells generated from CD45RO- and CD45RO+ subsets. J Immunol 1995;155:3322–3328. Ramirez F, Fowell DJ, Puklavec M, et al. Glucocorticoids promote a Th2 cytokine response by CD4+ T cells in vitro. J Immunol 1996; 156:2406–2412. Vieira PL, Kalinski P, Wierenga EA, et al. Glucocorticoids inhibit bioactive IL-12p70 production by in vitro-generated human dendritic cells without affecting their T cell stimulatory potential. J Immunol 1998;161:5245–5251. Rook GA, Steele J, Ainsworth M, et al. A direct effect of glucocorticoid hormones on the ability of human and murine macrophages to control the growth of M. tuberculosis. Eur J Respir Dis 1987; 71:286–291. Spence DP, Hotchkiss J, Williams CS, et al. Tuberculosis and poverty. BMJ 1993; 307:759–761. Brown DH, Sheridan J, Pearl D, et al. Regulation of mycobacterial growth by the hypothalamuspituitary-adrenal axis: differential responses of Mycobacterium bovis BCG-resistant and -susceptible mice. Infect Immun 1993;61:4793–4800. Griffin JF, Buchan GS. Aetiology, pathogenesis and diagnosis of Mycobacterium bovis in deer. Vet Microbiol 1994;40:193–205.
80. Rook GAW, Honour J, Kon OM, et al. Urinary steroid metabolites in tuberculosis; a new clue to pathogenesis. Q J Med 1996;89:333–341. 81. Baker RW, Walker BR, Shaw RJ, et al. Increased cortisol-cortisone ratio in acute pulmonary tuberculosis. Am J Respir Crit Care Med 2000; 162:1641–1647. 82. Escher G, Galli I, Vishwanath BS, et al. Tumour necrosis factor and interleukin 1 enhance the cortisone/cortisol shuttle. J Exp Med 1997; 186:189–198. 83. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–462. 84. Hernandez-Pando R, de la Luz Streber M, Orozco H, et al. The effects of androstenediol and dehydroepiandrosterone on the course and cytokine profile of tuberculosis in Balb/c mice. Immunology 1998;95:234–241. 85. Hernandez-Pando R, Aguilar-Leon D, Orozco H, et al. 16 alpha Bromoepiandrosterone restores T helper cell type 1 activity and accelerates chemotherapy-induced bacterial clearance in a model of progressive pulmonary tuberculosis. J Infect Dis 2005;191:299–306. 86. Davies PD, Yew WW, Ganguly D, et al. Smoking and tuberculosis: the epidemiological association and immunopathogenesis. Trans R Soc Trop Med Hyg 2006;100:291–298. 87. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384. 88. Ludvigsson JF, Wahlstrom J, Grunewald J, et al. Coeliac disease and risk of tuberculosis: a population-based cohort study. Thorax 2007; 62:23–28. 89. Alisjahbana B, van Crevel R, Sahiratmadja E, et al. Diabetes mellitus is strongly associated with tuberculosis in Indonesia. Int J Tuberc Lung Dis 2006;10:696–700. 90. Fine PE, Floyd S, Stanford JL, et al. Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy. Epidemiol Infect 2001;126:379–387. 91. Tuberculosis Research Centre (ICMR) C. Influence of sex, age and nontuberculous infection at intake on the efficacy of BCG: re-analysis of 15-year data
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from a double-blind randomized control trial in south India. Indian J Med Res 2006;123:119–124. Rook G, Dheda K, Zumla A. Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting? Vaccine 2005;23: 2115–2120. Malhotra I, Mungai P, Wamachi A, et al. Helminthand Bacillus Calmette-Guerin-induced immunity in children sensitized in utero to filariasis and schistosomiasis. J Immunol 1999;162:6843–6848. Elias D, Akuffo H, Britton S. Helminthes could influence the outcome of vaccines against TB in the tropics. Parasite Immunol 2006;28:507–513. Zuany-Amorim C, Sawicka E, Manlius C, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002;8:625–629. Hernandez-Pando R, Pavon L, Orozco EH, et al. Interactions between hormone-mediated and vaccine-mediated immunotherapy for pulmonary tuberculosis in Balb/c mice. Immunology 2000;100:391–398. Delgado JC, Tsai EY, Thim S, et al. Antigenspecific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc Natl Acad Sci USA 2002;99: 7576–7581. Toossi Z, Ellner JJ. The role of TGF beta in the pathogenesis of human tuberculosis. Clin Immunol Immunopathol 1998;87:107–114. Guyot-Revol V, Innes JA, Hackforth S, et al. Regulatory T cells are expanded in blood and disease sites in tuberculosis patients. Am J Respir Crit Care Med 2005;173:803–810. Ribeiro-Rodrigues R, Resende Co T, Rojas R, et al. A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol 2006;144:25–34. Gerosa F, Nisii C, Righetti S, et al. CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 1999;92:224–234. Joosten SA, van Meijgaarden KE, Savage ND, et al. Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. Proc Natl Acad Sci USA 2007;104(19):8029–8234.
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Co-pathogenesis of tuberculosis and HIV Stephen D Lawn and Linda-Gail Bekker
INTRODUCTION The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic has had a devastating impact on TB control globally and TB has emerged as one of the principal causes of HIV-associated morbidity and mortality worldwide.1,2 The countries of sub-Saharan Africa have been hit hardest, with annual notification rates rising two- to threefold in many countries since 1990; more than half of patients with TB in these countries also have HIV-1 coinfection.1 Whereas TB notification rates continue to decrease in most countries of the world, the African epidemic fuelled by HIV was reported in 2005 to be driving up the global incidence of TB by 1% per year.3 While the effects of HIV on the epidemiology of TB became quickly apparent, it also emerged that the interaction between these diseases was bidirectional. In the 1990s, studies showed that immunological activation associated with TB could also enhance the pathogenesis of HIV infection, potentially causing accelerated decline in immune function in coinfected patients.4,5 The bidirectional synergy between these two infections continues to exact a very heavy toll particularly in communities in resourcelimited settings with a high prevalence of HIV. In this chapter, a brief overview of these interactions as revealed by epidemiological, clinical, and histopathological data is followed by an exploration of the immunological mechanisms underlying these observations. The specific defects in cellular antimycobacterial immunity caused by HIV-1 infection are reviewed in detail. Thereafter we examine the impact of TB-induced immune activation on the replication and immunopathogenesis of HIV at sites of TB disease and systemically.
IMPACT OF HIV ON TB EPIDEMIOLOGICAL DATA Infection with HIV-1 has emerged as the single strongest risk factor for development of active TB. This may be the result of a number of different processes and underlying immunological mechanisms. HIV-infected individuals may be more frequently exposed to Mycobacterium tuberculosis infection and outbreaks of TB have been described among patients attending healthcare facilities in both high-income and resource-limited settings.6–8 It is not known, however, whether HIV-infected individuals have a greater risk of
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acquiring M. tuberculosis infection than HIV-uninfected individuals following a similar exposure to the organism. The fact that certain aspects of innate immune function are impaired by HIV infection might potentially increase host susceptibility to M. tuberculosis infection following exposure. Data from outbreaks among drug abusers in New York, however, found no increased risk of M. tuberculosis infection among those individuals who were HIV-infected.9 This study was limited, though, as these data were derived using the tuberculin skin test (TST), which has lowered sensitivity to detect M. tuberculosis infection in the context of HIV coinfection. The high incidence of active TB reported in outbreaks among HIV-infected people may instead reflect more rapid progression of M. tuberculosis infection to active primary disease rather than an increased incidence of initial M. tuberculosis infection.10 The risk of progressive primary disease is indeed high following infection with M. tuberculosis. Attack rates of 30–40% have been reported among HIV-infected patients exposed to M. tuberculosis in healthcare settings, with many patients developing disease within 1–2 months of initial exposure.6,10 This suggests that the host granulomatous response to early M. tuberculosis infection is impaired by HIV infection. A great majority of HIV-uninfected individuals with latent M. tuberculosis infection do not develop TB disease as their cellular immune function is adequate to maintain the mycobacterial infection in a clinically latent state. The lifetime risk of active TB among HIV-uninfected individuals with latent M. tuberculosis infection is estimated to be 2–23%.11 In contrast, HIV-infected patients with latent M. tuberculosis infection have a high risk of reactivation, with approximately 10% of such individuals developing active TB disease each year.9 This observation strongly suggests that the ability to maintain M. tuberculosis latency within granulomas long term is abrogated by HIV-1 coinfection.12 An estimated one-third of the world’s population is infected with M. tuberculosis, with much higher rates in poor communities in resource-limited settings that have high HIV prevalence. The broad geographical overlap of these infections is a critical factor explaining the huge impact of HIV on global TB control.
CLINICO-RADIOLOGICAL DATA The HIV-1 epidemic has not only had a great impact on the epidemiology of TB, but the clinical, radiological, and histopathological features of the disease are often modified in coinfected patients. In contrast to many other opportunistic infections, TB occurs across a wide spectrum of immunodeficiency.13 This reflects the greater virulence
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of M. tuberculosis compared with other opportunistic pathogens such as Mycobacterium avium complex, Pneumocystic jiroveci, and Cryptococcus neoformans, which typically only cause disease among patients with advanced immunodeficiency. The features of TB in HIV-1-infected individuals with wellpreserved CD4 T cell counts are indistinguishable from those of individuals with TB but no HIV-1 coinfection. However, progressive immunodeficiency is associated with an increasing frequency of miliary and disseminated forms of disease, reflecting failure of containment of the mycobacterial infection.14,15 Impaired tissue inflammatory response to infection affects the radiographic appearances of pulmonary TB, with reduced consolidation, fibrosis, and cavitation, and also results in sputum smear microscopy for acidfast bacilli (AFB) being less frequently positive.15,16 Mortality rates among patients with TB and HIV-1 coinfection are high and may be due to either TB itself or another HIV-associated illness.17,18 HIV coinfection is also associated with high rates of cutaneous anergy to TST, indicating failure of delayed type hypersensitivity responses to mycobacterial antigens.15,19 Interestingly, though, TST responses do not gradually diminish with progressive immunodeficiency as one might expect but instead appear to be an ‘all-ornothing’ phenomenon.19 Although the proportion of HIV-infected
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patients who have cutaneous anergy to TST increases with progressive immunodeficiency, positive TST responses of HIV-infected patients are nevertheless similar in magnitude to the positive responses of HIV-uninfected patients.15,19
HISTOPATHOLOGICAL DATA Autopsy specimens from patients with AIDS who died of TB reveal a very high frequency of extrapulmonary and disseminated disease with multiorgan involvement.20 Occult-disseminated TB is a frequent finding in postmortem studies of people from subSaharan Africa who died with AIDS.21,22 Histological studies of tissue specimens from individuals with TB and HIV-1 coinfection reveal a spectrum of appearances that reflects the degree of immunosuppression. Lucas et al.23 described three histological stages of cellular immune response that correlate with depletion of the peripheral blood CD4 T-cell count (Fig. 10.1): 1. Immunocompetent individuals with HIV-1 infection develop TB granulomas characterized by abundant epithelioid macrophages, Langhans giant cells, peripherally located CD4 T cells, and a paucity of AFB.
B
A
C Fig. 10.1 (A) Low-power photomicrograph of haematoxylin and eosin-stained tissue containing a typical well-formed tuberculous granuloma in an immunocompetent individual showing central caseous necrosis, mononuclear cell infiltrate, and surrounding fibrosis. (B) Medium-power photomicrograph of tissue from an HIV-infected patient with TB and advanced immunodeficiency showing a mononuclear cell infiltrate but complete absence of granuloma formation. (C) High-power tissue section from the specimen in (B) with Ziehl–Neelsen staining showing numerous bacilli of M. tuberculosis that have multiplied in the absence of an effective host response. Photomicrographs kindly supplied by the Department of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, South Africa.
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2. In those with moderate HIV-associated immunodeficiency, Langhans giant cells are not seen, epithelioid differentiation and activation of macrophages are absent, there is CD4 lymphocytopenia, and AFB are more numerous. 3. In patients with advanced HIV-associated immunosuppression and AIDS, there is a striking paucity of granuloma formation with little cellular recruitment, very few CD4 T cells, and even larger numbers of AFB. These data indicate that progressive HIV-associated immunodeficiency is associated with progressive profound impairment of the granulomatous host response to M. tuberculosis. This spectrum of histological appearances bears a striking resemblance to that of leprosy, which is also the result of broadly divergent immune responses to the causative organism, Mycobacterium leprae. Patients with tuberculoid leprosy have strong cellular immune responses to M. leprae and so their disease is paucibacillary and is characterized by abundant granuloma formation. This resembles the histological appearances of TB in HIV-infected patients who have well-preserved immunity. In contrast, patients with lepromatous leprosy have very poor cellular responses to M. leprae; their disease is multibacillary with no granuloma formation, similar to the histological appearances of TB in HIV-infected patients who have advanced immunodeficiency.
IMPAIRMENT OF IMMUNE RESPONSES TO M. TUBERCULOSIS The immune response to M. tuberculosis is multifaceted, engaging several arms of the immune system. Macrophages are the key cell type effecting anti-mycobacterial immune responses. However, M. tuberculosis may evade intracellular killing mechanisms and persisting organisms then replicate within the intracellular environment of macrophages. Antigen presentation to CD4 T cells leads to the development of cell-mediated immune responses and delayed-type hypersensitivity (DTH) within 2–4 weeks of initial infection.24,25 Secretion of interleukin-12 (IL-12) by macrophages facilitates clonal expansion of CD4 T-helper type-1 lymphocytes, which secrete interferon-g (IFN-g). This cytokine is a potent activator of macrophages, promoting mycobacterial killing.26 Further release of chemokines, such as IL-8, and proinflammatory cytokines, such as tumour necrosis factor-a (TNF-a), facilitate mononuclear cell recruitment and activation, respectively. Subsequent orchestration of the granulomatous host response provides the critical environment within which the host limits M. tuberculosis infection.27 The TB granuloma is characterized by activation and epithelioid differentiation of macrophages and by development of multinucleate Langhans giant cells.28 CD4 T cells located within the periphery of the granuloma play a major role in orchestrating cell-mediated immune function. Central caseous necrosis inhibits extracellular bacillary growth. When granulomas fail to limit M. tuberculosis infection, however, the caseous centre liquefies, permitting rampant, uninhibited extracellular bacterial replication. Subsequent spreading tissue destruction and cavity formation result in TB disease.24 The pivotal role of CD4 T cells in orchestrating the acquired cellular response to M. tuberculosis has been emphatically demonstrated by the impact of HIV coinfection on these processes.12,29 Here we describe the impact of HIV on the critical cellular processes involved in these responses.
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IMPACT ON MONONUCLEAR PHAGOCYTES Macrophages are central to the pathogenesis of both TB and HIV-1 infection. They serve as the principal effector cells within both the innate and adaptive immune responses to M. tuberculosis. However, these cells also provide the preferred intracellular environment for mycobacterial growth and support HIV replication. Mononuclear phagocytes are not numerically depleted during HIV infection in vivo. However, monocyte/macrophage functions essential for adequate innate and adaptive responses to pathogens, such as chemotaxis, phagocytosis, intracellular killing, antigen presentation, and cytokine production, may all be affected by HIV-1 infection.12,30,31 Most data concerning this are derived from in vitro studies using non-mycobacterial organisms, although studies have reported that HIV impairs phagocytosis of M. avium complex and is associated with increased growth of M. tuberculosis within macrophages.32,33 Alveolar macrophages account for >85% of the immune cells of the lung and play a central role in the innate immune response to numerous pulmonary pathogens, including M. tuberculosis. Defects in mononuclear cell function may therefore render individuals more susceptible to M. tuberculosis infection following aerosol inhalation. However, the relevance of much of these data generated in vitro using non-mycobacterial organisms and using cell lines rather than primary alveolar macrophages must be limited. Furthermore, as discussed earlier, there is no epidemiological evidence that HIV-1-infected individuals have increased rates of M. tuberculosis infection following exposure. Thus, any impact of HIV on host innate immune function is likely to be less important than the effects on acquired immune responses that require the complex coordinated interplay between CD4 T cells and macrophages. Dendritic cells (DCs) are vital in the defence against many pathogens, serving as efficient antigen-presenting cells and playing an important role in determining the phenotype of subsequent acquired immune responses. Both plasmacytoid (pDC) and myeloid (mDC) subsets are reduced in numbers in HIV infection but the impact of this on immune responses to M. tuberculosis is unknown.34 However, in recent years it has emerged that both HIV and M. tuberculosis are independently able to subvert DC functions to escape immune surveillance.35,36 HIV-1 targets DC-SIGN (DC-specific-intercellular-adhesion-molecule-3-grabbing-nonintegrin) to protect it from antigen processing and to facilitate its transport to lymphoid tissue. Mycobacterium tuberculosis is also able to bind to DC-SIGN, leading to IL-10 production and inhibition of the immuno-stimulatory function of dendritic cells.
IMPACT ON CD4 T CELLS Although HIV infection is characterized by progressive CD4 T-cell loss, CD4 T cells in HIV-infected persons are functionally impaired prior to significant decreases in CD4 T-cell counts in peripheral blood.37 The various mechanisms potentially responsible for this are summarized in Fig. 10.2 and cause sequential loss of responses to recall antigens, antigens, alloantigens, and finally mitogens.37 These defects progress as the CD4 T-cell count decreases. Functional impairment of M. tuberculosis-specific CD4 T cells provides a likely explanation for the doubling of TB risk following acquisition of HIV infection among patients despite well-preserved CD4 T-cell counts.38 A number of different mechanisms may inhibit TB-specific CD4 T-cell function. Activation and proliferation of both HIV-infected
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Co-pathogenesis of tuberculosis and HIV ØIL-12, ¹IL-10 5.
ØIL-2
ØIFN-g 4.
1. 3. Macrophage
2.
CD4+ lymphocyte
¹¹TNF-a
Fig. 10.2 Mechanisms that may contribute to the impact of HIV-1 on
generation of cell-mediated immune responses to M. tuberculosis include: (1) binding and phagocytosis of M. tuberculosis by macrophages; (2) M. tuberculosis intracellular killing; (3) M. tuberculosis antigen processing and presentation; (4) CD4 T-cell activation and proliferation; and (5) effector cytokine production. Adapted from Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002 May;4:635–46.
and -uninfected CD4 T cells is impaired through inhibition of the IL-2 signalling pathway.39 The HIV-1 major surface envelope glycoprotein 120 (gp120) inhibits both antigen-driven IL-2 production and surface IL-2-receptor-a (IL-2R-a) expression.40 This is mediated, at least in part, by HIV gp120 binding to CD4 receptors. This hinders the physiological binding of the natural ligand, class II human lymphocyte antigen (HLA class II), which is essential to T-cell recognition of foreign antigen. HIV-1 also directly downregulates CD4 receptors and blocks expression of HLA class II, further impeding antigen presentation.41,42 Furthermore, HIV-1 tat transactivator also directly inhibits both IL-2 and IL-2Ra expression in HIV-infected CD4 T cells.43 Together these mechanisms result in partial inhibition or failure of expansion and activation of M. tuberculosis-specific CD4 T cells at sites of M. tuberculosis infection. Effective cell-mediated immunity to M. tuberculosis is characterized by strong T-helper type-1 IFN-g-secreting lymphocyte responses, which develop in the presence of macrophage-derived IL-12. The pivotal role of this cytokine pathway in mediating immune responses to mycobacteria is clearly illustrated by the greatly increased susceptibility of individuals with IL-12-receptor or IFN-g-receptor deficiencies to diseases caused by these organisms.44 During progression of HIV-1 infection, mononuclear cells lose their ability to secrete T-helper type-1 cytokines (IL-2, IFN-g, IL-12) and instead produce increased levels of the T-helper type-2 cytokines, IL-4 and IL-10.45 IL-10 antagonizes M. tuberculosis-induced Thelper type-1 responses and diminishes macrophage effector function in mycobacterial infection.46,47 TNF-a, which is secreted in high concentrations in individuals with TB and HIV-1 coinfection, also negatively regulates IL-12 production.48 Moreover, HIV-1 infection decreases expression of CD40 ligand (CD40L) on CD4 T cells, leading to diminished activation of macrophages via the CD40 receptor and thereby decreasing IL-12 secretion.49 Thus, Thelper type-2 skewing of lymphocyte responses in individuals with HIV-1 infection may further undermine their ability to generate effective cell-mediated responses to M. tuberculosis infection. Generalized loss of CD4 T cells in HIV-1-infected persons is the result of a complex pattern of gradual changes in the composition
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of T-cell subsets with depletion of both the CD4 and CD8 naı¨ve (CD45RA) subsets and the CD4 memory (CD45RO) subset.50 Several distinct processes contribute to loss of these cell subsets, including virus-induced cell death, the immune destruction of infected cells, apoptosis, and impaired lymphocyte regeneration. These losses may be accelerated in patients with TB as discussed later in this chapter. However, in addition to depletion of the systemic pool of CD4 T cells, cellular response at sites of TB disease are particularly impaired. Examination of bronchoalveolar lavage (BAL) fluid obtained from diseased lung segments of patients with pulmonary TB reveals a failure of recruitment and activation of CD4 T cells in patients who are HIV infected.51 Local depletion of CD4 T cells at sites of TB may be the result of impaired chemotaxis and inhibition of T-cell proliferation. Rates of cell loss may be high due to virus-induced cytolysis, with HIV-1 replication being greatly enhanced at sites of TB infection. Moreover, immune activation associated with TB and HIV-1 coinfection provides a potent stimulus for activation-induced cell apoptosis, depleting both HIV-1-infected CD4 T cells and uninfected bystander CD4 and CD8 T cells at the site of disease.52–56
IMPACT ON THE TUBERCULOSIS GRANULOMA The development of the TB granuloma can be divided into three steps: 1. development of a monocytic infiltrate; 2. aggregation, maturation, and organization of mononuclear cells into a granuloma; and 3. further evolution into an epithelioid granuloma.28 Although granulomatous lesions have been well characterized at the histological level, the cellular mechanisms and cytokine and chemokine pathways involved in the initiation, organization, and maintenance of granulomas are poorly understood.27 However, many of the HIV-induced defects in mononuclear cell function described above are likely to culminate in failure of the assembly and function of effective TB granulomas. These defects include impaired chemotaxis, cytokine dysregulation, bactericidal functioning of macrophages, and proliferative T-cell responses. Furthermore, progressive immunosuppression associated with the development of AIDS also results in failure of epithelioid differentiation of macrophages, formation of Langhans giant cells, and caseous necrosis.23 Thus, HIV impairs the formation of granulomas needed to contain new or spreading M. tuberculosis infection. Many patients living in high TB burden countries are likely to have acquired latent M. tuberculosis infection prior to acquisition of HIV infection. In such patients, increased risk of TB may largely be due to the impact of HIV on pre-existing granulomas, leading to reactivation TB. Very little is known about the mechanisms whereby HIV-1 coinfection actually disrupts established granulomas but the virus must presumably enter those granulomas. Various lines of evidence suggest that latent M. tuberculosis infection represents a dynamic host–pathogen relationship in which the granuloma serves to restrain bacilli, which are present as viable and metabolically active forms rather than inactive spore-like structures. Unlike the relatively inactive foreign-body granulomas formed in response to inert particulate matter, tuberculous hypersensitivitytype granulomas are immunologically active structures with a continual level of mononuclear cell death and cell replacement by active recruitment.28 It is likely that HIV-1 infection impairs granuloma functions via two basic means:
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HIV-infected mononuclear cell within the granuloma serves as a source of HIV production and transmission to other cells
Cell-free HIV-1 particles
HIV-infected mononuclear cells being recruited to the TB granuloma by chemotaxis
Fig. 10.3 A granuloma containing latent M. tuberculosis (red dots) infection in an HIV-infected person. Ongoing dynamic cell turnover within the granuloma requires continual mononuclear cell recruitment (arrows). Entry of HIV-infected cells is likely to lead to replication and intercellular transmission of HIV, leading to spreading infection, cell dysfunction and death (blue cells), and subsequent failure of the granuloma permitting uncontrolled M. tuberculosis replication.
1. systemic depletion of the mononuclear cells required for the ongoing maintenance and functioning of granulomas; and 2. the effects of HIV-1-infected cells (either lymphocytes or macrophages) trafficking into the granuloma itself 12 (Fig. 10.3). After gaining access to the granuloma, the immunologically active microenvironment may quickly promote HIV-1 replication and intercellular spread of the virus. Resulting virus-induced cellular dysfunction and cytopathic effect may permit active mycobacterial proliferation. By a process of cyclic augmentation, additional inflammatory activity may further accelerate HIV-1 replication, promote mononuclear cell apoptosis, and further increase recruitment of potentially HIV-infected mononuclear cells. In this way, the critical host–pathogen equilibrium may be skewed in favour of M. tuberculosis, leading to unchecked mycobacterial proliferation and active TB.12
IMPACT OF ANTIRETROVIRAL TREATMENT ON THE HOST RESPONSE TO M. TUBERCULOSIS The development of highly active antiretroviral treatment (ART) in 1996 revolutionized the care and prognosis of HIV-infected individuals. For the first time, robust suppression of viral replication permitted substantial immunological recovery, resulting in reduced morbidity and mortality risk. This has markedly altered both the risk and manifestations of TB among patients receiving ART. Risk of TB decreases by 80–90% in the first 1–2 years of ART with smaller gains thereafter.57–59 Cutaneous hypersensitivity responses to tuberculin are restored and pulmonary TB developing during ART is less likely to be radiographically atypical than that developing in untreated patients. Mortality in patients with HIVassociated TB is also greatly reduced.58,60,61
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The impact of ART on TB reflects the fact that ART reverses the effects of HIV on the host response to M. tuberculosis.58 Proliferative responses and IFN-g secretion to mycobacterial antigens by T cells in vitro are restored.62–64 The rapidity of this immune recovery is vividly illustrated by immune reconstitution disease (or immune reconstitution inflammatory syndrome (IRIS)).65 This typically occurs among patients with TB within the initial weeks of ART. Rapid recovery of immune responses to persisting mycobacteria and to shed antigen trigger clinical deterioration of the TB, which can occasionally be severe. These phenomena are associated with rapid expansion of mycobacteria-specific T cells in the peripheral circulation and rapid restoration of T-cell proliferation.66,67 Histopathological examination of affected tissues shows that these manifestations are associated with recovery of the ability of the host to form granulomas in response to M. tuberculosis, and this response may be unusually florid.65 Reports of the development of hypercalcaemia during TB-associated immune reconstitution disease also provide indirect evidence of the restoration of granuloma physiology.68 Despite the dramatic effects of ART in reversing the impact of HIV on TB, these effects are nevertheless only partial. Laboratory evidence indicates that restoration of functional immune responses to M. tuberculosis and other pathogens during long-term ART is incomplete.58 As a result, the risk of TB among patients receiving ART long term in a study in South Africa, although very substantially reduced, nevertheless remained 5- to 10-fold greater than the risk among HIV-uninfected patients living in the same community.69 Thus, strategies whereby restoration of M. tuberculosisspecific immunity is maximized during ART need to be identified. This may require initiation of ART prior to the development of severe immunodeficiency. In addition, future development of adjunctive immunotherapeutic measures or a novel vaccine may help to further improve M. tuberculosis-specific immune recovery.
IMPACT OF TUBERCULOISIS ON HIV EPIDEMIOLOGY Data from various studies support the hypothesis that active TB causes an accelerated rate of immunological decline among HIV-infected patients. The first such study conducted in the USA by Whalen et al.4 was a retrospective analysis. Survival among 106 HIV-infected patients with TB (cases) was compared with survival among HIVinfected control patients who remained TB free and who were matched for baseline degree of immunodeficiency and patient characteristics. The adjusted odds for mortality among cases were significantly increased (approximately twofold). Subsequent prospective studies in France, Uganda, and South Africa have produced findings consistent with this.70–72 In the two studies from sub-Saharan Africa, significantly increased mortality risk was observed only among TB patients with CD4 T-cell counts 200 cells/ml, suggesting that any long-term impact of TB on HIV pathogenesis occurs among those with greater immunological reserve. A substantial body of laboratory data is consistent with the hypothesis that TB has a co-factor effect on the pathogenesis of HIV-1 infection. The interpretation of the epidemiological data highlighting this potential co-factor has been questioned.73 A suggested alternative explanation for the data is that TB is a marker of advanced immunodeficiency independent of CD4 T-cell count and clinical stage of disease. Contradictory data have also been published, although
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0
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In vitro and in vivo data show that immune activation associated with M. tuberculosis increases HIV-1 replication.5 In vitro M. tuberculosis and certain mycobacterial cell wall components not only induce HIV-1 replication within cells of the monocytic lineage and CD4 T cells but also enhance viral infectivity for this cell type and increase transmission of HIV-1 from antigen-presenting cells to lymphocytes.75–82 Proinflammatory cytokines (TNF-a, IL-1, and IL-6) released by monocytes and macrophages up regulate HIV-1 expression by acting in an autocrine fashion and in a paracrine fashion on virus-infected lymphocytes.76,83–85 Intercellular adhesion between macrophages and activated lymphocytes that occurs within the inflammatory microenvironment at sites of TB disease is a further key mechanism causing marked cellular activation and increased HIV replication.86–88 Goletti et al.75 reported the first in vivo data showing that development of active TB was associated with marked (5- to 160-fold) increases in plasma HIV-1 load. In a cross-sectional study in Uganda, both cell-free and cell-associated plasma viral loads were also higher in HIV-infected patients with TB than in patients with similar CD4 T-cell counts but who were TB-free.89 Higher viral loads were found only among the subset of patients with wellpreserved CD4 T-cell counts (> 500 cells/ml), suggesting the impact of active TB on HIV pathogenesis may be most marked earlier in the course of HIV infection. This is broadly consistent with the two epidemiological studies from Uganda and South Africa.71,72 Prospective data from three studies in Uganda, Ethiopia, and South Africa each found that increases in plasma HIV-1 load occur with development of active TB.89–91 In contrast, latent M. tuberculosis infection has no impact on systemic viral load.92 In addition to increases in viral load in the systemic circulation, the impact of TB on viral replication may be greatest at anatomic sites of TB disease. Among patients with pulmonary TB, HIV-1 load is greater in BAL fluid obtained from diseased lung segments than in fluid from segments not involved.93 In patients with pleural TB, cell-free and cell-associated HIV-1 load are greater in pleural fluid than in plasma94,95 (Fig. 10.4). Similarly, among HIV-infected persons with TB meningitis, the viral load in cerebrospinal fluid is higher than that in blood.96 In the study by Goletti et al.75 plasma HIV-1 load in a small number of subjects studied in the USA and Italy decreased following successful treatment of TB. However, several studies from Africa have since found that increases in viral load associated with development of TB are generally sustained despite successful TB treatment.53,89– 91,97 One other study found that decreases occurred only in a subset of patients.98 The chronic nature of TB may be an important factor leading to these sustained increases in viral load, possibly causing development of a new higher viral load set-point. The effect of immune activation on viral load is not specific to TB. A wide variety of other immune-activating stimuli including viral, bacterial, parasitic, and fungal infections and immunizations
P = 0.003
400
TNF-a pg/ ml
comparison of survival among patients with TB and those with AIDS-defining illnesses such as Kaposi’s sarcoma or pneumocystis pneumonia is perhaps a less informative approach, especially when the co-factor effect may predominantly occur during the earlier stages of HIV infection.74 Nevertheless, the importance of any co-factor effect of TB on HIV pathogenesis at a population level in countries with a high TB burden does remain unclear.
10
5.0 4.0 3.0 2.0
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Pleural fluid
Fig. 10.4 Concentrations of (A) tumour necrosis factor (TNF)-a and (B) HIV-1 load (log RNA copies/mL) in paired plasma and pleural fluid samples from patients with pleural TB and HIV-1 coinfection (n ¼ 9). In (A) box and whisker plots indicate the median, 25th and 75th centiles, and the range of TNF-a concentrations. (B) Lines join the paired viral load values and the median is indicated by a square symbol. The compartmentalized proinflammatory cytokine response in the pleural fluid at the site of TB was associated with higher HIV-1 load at that site. Data from Lawn SD, Pisell TL, Hirsch CS, et al. Anatomically compartmentalized human immunodeficiency virus replication in HLA-DR+ cells and CD14+ macrophages at the site of pleural tuberculosis coinfection. J Infect Dis 2001 Nov 1;184:1127–33.
have also been found to be associated with increases in HIV-1 load.5,99 However, the effects on plasma viral load of many of these stimuli appear to be more transient than that caused by TB, suggesting that TB has the greater potential to affect HIV-1 pathogenesis.100,101 Furthermore, compared with many other opportunistic infections, TB develops across a wide spectrum of CD4 T-cell counts and the co-factor effect may be more marked among patients with higher CD4 T-cell counts.
MECHANISMS OF ENHANCEMENT OF HIV-1 PATHOGENESIS Stimulation of monocytes with M. tuberculosis in vitro results in production of high levels of proinflammatory cytokines, including TNF-a, IL-1, and IL-6.102,103 In vivo, immunological activation at the site of disease and in blood are greatly heightened among patients with TB and HIV coinfection.53–55,104,105 The importance of this to HIV-1 pathogenesis is that the HIV-1 life cycle is intimately related to the level of activation of the mononuclear cell reservoirs of HIV. Mononuclear cell activation during responses to TB, other coinfections, and immunizations enhances viral replication by promoting three key stages of the viral life cycle – viral cellular entry, reverse transcription, and proviral transcription5 (Fig. 10.5).
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BASIC SCIENCE 1. Immune cell activation causes upregulation of chemokine co-receptors CCR5 and CXCR4, facilitating entry of HIV to cells CD4 receptor
2. Immune cell activation facilitates completion of reverse transcription of HIV-1, converting the RNA genome into DNA
CCR5 receptor HIV RNA
CXCR4 receptor Human DNA
HIV DNA Human DNA
HIV DNA 3. Immune cell activation enhances pro-viral transcription to produce new virus particles
Fig. 10.5 Diagram of the HIV-1 life cycle showing the three key stages of the life cycle that may be facilitated by immune activation at sites of TB: (1) viral cellular entry, (2) reverse transcription of HIV-1 RNA, and (3) proviral transcription.
HIV-1 cellular entry HIV-1 particles typically enter host cells by binding to the cell surface CD4 receptor and a chemokine co-receptor – most commonly CCR5 or CXCR4. These chemokine receptors are inducibly expressed and immune activation associated with coinfections may cause upregulation of expression of these coreceptors, facilitating viral cellular entry. Mycobacterium avium, for example, causes upregulation of CCR5 on peripheral blood mononuclear cells in vitro, whereas blood CD4 T cells from patients with TB have increased membrane expression of both CXCR4 and CCR5.95,106,107 HIV-1 reverse transcription Compared with activated cells, completion of reverse transcription of HIV-1 RNA is less likely to be successful in immunologically quiescent cells.108 Cellular activation, however, increases cytoplasmic concentrations of certain mediators such as nuclear factor of activated T cells (NFATc) that facilitate reverse transcription.109
TB and other coinfections may thereby increase the pool of activated cells able to support productive viral infection.
HIV-1 proviral transcription The rate of transcription of proviral DNA is highly related to the activation state of the cell and is regulated by sequences within the long terminal repeat (LTR) at the 50 end of the viral genome110 (Fig. 10.6). These sequences include receptors for host-encoded transcription factors, including nuclear factor-kB (NF-kB). Proinflammatory cytokines released in response to TB act in an autocrine and paracrine fashion on mononuclear cell surface receptors, triggering release of high intracellular concentrations of physiologically active NF-kB and other transcription factors.111,112 As well as enhancing transcription of host cell genes, these transcription factors also activate the HIV-1 LTR, greatly increasing rates of HIV-1 proviral transcription.110,112 In this way, HIV-1 provirus harnesses the host cell transcriptional regulatory mechanisms to promote its own replication. Compared with the effect on HIV-1 infection, the
NF-kB from cytoplasm
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Fig. 10.6 Structure of the long terminal repeat (LTR) of the HIV-1 genome. The HIV-1 promoter is functionally divided into the modulatory enhancer region, core promoter region, and transactivation response region (TAR). Following cellular activation due, for example, to coinfections such as TB, increased concentrations of cellular transcription factors including nuclear factor-kB (NF-kB) activate receptors in the HIV-1 promoter, resulting in marked upregulation of HIV-1 transcription. Adapted from Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002 May;4:635–46.
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impact of TB and other coinfections on the pathogenesis of HIV2 infection is likely to be less since the HIV-2 LTR has only a single functionally active binding site for NF-kB, whereas the HIV-1 LTR has two.113 In addition to the role of proinflammatory cytokines, it has also been suggested that the beta-chemokine macrophage chemoattractant protein-1 (MCP-1) may play an important role in promoting HIV-1 transcription at sites of TB disease.95,114
Immune activation and CD4 lymphocyte depletion As well as increasing HIV-1 replication, coinfections may also accelerate CD4 T-cell loss by a number of mechanisms.5 Firstly, increased HIV-1 replication accelerates cell loss by virus-induced lysis or immune destruction of infected cells. Immune activation associated with coinfections may also have a generally suppressive effect on haematopoiesis. However, most importantly, generalized immune activation augments apoptotic cell loss, which is numerically the dominant mechanism of mononuclear cell loss in HIV infection.50 Apoptosis leads to loss of both HIV-infected and -uninfected bystander lymphocytes. Studies of patients with pleural TB and HIV-1 coinfection show very high rates of apoptosis of M. tuberculosis-specific T cells at sites of TB disease.56 These cell losses may undermine the host response to M. tuberculosis, favouring persistence of the organism and an ongoing inflammatory process. Immune activation and genotypic diversification Chronic HIV-1 infection is characterized by marked genotypic heterogeneity of the systemic virus pool. Increased rates of viral replication associated with immune-activating stimuli may promote further genotypic diversification by mutation or by leading to additional expression of previously latent proviral genotypes.100 It is hypothesized that, by these means, new viral quasi-species able to evade the established host anti-viral responses, increasing viral replication and disease progression, may be expressed. In patients with pulmonary TB, Nakata et al.93 found increased genotypic heterogeneity within BAL samples obtained from lung segments affected by TB compared with samples from uninvolved segments. HIV-1 heterogeneity in the systemic circulation is similarly increased in patients with TB compared with that in matched patients without TB.115 Comparison of the viral genotypes expressed in the plasma and pleural compartments of patients with pleural TB showed that this heterogeneity is likely to arise largely at sites of TB disease driven by increased HIV-1 replication in response to the proinflammatory drive.94,116 Further data suggest that increased heterogeneity can lead to the emergence of quasi-species that have increased replicative fitness and this may be an important factor in disease progression.117 Cellular sources of HIV-1 replication CD4 T cells and cells of the monocyte–macrophage lineage both support HIV replication. Mathematical modelling estimates, though, suggest that macrophages contribute very little (<2%) to the total plasma viral pool in patients with chronic HIV-1 infection.118 However, the number of HIV-infected macrophages is greatly expanded at sites of TB and these are highly activated. As a result, the proportion of HIV-1 particles derived from macrophages is therefore greatly increased both at sites of TB and within the systemic circulation.94,119–121 In contrast to lymphocytes which are estimated to have an average lifespan of approximately 2 days, macrophages do not succumb to virus-induced cytolysis and are resistant to Fas-mediated apoptosis.122 They therefore serve as much longer-lived reservoirs of HIV infection at sites of TB disease and are therefore likely to play a central role in the impact of TB on HIV-1 pathogenesis. These cells not only support high rates
MTB-specific CD4 T cells
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Fig. 10.7 Replication and intercellular transmission of HIV-1 is increased during antigen presentation at the site of M. tuberculosis infection. Following phagocytosis of M. tuberculosis, M. tuberculosis-specific CD4 T cells are attracted by chemotaxis (A). Subsequent intimate intercellular apposition and integrin–ligand interactions trigger marked cellular activation and secretion of proinflammatory cytokines, including TNF-a. Transmission of HIV to recruited CD4 T cells occurs and the inflammatory environment supports high rates of HIV-1 replication in both cell types. High rates of CD4 T-cell loss occur via virus-induced or immune-mediated lysis together with activation-induced apoptosis. Adapted from Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002 May;4:635–46.
of HIV-1 replication but also serve as a source of transmission of HIV infection to M. tuberculosis-specific CD4 T cells during the process of antigen presentation at the site of disease (Fig. 10.7). The cellular source of HIV replication may affect the surface phenotype of the virions produced. As virions bud from host mononuclear cells, host cell-surface molecules are incorporated into the virion envelope.121,123 Cellular expression of human lymphocyte antigen direct repeat (HLA-DR) reflects mononuclear cell activation and this molecule is incorporated at high levels into the envelope of budding virions. The proportion of the virus pool bearing HLA-DR in the envelope is greatly increased in patients with TB, especially at local sites of TB disease.94,124 This reflects high rates of viral replication within highly activated mononuclear cells. Interestingly, some data suggest that presence of HLA-DR in the viral envelope enhances viral infectivity for CD4 T cells since this molecule is the natural ligand for the CD4 T-cell receptor and is therefore likely to enhance virus–cell interactions.125 This is a further potential mechanism promoting HIV replication at sites of TB.
The inflammatory microenvironment at sites of tuberculosis While systemic immune activation associated with TB in HIVinfected patients is likely to have important effects on HIV pathogenesis, it is clear that these effects are maximal at the actual sites of TB disease. Table 10.1 summarizes the effects of the host inflammatory response on HIV-1 pathogenesis at sites of TB disease. The intense inflammatory milieu provides the ideal microenvironment for high rates of HIV-1 replication and genotypic diversification, further undermining host responses to the M. tuberculosis infection.93–95,116,126 However, genotypic studies of HIV replication at pleural sites of TB also show that the anatomic compartmentalization of these effects is only partial and that there is interplay between this HIV-1 pool and that in the systemic circulation. Thus, localized TB may also have important effects on HIV-1 pathogenesis systemically.
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Table 10.1 Summary points: effects of the host inflammatory response on the pathogenesis of HIV-1 at sites of tuberculosis disease
Increased HIV-1 replication within macrophages and CD4 T cells, leading to increased cell-associated and cell-free virus load. Enhanced susceptibility of mononuclear cells to infection with HIV. Transmission of HIV-1 from antigen-presenting cells to M. tuberculosis-specific CD4 T cells during antigen presentation. Increased loss of M. tuberculosis-specific CD4 T cells by activationinduced apoptosis or virus-induced/immune-mediated lysis. Increased HIV-1 genotypic heterogeneity, increasing potential for evolution of quasi-species with increased replicative capacity. Expansion of macrophages as long-lived reservoirs of HIV-1. Increased incorporation of HLA-DR into the virion envelope enhancing infectivity.
USE OF IMMUNOTHERAPY TO ADDRESS TUBERCULOSIS/HIV-1 CO-PATHOGENESIS The fact that immune activation and the effects of proinflammatory cytokines such as TNF-a are central to the impact of TB on the pathogenesis of HIV-1 infection has led to various trials of immunotherapeutic strategies to block these effects. Thalidomide and pentoxifylline are both drugs that provide inhibition of the TNF-a pathway and monoclonal antibodies directed against TNF-a have provided an even more targeted approach. Trials of these agents and of corticosteroids, which have more generalized immunosuppressive activity, have been conducted among patients with HIV-associated TB. Despite some indicators of beneficial immunomodulatory effect among such patients treated with thalidomide or pentoxifylline, trials of these agents found either no reductions in plasma TNF-a concentration and viral load or only small reductions unlikely to be of prognostic benefit.127–129 A trial of monoclonal TNF-a antibody showed a trend towards an increased CD4 T-cell count but no change in plasma viral load.130 Use of prednisolone therapy similarly showed an increase in CD4 T-cell count but paradoxically was associated with a transient increase in plasma viral load and a high rate of adverse events.131 The failure of these strategies probably reflects the complexity of the co-pathogenesis of TB and HIV-1. It currently seems unlikely that any such agents will prove to be useful, cost-effective
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adjunctive treatments in clinical practice. Many of the trials of immunomodulatory adjunctive treatments were conducted in resource-limited settings prior to the widespread availability of ART. Availability of this treatment has revolutionized the prognosis of patients with HIV-associated TB and is now expanding in resource-limited settings. Thus, the need of immunomodulatory treatment for such patients has largely been superseded.
CONCLUSIONS HIV-1 infection is one of the principal factors underlying the resurgence of TB over the past 20 years. An effective host cellular immune response with granuloma formation is required to contain M. tuberculosis infection and prevent the reactivation of latent infection, which is present in approximately one-third of the world’s population. The devastating impact of HIV-1 on the natural history of TB highlights the critical impact of the virus on the establishment and functioning of the granulomatous host response to M. tuberculosis. Via multiple mechanisms HIV-1 coinfection leads to functional and numeric depletion of M. tuberculosis-specific CD4 T cells and diminished type-1 cytokine responses. Dysfunction of the CD4 T cell–macrophage axis impairs the host’s ability to generate cell-mediated immune responses and form immunologically competent granulomas. Sites of TB disease and granulomas themselves provide the ideal microenvironment for the propagation of HIV-1, thereby maximizing the deleterious impact of HIV-1 at the critical interface between M. tuberculosis and the host. Moreover, immune activation generated during the host response to M. tuberculosis drives HIV-1 replication and genotypic diversification, potentially accelerating immunological decline. Substantial reversal of these effects is currently achievable only through use of ART, further emphasizing the need for rapid expansion of access to this treatment in resourcelimited settings where the burden of HIV-associated TB is greatest.
ACKNOWLEDGEMENTS Dr Stephen D. Lawn is funded by the Wellcome Trust, London, UK. Dr Linda-Gail Bekker is funded, in part, by the National Institutes of Health, USA, through CIPRA Grant 1U19AI53217-01.
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61. Dheda K, Lampe FC, Johnson MA, et al. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis 2004;190: 1670–1676. 62. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4þ T cell homeostasis and function in advanced HIV disease. Science 1997;277:112–116. 63. Li TS, Tubiana R, Katlama C, et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998;351: 1682–1686. 64. Schluger NW, Perez D, Liu YM. Reconstitution of immune responses to tuberculosis in patients with HIV infection who receive antiretroviral therapy. Chest 2002;122:597–602. 65. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–373. 66. Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1–F7. 67. Foudraine NA, Hovenkamp E, Notermans DW, et al. Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients. AIDS 1999;13:177–184. 68. Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis 2004;38:154–155. 69. Lawn SD, Myer L, Bekker LG, et al. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS 2006;20:1605–1612. 70. Leroy V, Salmi LR, Dupon M, et al. Progression of human immunodeficiency virus infection in patients with tuberculosis disease. A cohort study in Bordeaux, France, 1988-1994. The Groupe d’Epidemiologie Clinique du Sida en Aquitaine (GECSA). Am J Epidemiol 1997;145:293–300. 71. Badri M, Ehrlich R, Wood R, et al. Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area. Int J Tuberc Lung Dis 2001;5:225–232. 72. Whalen CC, Nsubuga P, Okwera A, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 2000;14:1219–1228. 73. Del AJ, Malin AS, Pozniak A, et al. Does tuberculosis accelerate the progression of HIV disease? Evidence from basic science and epidemiology. AIDS 1999;13:1151–1158. 74. Del Amo J, Perez-Hoyos S, Herna´ndez Aguado I, et al. Impact of tuberculosis on HIV disease progression in persons with well-documented time of HIV seroconversion. J Acquir Immune Defic Syndr 2003;33:184–190. 75. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication. Role of immune activation. J Immunol 1996;157:1271–1278. 76. Lederman MM, Georges DL, Kusner DJ, et al. Mycobacterium tuberculosis and its purified protein derivative activate expression of the human immunodeficiency virus. J Acquir Immune Defic Syndr 1994;7:727–733. 77. Shattock RJ, Friedland JS, Griffin GE. Phagocytosis of Mycobacterium tuberculosis modulates human immunodeficiency virus replication in human monocytic cells. J Gen Virol 1994;75(Pt 4):849–856. 78. Zhang Y, Nakata K, Weiden M, et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat. J Clin Invest 1995;95:2324–2331. 79. Bernier R, Barbeau B, Olivier M, et al. Mycobacterium tuberculosis mannose-capped lipoarabinomannan can induce NF-kB-dependent activation of human immunodeficiency virus type 1 long terminal repeat in T cells. J Gen Virol 1998;79(Pt 6):1353–1361.
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97. Morris L, Martin DJ, Bredell H, et al. Human immunodeficiency virus-1 RNA levels and CD4 lymphocyte counts, during treatment for active tuberculosis, in South African patients. J Infect Dis 2003;187:1967–1971. 98. Kizza HM, Rodriguez B, Quinones-Mateu M, et al. Persistent replication of human immunodeficiency virus type 1 despite treatment of pulmonary tuberculosis in dually infected subjects. Clin Diagn Lab Immunol 2005;12:1298–1304. 99. Bentwich Z, Maartens G, Torten D, et al. Concurrent infections and HIV pathogenesis. AIDS 2000;14:2071–2081. 100. Ostrowski MA, Krakauer DC, Li Y, et al. Effect of immune activation on the dynamics of human immunodeficiency virus replication and on the distribution of viral quasispecies. J Virol 1998; 72:7772–7784. 101. Stanley SK, Ostrowski MA, Justement JS, et al. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 1996;334:1222–1230. 102. Kaplan G, Freedman VH. The role of cytokines in the immune response to tuberculosis. Res Immunol 1996;147:565–572. 103. Toossi Z. Cytokine circuits in tuberculosis. Infect Agents Dis 1996;5:98–107. 104. Vanham G, Edmonds K, Qing L, et al. Generalized immune activation in pulmonary tuberculosis: co-activation with HIV infection. Clin Exp Immunol 1996;103:30–34. 105. Lawn SD, Labeta MO, Arias M, et al. Elevated serum concentrations of soluble CD14 in HIV- and HIVþ patients with tuberculosis in Africa: prolonged elevation during anti-tuberculosis treatment. Clin Exp Immunol 2000;120:483–487. 106. Wahl SM, Greenwell-Wild T, Peng G, et al. Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression. Proc Natl Acad Sci USA 1998;95:12574–12579. 107. Juffermans NP, Speelman P, Verbon A, et al. Patients with active tuberculosis have increased expression of HIV coreceptors CXCR4 and CCR5 on CD4(þ) T cells. Clin Infect Dis 2001;32: 650–652. 108. Zack JA, Arrigo SJ, Weitsman SR, et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 1990;61:213–222. 109. Kinoshita S, Chen BK, Kaneshima H, et al. Host control of HIV-1 parasitism in T cells by the nuclear factor of activated T cells. Cell 1998;95:595–604. 110. Gaynor R. Cellular transcription factors involved in the regulation of HIV-1 gene expression. AIDS 1992;6:347–363. 111. Baeuerle PA. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta 1991;1072:63–80. 112. Pereira LA, Bentley K, Peeters A, et al. A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter. Nucleic Acids Res 2000;28:663–668. 113. Tong-Starksen SE, Welsh TM, Peterlin BM. Differences in transcriptional enhancers of HIV-1 and HIV-2. Response to T cell activation signals. J Immunol 1990;145:4348–4354. 114. Vicenzi E, Alfano M, Ghezzi S, et al. Divergent regulation of HIV-1 replication in PBMC of infected individuals by CC chemokines: suppression by RANTES, MIP-1alpha, and MCP-3, and enhancement by MCP-1. J Leukoc Biol 2000;68: 405–412. 115. Collins KR, Mayanja-Kizza H, Sullivan BA, et al. Greater diversity of HIV-1 quasispecies in
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11
Tuberculosis vaccines Gregory D Hussey, Tony Hawkridge, and Willem A Hanekom
INTRODUCTION The world is witnessing an escalation of the TB epidemic, particularly in sub-Saharan Africa and South-East Asia.1 The problem has been compounded by the evolution of the human immunodeficiency virus (HIV) epidemic, the increase in multidrug-resistant (MDR) TB and the emergence of extensively drug-resistant (XDR) TB.2 The escalation of the TB epidemic worldwide has occurred despite the widespread use of Bacillus Calmette–Gue´rin (BCG) vaccine, currently the only licensed vaccine.3 BCG is safe and may induce long-lasting protective immunity,4 but we do not fully understand the mechanisms underlying this immunity. BCG affords approximately 80% protection against TB meningitis and miliary TB in infancy and in young children, but protection against lung disease, at all ages, is highly variable.5 In some trials, efficacy in excess of 70% against lung TB has been reported; however, in the majority, efficacy has been closer to 0%.4 The failure of BCG vaccine and increasing global mortality due to TB has emphasized the urgent need to develop more effective vaccines against the disease. New genetic technology and the sequencing of the Mycobacterium tuberculosis genome in the late 1990s have made rational development of new TB vaccines a reality.6 To date, more than 200 new candidate TB vaccines have been tested in animal models, and five have undergone phase I trials in humans.7 The licensing of an effective new TB vaccine by 2015 is now becoming a possibility. The introduction of new TB vaccines is seen as an essential part of the global strategy to eliminate TB by 2050.8 This chapter reviews the development of new TB vaccines, strategies for implementation and the challenges to such strategies.
THE IDEAL TUBERCULOSIS VACCINE An ideal new TB vaccine should have all or most of the characteristics listed in Table 11.1. It is unlikely that a single candidate will meet all or even most of these requirements and it is likely that more than one candidate vaccine may be needed.
NEW TUBERCULOSIS VACCINE APPROACHES IN RELATION TO THE NATURAL HISTORY OF THE DISEASE The choice of a new vaccine candidate will depend, to some extent, upon which phase of the natural history of TB is targeted.9
Three general approaches to new vaccines are being pursued (Fig. 11.1). The first aims to deliver vaccines prior to exposure of individuals to mycobacterial infection, a pre-infection vaccination strategy. In high-burden countries this would be the most ideal option. As TB is common in early life in these settings, vaccination would ideally have to be as close to birth as possible. This vaccine would also have to be more effective than the current BCG vaccine. Alternatively, a new TB vaccine may be used to boost immunity induced by neonatal BCG vaccination. A boost vaccine should preferably be administered together with other Expanded Programme on Immunization (EPI) vaccines.10 The second approach is to enhance or boost immunity in individuals already primed through natural infection with M. tuberculosis, a post-infection vaccine strategy. This approach is attractive because more than two billion persons are already infected with the pathogen worldwide and thus are at risk of progression to disease. This is also an attractive option for countries with high rates of HIV infection, if such a vaccine will be safe in this population. A therapeutic vaccine as an adjunct to treatment to shorten therapy or reduce the risk of relapse is a third option, and may be particularly relevant in settings where MDR- or XDR-TB are common, and in areas where TB control programmes are not managing to hold cases adequately.9 It is unlikely that a single vaccine will be able to be used at all stages.
NEW CANDIDATE TUBERCULOSIS VACCINES TYPES OF VACCINES Traditionally, vaccines have been divided into inactivated, live attenuated, toxoid and subunit vaccines. Over the past two decades novel approaches to vaccine development have emerged, with resulting conjugate, recombinant vectored and DNA vaccines. The chief characteristics of each vaccine type are summarized in Table 11.2.
LEADING CANDIDATE TUBERCULOSIS VACCINES Several novel TB vaccine candidates appear to afford protection against TB that is either similar or superior to that afforded by BCG, in animal models. To date, six of these candidates have entered clinical trials; data on the status of five accessible at the time of writing this chapter will be addressed: MVA85A, rBCG30, Mtb72f/M72, Aeras-402 and Mycobacterium vaccae. Other candidates, some of which appear very promising (Table 11.3), have recently been described in excellent reviews.11,12
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Table 11.1 Characteristics of the ideal tuberculosis vaccine
Table 11.2 Types of vaccines
1. 2. 3. 4. 5.
Type
6. 7. 8. 9.
Easily administered. Low cost. Single dose administered at or soon after birth. Safe, immunogenic and effective in newborns, children and adults. Safe, immunogenic and effective in mycobacterial naı¨ve as well as exposed individuals, including persons infected with non-tuberculous mycobacteria and previously vaccinated with BCG. Does not induce tuberculin reactivity. Effective in preventing primary TB, reinfection and reactivation disease. Effective in preventing pulmonary, extrapulmonary and disseminated disease. Safe, immunogenic and effective in preventing TB in individuals with HIV infection or AIDS, other immune deficiencies and malnutrition.
Uninfected person
Cure
Therapeutic vaccine
Disease
Pre-infection vaccine
Post-infection vaccine
Infected person
Fig. 11.1 Tuberculosis vaccine strategies in relation to the natural history of TB.
Clinical trials generally allow for a step-wise increase in mycobacterial exposure among participants, as a precaution against a possible Koch-like reaction. The Koch phenomenon is development of immunopathology in a person with TB when an exaggerated mycobacterial immune response is stimulated.13 The risk of a Koch-like reaction is likely to increase in the presence of a high mycobacterial load, such as in the presence of TB disease,14 while the risk in the setting of asymptomatic latent infection is likely to be low.
MVA85A MVA85A was developed at Oxford University by Helen McShane and Adrian Hill. The vaccine consists of Modified Vaccinia Ankara (MVA) engineered to express the immunodominant M. tuberculosis antigen 85A. This secreted protein is a member of the antigen 85 complex,15 which is involved in the binding of mycobacteria to fibronectin. The mycolyltransferase activity of the proteins is critical for the biogenesis of cord factor. The antigen 85 complex is highly conserved across mycobacterial species, including all strains of the BCG vaccine and environmental mycobacteria sequenced to date. MVA is a replication-incompetent strain of vaccinia virus which can still synthesize proteins during its abortive infection. The viral genome remains stable during passage in cell culture. MVA has been administered to more than 120,000 human vaccinees in the smallpox eradication programme of the 1970s, with no serious adverse effects.16,17 MVA-based vaccines are safe and immunogenic when given to immunosuppressed recipients; recombinant MVA vaccines expressing HIV antigens have been administered to HIV-infected participants receiving or not receiving anti-retroviral therapy in phase I trials, with no serious adverse events reported.18,19
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Traditional types of vaccines Inactivated vaccines Organisms innately capable of causing disease that have undergone treatment with chemicals or heat, which has rendered them unable to cause the disease. This approach has been tested in TB, but has not been found useful, with the possible exception of the M. vaccae vaccine. Live, attenuated Live organisms which through culture under vaccines certain conditions have lost their virulent properties. BCG is an example. Toxoids Illness-causing components produced by pathogens that have been inactivated. This approach is not so far proved relevant to TB. Subunit vaccines A part of the organism, rather than the whole organism, is used to create an immune response. Examples include TB vaccines which consist of TB proteins (antigens) delivered with adjuvants or in specialized vehicles. Newer approaches to vaccine development Conjugate vaccines Linking the outer polysaccharide coats of certain organisms to proteins can lead to a better immune response. This approach is not relevant to TB vaccine development. Recombinant A gene thought to code for a protective protein vectored vaccines is isolated and then recombined with DNA of a vector. Examples include the vaccinia and adenovirus vectored vaccines currently in phase I and II trials. DNA vaccines The vaccine is created from the infectious agent’s DNA. Delivering this to human or animal cells leads to expression of the infectious agent’s proteins and triggers immune system recognition. Some TB DNA vaccine candidates have shown promise in animal models, but none have so far reached clinical testing.
Preclinical studies In mice, a BCG prime followed by a MVA85A boost induced higher levels of antigen-specific interferon-gamma (IFN-g)-secreting CD4þ and CD8þ T cells and greater levels of protection against aerosol TB challenge than a BCG prime with no boost.20 In guinea pigs, a BCG prime followed by boosting with MVA85A plus a second fowlpox vector expressing antigen 85A induced greater protection against high-dose TB challenge than BCG prime alone.21 This regimen was also immunogenic and protective in rhesus macaques.22 Clinical studies Phase I trials of MVA85A were first conducted in the UK, then in the Gambia and then in South Africa, as the expected degree of exposure of participants to M. tuberculosis is least in the UK, greater in the Gambia and greatest in South Africa. The primary immunological outcome was the ex vivo IFN-g Elispot assay, which assessed specific T-cell responses to M. tuberculosis purified protein derivative (PPD), antigen 85 and its constituent peptides. In all studies latent TB infection was defined by T-cell reactivity to ESAT-6 and CFP-10, antigens present in M. tuberculosis but absent from BCG and most environmental mycobacteria.
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Tuberculosis vaccines
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Table 11.3 Summary of new-generation tuberculosis vaccine work in progress Name
Description
Developmental stage
Researcher
Sponsor
rBCG30 BCG
BCG Tice strain engineered to overexpress Ag85B
Phase I trial in USA, completed in 2004; no serious adverse events, immunogenicity shown
M Horwitz, D Hoft, T Littlejohn
rBCG-Aeras 403
BCG Danish strain with an endosome escape mechanism (perfringolysin) and over expression of Ag85A, Ag85B and TB10.4 BCG Pasteur strain with an endosome escape mechanism (listeriolysin) BCG Pasteur strain with reintroduction of RD-1 locus which contains presumedly protective Ag’s BCG Tice strain with diminished superoxide dismutase activity
Ongoing pre clinical studies and GMP production
R Sun, D Hone, M Stone, J Sadoff
Sequella, Aeras Global TB Vaccine Foundation Aeras Global TB Vaccine Foundation
Ongoing pre clinical studies and GMP production Ongoing pre clinical studies
S Kaufmann, L Grode, S Cole
Ongoing pre clinical studies
D Kernodle
Deletion of the virulence-associated gene phoP from Mtb MT103 strain Mtb H37Rv with deletion of panCD and RD1 locus Mtb H37Rv with deletion of the lysA and the panCD locus Recombinant fusion protein (Mtb39 and Mtb32) in AS02A and AS01B adjuvants
Ongoing pre clinical studies and GLP production Ongoing pre clinical studies and GMP production Ongoing pre clinical studies and GMP production Phase I trials completed in the USA and Europe; no serious adverse events; additional trials ongoing in Europe Phase I clinical trials commenced
B Martin, B Gicquel W Jacobs
NIH
W Jacobs
NIH
Y Skeiky, S Reed
GlaxoSmithKline, Aeras Global TB Vaccine Foundation SSI, TBVAC
rBCGDUre:Hlyþ BCG::RDI
Pro-apoptotic BCG
M. tuberculosis PhoP M. tuberculosis mc26030 M. tuberculosis mc26020 Mtb72F
Hybrid-1 (Ag85B– ESAT6) HyVac-4 (Ag85B– TB10.4)
Recombinant fusion of Ag85B–ESAT-6 in IC31 adjuvant Recombinant fusion of Ag85B–TB10.4 in IC31 adjuvant
Heatshock protein
Hsp65 (GroEL) MVA85A
P Andersen
Ongoing pre clinical studies and GLP production
P Andersen
Nascent BCG proteins associated with purified heatshock proteins
Ongoing pre clinical studies
C Colaco
DNA: conserved antigen from Mycobacterium leprae for immunotherapy Attenuated strain of vaccinia expressing Ag85A
Ongoing pre clinical studies
D Lowrie
Completed and ongoing phase I and II clinical trials; immunogenic, no serious adverse events reported Clinical studies started 2006 and ongoing
A Hill, H McShane
Ongoing pre clinical studies
J Fulkerson, D Hone, M Stone, D Onyabe, J Sadoff
Aeras 402
Non-replicating Ad35-expressing multiple TB proteins including Ag85A, Ag85B and TB10.4
Double-stranded RNA capsids
Double-stranded RNA capsids encoding TB antigens for oral delivery
NIH, Aeras Global TB Vaccine Foundation
SSI, Aeras Global TB Vaccine Foundation ImmunoBiology, Aeras Global TB Vaccine Foundation Sequella Inc. Wellcome Trust
Aeras Global TB Vaccine Foundation, Crucell Aeras Global TB Vaccine Foundation
Adapted from Macmillan Publishers Ltd: Nature Reviews Microbiology, Skeiky Y, Sadoff J. Advances in tuberculosis vaccine strategies. Nat Rev Microbiol 2006;4:469–476. Copyright 2006.
In the first UK trial, 14 mycobacteria-naı¨ve, i.e. ESAT-6 and CFP-10 Elispot negative and no history or physical evidence of prior BCG vaccination, asymptomatic adults were vaccinated with intradermal MVA85A, administered twice, 3 weeks apart.23 All participants experienced some local side effects, predominantly redness and itching, which lasted for 3–7 days following vaccination. One-third of the vaccinees experienced systemic symptoms, principally myalgia and headache, for the first 12–24 hours after vaccination. All adverse effects resolved spontaneously. There were no
severe adverse events. The vaccine induced high levels of specific effector T-cell responses 1 week after vaccination. The safety of MVA85A was then tested in 17 UK adults who had been vaccinated with BCG from 6 months to 37 years previously.23 A safety profile similar to that of vaccinated BCGnaı¨ve persons was observed. Higher peak levels of antigen-specific T cells 1 week post-vaccination were shown, compared with those who received MVA85A alone. Prior BCG vaccination was associated with maintenance of higher levels of antigen-specific
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T cells after MVA85A boost, for up to 24 weeks after vaccination, compared with prior BCG vaccination or MVA85A alone. The next UK trial investigated the effect of boosting MVA85A 1 month after BCG vaccination in 10 healthy, BCG-naı¨ve adults. Safety and boosting efficacy were comparable to that shown following prolonged intervals between BCG and MVA85A boosting.24 This was followed by a UK trial in asymptomatic adults who were latently infected with M. tuberculosis.25 Individuals with latent TB infection (LTBI) are thought to have a very low-level persistent bacterial infection, no clinical or radiological evidence of disease but a detectable immune response against M. tuberculosis. Twelve participants were vaccinated with a single dose of MVA85A and followed up with detailed chest radiological and clinical safety assessments. The safety and immunogenicity profile of the vaccine in this trial was identical to that seen in previous studies of MVA85A boosting BCG vaccination. There was no clinical, radiological or immunological evidence of a Koch reaction. Ongoing UK trials involve MVA85A vaccination of 20 HIVinfected individuals who are otherwise healthy. The first volunteer was vaccinated in November 2006. In collaboration with the British Medical Research Council (BMRC) unit in the Gambia, MVA85A was first evaluated in 11 Gambian BCG-naı¨ve participants, and subsequently in 10 BCGprimed participants.26 The safety and immunogenicity profiles obtained were comparable with those seen in the UK studies. A current ongoing study in the Gambia is evaluating the immune response of the vaccine given to BCG-vaccinated infants, and whether the vaccine would interfere with other routine childhood vaccines. In South Africa, a phase II study in 24 healthy, M. tuberculosisnaı¨ve and HIV-uninfected adults, half of whom were previously vaccinated with BCG, was performed at the South African Tuberculosis Vaccine Initiative (SATVI) site at Worcester, near Cape Town. This population was very different from those in the UK and the Gambia, in terms both of ethnic background and of mycobacterial exposure. The annual risk of M. tuberculosis infection is 3–4% in Worcester, but exposure to environmental mycobacteria is less than in the Gambia. The safety and immunogenicity results were comparable with the experience in the UK and the Gambia.27 Twenty-four healthy adolescents were then vaccinated; to date, safety and immunogenicity in the adolescents vaccinated appear similar to those seen in adults. The next South African studies are testing the vaccine’s safety and immunogenicity in HIV-infected, TB-infected and HIV/TB coinfected individuals in this high-prevalence setting, and in healthy children and infants, leading to a phase IIB proof of concept study in infants planned to start in 2009.
rBCG30 This live recombinant vaccine was constructed by Marcus Horwitz and his research team at the University of California in Los Angeles. The Tice strain of BCG was modified to over expresses Ag85B, another member of the antigen 85A family.28,29 In vitro, rBCG30 produces up to five times more extracellular Ag85B than Tice BCG. Preclinical studies rBCG30 has been shown to stimulate a cell-mediated immune response in guinea pigs, as indicated by a DTH reaction against Ag85B, with significantly greater induration than that induced by Tice BCG or sham vaccination.28 The vaccine provided greater
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protection against virulent M. tuberculosis in this animal model than did various strains of BCG alone, including Tice BCG. At week 10 post-challenge, animals immunized with rBCG30 had significantly fewer M. tuberculosis bacilli in the lungs and spleen than animals immunized with Tice BCG.28 In another 62-week experiment, animals immunized with rBCG30 survived significantly longer than animals immunized with Tice BCG.28
Clinical studies A phase I rBCG30 study was conducted in the USA among 30 healthy adults at the Center for Vaccine Development, St. Louis University, Missouri, and in Winston-Salem, North Carolina.30 There were no significant safety issues. Increased immunogenicity, compared with the parent BCG strain, was reported. After completion of the trial the sponsor decided, for various technical reasons, to delay further trials and re-engineer the vaccine. At the time of writing, no further trials of the vaccine have commenced. Mtb72F/M72 Mtb72F was developed by Yasir Skeiky and Steve Reed at Corixa Corporation under an agreement with GlaxoSmithKline Biologicals (GSK Bio). The vaccine antigen is a fusion protein of two immunogenic M. tuberculosis proteins, Mtb39a and Mtb32a, which are also expressed in BCG. Adjuvants in the vaccine have included an oil-in-water emulsion (AS02) or a liposomal formulation (AS01). The developers of the vaccine have made minor changes to the amino acid sequence of one of the component proteins in order to make it more stable; the vaccine is now referred to as M72. Preclinical studies The adjuvanted polyprotein vaccine has been shown to protect against virulent M. tuberculosis in several animal models of TB, and also to boost and prolong the protective effect of BCG.31,32 Some data from mouse studies suggest that M. tuberculosis-specific CD8þ T cells may be targeted by vaccination with Mtb72F.33 Recombinant Mtb72F protein in AS02A has been shown to enhance the Th1 response to BCG in mice.34 Immunization of mice with Mtb72F DNA resulted in IFN-g responses and a strong CD8þ T-cell response, whereas Mtb72F protein in AS02A stimulated a moderate IFN-g response and a weak CD8þ T-cell response.34 Immunization with Mtb72F protein in AS01B generated a comprehensive and robust immune response.34 All three forms of Mtb72F immunization (DNA, protein in AS02A and protein in AS01B) resulted in protection of mice against aerosol challenge with virulent M. tuberculosis.34 Mtb72F in selected adjuvants protects guinea pigs as well and as long as BCG following M. tuberculosis challenge.31–35 When coadministered with BCG, the mixture substantially increased the survival time of infected guinea pigs, compared with BCG alone, with some animals still alive and healthy in appearance more than 100 weeks post-aerosol challenge and the majority of animals living well over 100 weeks. The majority had clear lungs with minimal granulomatous lesions. Adding Mtb72F to BCG appears to prevent progressive consolidating lung pathology and promotes lesion healing and reabsorption. In the cynomolgus monkey model, Mtb72F was shown to provide long-term protection against a fatal M. tuberculosis challenge when administered as a boost following immunization with BCG, which alone does not confer such protection.32 Immunogenicity in mice and protection in guinea pigs of the adjuvanted new vaccine formulation (M72) are unchanged.
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Clinical studies Preclinical studies in mice, guinea pigs, rabbits and monkeys had supported the initiation of clinical development of Mtb72F in AS02A. In 2004, the vaccine formulation (three doses of 10 mg in adjuvant) entered a phase I clinical trial in 12 healthy M. tuberculosis-uninfected adult volunteers in the USA. The vaccine was found to be highly immunogenic, safe and well tolerated in this trial.36,37 Subsequently, the 40-mg dose of Mtb72F in adjuvant or adjuvant alone was evaluated in 38 adult volunteers in Switzerland, all of whom were PPD-reactive, 20 due to prior exposure to BCG and/or environmental (non-tuberculous) mycobacteria and 18 due to prior exposure to M. tuberculosis. The formulations were found to be highly immunogenic and well tolerated in the former group, and highly immunogenic but more reactogenic in the latter group. The adverse events reported were usually self-limiting and resolved without sequelae.38 GSKBio is proceeding with development of the vaccine to prevent primary or reactivation of TB in PPD-negative or -reactive individuals who are at low risk of active TB disease. The adjuvanted M72 vaccine is currently undergoing clinical trials in Europe, at the SATVI site in South Africa and further trials are planned at other sites in Asia and Africa. AERAS-402 This vaccine was developed by Crucell at Leiden in The Netherlands as a boosting vaccine in BCG-primed individuals. A serotype 35 adenovirus (Ad35), incapable of replicating, has been modified to express a fusion protein of three immunodominant M. tuberculosis antigens: 85A, 85B and TB10.4. Antigen TB10.4 is a member of the ESAT-6 group of secreted M. tuberculosis proteins. Ad35 is capable of infecting human and animal cells in culture, including epithelial, muscle and lymphoid cells.39 Five per cent of individuals in Europe, North America and Japan have been found to have pre-existing cross-reactive neutralizing antibodies to Ad35, compared with around 50% against Ad5, another prominent candidate vaccine vector.39,40 Preclinical studies The vaccine was shown to be safe, immunogenic and protective in animal models.41,42 Three doses of the vaccine were given to guinea pigs with and without BCG priming. No toxicity was detected either during life or in autopsies. The vaccine is immunogenic in mice, both when given alone and when given as a booster in mice which have been primed with BCG. The vaccine given alone gives some protection to mice subsequently challenged with M. tuberculosis. Clinical studies A trial of the vaccine was started in November 2006 and is in progress in Kansas in the USA, but no results have yet been published. The first trial of AERAS-402 in South Africa, a dose escalation study targeting four groups of 10 healthy, HIV-uninfected, TB-naive adults, started at the SATVI site in April 2007. Further trials of the vaccine in adults with evidence of TB disease or just TB infection are due to start in 2008. Mycobacterium vaccae Mycobacterium vaccae is an environmental saprophyte. The hypothesis underlying use of adjunctive M. vaccae in TB treatment is that entrenched Th2 (humoral) dominant responses in the lung lead to inflammation, necrosis and cavitation. Mycobacterium vaccae is believed to promote Th1 responses, important to host defences against intracellular pathogens.43 The hope is that immunotherapy with M. vaccae will shorten short-course anti-TB chemotherapy. Clinical studies Heat-killed M. vaccae vaccine was first tested in a three-dose (0, 2 and 10 months) intradermal schedule in healthy adults.44
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Immunization was safe and well tolerated. Seven participants completed the three-dose schedule; pre-existing immunologic responses to mycobacteria were boosted in three, and a new response was elicited in one. The safety and immunogenicity of M. vaccae in patients with HIV infection were then assessed.45 Fifteen (seven healthy and eight HIV-infected participants) received five doses of the vaccine. The vaccine was well tolerated in all 15 participants. The safety of the vaccine in 35 HIV-infected children, aged 1 to 8 years, with CD4þ T-lymphocyte counts 300/mm3 was then assessed.46 Immunization was found to be safe and well tolerated. No effects on viral load or CD4þ T-lymphocyte count were observed. In 1999, a South African group reported on a trial designed to test the hypothesis that the addition of M. vaccae to standard short-course anti-TB chemotherapy would decrease the time to achieve a negative sputum culture.47 Patients with newly diagnosed TB were randomly assigned an injection of saline (placebo, n ¼ 175) or M. vaccae (n ¼ 175) on day 8. All patients received fourdrug anti-TB chemotherapy. At 8 weeks, 70 patients in the M. vaccae group and 65 patients in the placebo group had a negative culture; there was no difference between groups in the time to a negative culture. The group concluded that M. vaccae immunotherapy has no benefit when added to standard anti-TB chemotherapy. A further trial was conducted in Zambia: five doses of inactivated M. vaccae were administered intradermally to 22 HIVinfected patients, whose CD4þ lymphocyte counts were 200 cells/mm3, 11 of whom were BCG-exposed.48 Immunization was found to be safe in these patients and to induce lymphocyte proliferation responses to the vaccine antigen. In 2002 the LUSKAR collaboration reported the results of a trial which aimed to assess the effect on mortality of immunotherapy with single-dose SRL172 (M. vaccae) added to standard anti-TB chemotherapy in HIV-infected patients treated for TB.49 No significant effect on survival or bacteriological outcome was shown, though it was safe and well tolerated. The attention to M. vaccae has begun to shift to an investigation of its role in MDR-TB. In a randomized trial from China, sputum conversion, cavity closure and relapse were significantly better in patients with MDR-TB treated with M. vaccae every 3–4 weeks for 6 months plus susceptibility-directed chemotherapy than in those on chemotherapy alone.43 De Bruyn and Garner have conducted a Cochrane review of studies in which the effects of M. vaccae as an adjunct to chemotherapy for treating TB were investigated. Up to the year 2000 they identified only six trials for inclusion in their review. The main findings were that M. vaccae had no effect on mortality and no consistent effect on sputum negativity or sputum culture. They concluded that immunotherapy with M. vaccae does not benefit patients with TB.40
CHALLENGES TO NEW TUBERCULOSIS VACCINE DEVELOPMENT LACK OF UNDERSTANDING OF THE PROTECTIVE IMMUNE RESPONSE AGAINST TUBERCULOSIS An optimal knowledge both of vaccination-induced immune correlates of protection against TB and of protective immunity against TB is critical for vaccine development. Our knowledge is so incomplete that many regard current novel TB vaccine development to be in a
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first phase: the TB epidemic is so devastating that vaccines of limited efficacy, or of which we understand immune protection inadequately, should reach clinical trials. The second phase of vaccine development is likely to be guided by improved understanding of protective immunity, and may therefore yield vaccines with greater efficacy. Here, we will focus primarily on immune correlates of protection, as description of these markers would have an immediate impact on vaccine development. Studies of novel TB vaccine candidates in animal models provide some insight, regardless of differences between host responses to mycobacteria in animals and humans.31,50,51 The message from recent reports is that components of immunity shown to be critical for protection may not necessarily correlate with vaccination-induced protection. For example, specific IFN-g production has been used widely as a marker of vaccination-induced responses, as this cytokine has a central role in host protection against mycobacteria.52,53 Multiple animal studies have shown that increased vaccine efficacy is associated with enhanced specific IFN-g production.54–56 This has also been the case when the frequency of specific IFN-gproducing T cells, as measured by intracellular cytokine or Elispot assays, has been measured.20,54,57,58 However, recent studies have questioned whether IFN-g production should be used as an immune correlate of protection against TB. For example, Hovav et al.59 reported that, although strong IFN-g responses were induced in mice by vaccination with recombinant 27-kDa M. tuberculosis lipoprotein, M. tuberculosis challenge was associated with a worse outcome than that in unvaccinated mice. In studies of BCG vaccination of newborn calves, Hope et al.60 found that there was no correlation between specific IFN-g induced by the vaccine and subsequent protection, as measured by tissue pathology and bacterial load following virulent M. bovis challenge; rather, high levels of IFN-g were associated with more extensive lesions. Also in neonatal calves, Buddle et al.61 showed that double vaccination with BCG was associated with poorer protection against TB, despite significantly stronger specific IFN-g and interleukin-2 (IL-2) induction, compared with animals who received single vaccination. These sobering findings may be confounded by the assay systems used, by the time point and age at which the immune response was measured62,63 and by measurement at an immunological site distant from the disease site, the lung.58,64 Regardless, a critical foundation for directing human investigation into vaccination-induced immune correlates of protection against TB will only be achieved once renewed effort is made to delineate immune correlates in animal studies. A report by Bennekov et al.65 clearly illustrates why much more detailed examination of the induced immune response may be warranted. Mice were vaccinated with a fusion protein of Ag85A and ESAT-6 administered either within an adenovirus vector or within a liposomal adjuvant. After vaccination, specific IFN-g production was quantitatively greater when the adenovirus construct was used than when the liposome-based vaccine was used. However, the latter vaccine induced far better protection against virulent M. tuberculosis challenge. The adenovirus-based vaccine induced a CD8þ T-cell response primarily directed at a single ESAT-6 epitope, whereas the liposome-based vaccine induced a CD4þ T-cell response primarily directed at a single Ag85B epitope. Administration of the adenovirus construct within liposomes resulted in protection, and induction of the CD4þ T-cell responses directed at the Ag85B epitope. Most animal studies of immune correlates of protection have focused on CD4þ T cells, known to be critical for protection against mycobacteria. However, CD8þ T cells may be important
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for controlling the chronic phase of M. tuberculosis disease.66 This raises the possibility that T-cell responses other than a classical CD4þ T-cell IFN-g response may be attractive correlates. Although various candidates, such as IL-2, IL-10, IL-12, IL-13, IL-18 and tumour necrosis factor-alpha (TNF-a) production, have been suggested, none of these have, to date, been demonstrated to be correlates of protection in animal studies.61 Regulation of the immune response, through for example regulatory T cells or innate immune cells, has received virtually no attention. Similarly, humoral measures, such as the antibody response, have found limited application in evaluation as immune correlates of vaccinationinduced protection.67,68 In humans the tuberculin skin test reaction induced by BCG vaccination was initially suggested to be a surrogate of protection, only to be discarded as a poor correlate.69 No correlates, using modern immunological tools, exist today. However, some advances have been made in description of the BCG-induced immune response, which may guide immune analysis in the large projects. BCG does induce a robust type 1 immune response, at all ages, including infancy.70–74 This is characterized by IFN-g production and T-cell proliferation in peripheral blood mononuclear cells (PBMCs) or whole blood incubated with mycobacterial antigens. It has been demonstrated that Malawian vaccine recipients make significantly less IFN-g than their British counterparts, strongly suggesting that genetic and environmental factors, such as environmental mycobacterial exposure, may modulate this response.70,75 BCG induces both CD4þ and CD8þ T cells. Specific CD8þ T-cell cytotoxic activity has been demonstrated.76,77 In infancy, BCG-induced CD8þ T cells appear to have the capacity either to produce IFN-g or to have cytotoxic activity, but not both.77 Whereas subsets of specific CD4þ T cells induced by newborn vaccination produce combinations of IFN-g, IL-2 and/or TNF-a, CD8þ T cells appear to produce mostly IFN-g and/or IL-2, and little TNF-a.72 BCG vaccination of adults results in inhibition of mycobacterial growth in PBMCs or whole blood incubated with M. tuberculosis or M. bovis BCG, suggesting that the induced T cells are indeed functional.73 Finally, recent data indicate that BCG vaccination of newborns induces functional regulatory CD4þ T cells, and a strong specific antibody response.72 To date, it is not clear which of these immune responses are associated with protection against TB disease. However, linking results from our recent immunological study of BCG vaccination with those of a much larger phase IV clinical trial of BCG vaccine efficacy should have a sobering effect. We have demonstrated that percutaneous vaccination of newborns with a Japanese BCG strain resulted in quantitatively greater type 1 immune responses, i.e. IFN-g production measured in plasma and T cells from whole blood incubated with BCG, compared with intradermal vaccination with the same strain.71 Given the dogma of the importance of type 1 immunity for protection against TB, one would presume that intradermal vaccination would result in superior protection. However, when 11,680 newborns were randomized to receive either percutaneous or intradermal vaccination with the same Japanese BCG strain, and followed up for at least 2 years to compare occurrence of TB disease, no difference in efficacy between the two routes of vaccination could be demonstrated.78 Once again, these findings question use of type 1 immunity markers traditionally proposed as immune correlates of protection against TB disease. Multiple large collaborative efforts are currently ongoing to look for immune correlates of protection against TB. Once discovered, the correlates may only be validated in a phase III trial of a very
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efficacious TB vaccine. Until then, immunogenicity testing in phase I and II trials of novel TB vaccines have necessarily involved measurement of type 1 immunity, particularly of a specific IFN-g response with assays such as the Elispot and detection of intracellular cytokine expression with flow cytometry.23
DIFFICULTY IN IDENTIFYING LATENT INFECTION AND DIFFERENTIATING INFECTION FROM DISEASE Any new TB vaccine will first have to be tested in mycobacterianaı¨ve individuals. The Mantoux tuberculin skin test (TST) is currently the ‘gold standard’. However, it lacks sensitivity in immunocompromised individuals and is not specific.79 False-positive results are relatively common following exposure to BCG and environmental (non-tuberculous) mycobacteria.80 New immunodiagnostic tests have been developed and are based on the measurement of IFN-g secretion after stimulation with antigens said to be specific to M. tuberculosis. Two such tests are currently available commercially, i.e. T-spot TB (Oxford Immuntec) and QuantiFERON (Cellestis). In 2005, the QuantiFERON-TB Gold received approval from the US Food and Drug Administration as an aid for diagnosing M. tuberculosis infection.81 The performance of QuantiFERON assays to identify LTBI was compared with TST in a high-TB-burden community.82 Among 358 participants 81% had a TST result of 10 mm induration or more, and 52% 15 mm or more. QuantiFERON-TB was positive in 60%, QuantiFERON-TB Gold in 38% and QuantiFERON-TB Gold (In-Tube method) in 56%. There was poor agreement between TST and QuantiFERON tests, and between the different generations of QuantiFERON tests (k ¼ 0.12–0.50). In individuals with TST indurations of 15 mm or more, 30–56% had negative QuantiFERON tests.
DIFFICULTY IN DEFINING CLINICAL ENDPOINTS OF TRIALS The current gold standard for diagnosing TB disease is M. tuberculosis culture. Most immunocompetent adults with TB, who classically present with cavitary lung disease, are culture positive. However, children classically have paucibacillary disease, which manifests as hilar or mediastinal adenopathy with or without complications, and are culture positive in only about 30% of cases.83 The diagnosis of TB in most situations is thus based on clinical grounds including the TST and chest radiograph. This problem has been highlighted by the recent randomized clinical trial comparing the efficacy of two routes of vaccination in the prevention of TB in the first 2 years of life, mentioned earlier.78 The cumulative incidence rates over 2 years of definite plus probable and of definite plus probable plus possible TB in the trial was a staggering 6.3%. Of the 236 participants who had positive cultures, 70 (30%) had a Mantoux test with no (0 mm) induration and 108 (46%) a Mantoux test result of less than 15 mm, 130 (55%) had relatively few significant clinical symptoms (scored below the cut-off on a standard clinical scoring system) and only 142 (60%) had a chest radiograph judged to be compatible with TB.
UNCERTAINTY ABOUT SAFETY OF NEW TUBERCULOSIS VACCINES The evaluation of safety in target populations, including infants, mycobacteria-exposed individuals and HIV-infected persons is critical in novel vaccine trials.
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Koch phenomenon Robert Koch, in search of a cure for TB, found that individuals with TB when injected subcutaneously with a culture filtrate of whole organisms developed exaggerated disease.13 Although unlikely, it has been postulated that the Koch phenomenon could have contributed to failure of BCG vaccine in a trial conducted in Chingelput, South India, as many had prior mycobacterial exposure.84 Animal studies suggest that such reactions occur in situations where a high bacillary load pre-exists; it is unlikely that the Koch phenomenon will occur in latently infected persons who receive immunogenic vaccines.85 Safety in HIV-infected individuals HIV infection is a major risk factor for developing TB. A latently infected HIV-infected person has a 10% annual risk of developing TB disease, while this risk is 10% in the lifetime of HIV-uninfected persons. An estimated 60% of persons newly diagnosed with TB in sub-Saharan Africa are coinfected with HIV. Preventing TB in HIV-infected individuals is thus a high priority.1 BCG poses a risk to HIV-infected children. The risk of disseminated BCG disease in HIV-infected infants is likely to be several hundred-fold greater than that in HIV-uninfected infants.86 The WHO Global Advisory Committee on Vaccine Safety has recently recommended that BCG vaccine should not be used in children who are known to be HIV infected.87 The committee recognizes the difficulty in identifying infants infected with HIV at birth in settings where diagnostic and treatment services for mothers and infants are limited. In such situations, BCG vaccination should continue to be given at birth to all infants regardless of HIV exposure, especially considering the high endemicity of TB in populations with high HIV prevalence. Close follow-up of infants known to be born to HIV-infected mothers and who received BCG at birth is recommended in order to provide early identification and treatment of any BCG-related complication. In settings with adequate HIV services that could allow for early identification and administration of antiretroviral therapy to HIVinfected children, consideration should be given to delaying BCG vaccination in infants born to mothers known to be infected with HIV until these infants are confirmed to be HIV-uninfected. Live attenuated mycobacterial vaccines are unlikely to be recommended for use in HIV-infected persons or other immunocompromised individuals. However, auxotrophic mutant vaccines, which maintain their infective ability and have a limited period of replication in the host may be ideal candidates to use in this situation. Such attenuated mutant vaccines have been shown to be safer than BCG in immunocompromised animals.88 THE NEED FOR PHASE III TRIAL SITES Phase III trials of novel TB vaccines will require multiple sites for testing, for sample size reasons. Developing a field site for the assessment of new TB vaccines is difficult. Such sites should ideally be located in developing countries where the rates of TB are high. However, in most areas the infrastructure necessary to conduct clinical trials is suboptimal, the health services are overwhelmed, there is a shortage of trained professional staff and laboratory and diagnostic facilities are suboptimal. In the absence of a well-defined surrogate marker of protection, studies using clinical endpoints are essential to determine efficacy and require long-term follow-up. Cohort retention is thus essential and good surveillance systems for morbidity and mortality are vital for monitoring outcomes.
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A single site, the SATVI site in South Africa, is currently ready for phase III trials. The main aim of this site was to develop the capacity to do phase I to phase IV TB vaccine trials, to characterize the TB epidemic epidemiologically and to identify clinical, microbiological and immunological endpoints of key importance to all stages of vaccine trials. In developing the site a number of challenges had to be overcome. These included working with a research naı¨ve population in a poor, socially disadvantaged rural area, renowned for its political conservatism. The distance from microbiological and immunological laboratories in Cape Town was also a challenge. Significant investment in infrastructural development, training of research staff and the development of a non-exploitative and supportive partnership model between the research team, the sponsors, the health services, the community and the research collaborators were essential for success. Other sites in Kenya and Uganda, and in India and Indonesia, are being developed with funding from the European and Developing Countries Trials Partnership (EDCTP) and the Aeras Global TB Vaccine Foundation.
SPECIAL STRUCTURES ARE NEEDED FOR MORBIDITY AND MORTALITY SURVEILLANCE Routine health information systems in most high-burden countries do not provide age-stratified admission and discharge data with recorded diagnoses. The quality of case notes commonly varies widely, and in most situations is not adequate for vaccine trial purposes. Statutory reporting of deaths is also generally incomplete, of poor quality and slow. Pathological postmortem examinations are very seldom done and may be culturally unacceptable.89 SATVI has attempted to improve the quality of morbidity and mortality surveillance and attempts to verify TB as a cause for hospital admission or death have been developed. Health workers in the region are encouraged to refer all possible cases of TB to a special research case verification ward which has been established at the regional TB hospital for a comprehensive diagnostic work-up. The case notes of any trial participant admitted to the district hospitals in the region are reviewed as soon as the research team is notified of such an event. We are also putting in place a mechanism whereby we can do postmortems as soon as we have been notified of a trial participant’s death and we have validated a verbal autopsy methodology for use in situations where postmortems have not been done.
ETHICAL CONSIDERATIONS Informed consent is an ethical and legal requirement for research involving human participants.90 Developing countries which lack
REFERENCES 6. 1. Dye C. The global epidemiology of tuberculosis. Lancet 2006;367:938–940. 2. Lawn SD, Wilkinson R. Extensively drug resistant tuberculosis. BMJ 2006;333:559–560. 3. Fine P, Carneiro I, Milstein J, et al. Issues Relating to the Use of BCG in Immunization Programmes: A Discussion Document. WHO/V&B/199923. Geneva: World Health Organization, 1999. 4. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study. JAMA 2004;291:2086–2091. 5. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary
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well-organized Institutional Review Boards or Research Ethics Committees may have problems in protecting the rights of participants involved in clinical trials. In addition, concepts such as ‘voluntary participation’, ‘randomization’ and ‘benefits and risks’ may be difficult to explain to uneducated study participants. Poverty, disease, poor literacy and social insecurity make participants vulnerable to research exploitation. The informed consent process thus poses significant logistical and ethical challenges. SATVI has invested significantly in ensuring that our research staff are fully conversant with informed consent process and that the participants in our clinical trial understand what it means to be involved in clinical research projects.
ECONOMIC CONSIDERATIONS Given the magnitude of the problem worldwide it is imperative that there is a global strategy to coordinate collaborative efforts to develop vaccines that are effective in reducing TB. Strategic investments made by the European Union, the National Institutes of Health, the Bill and Melinda Gates Foundation and other agencies and governments have gone a long way towards meeting the intended goal. However, significant additional resources and commitments are needed to support additional research, preclinical development, vaccine production and clinical trials. In 2005, it was estimated that the investment in TB research and development in general amounted to approximately $400 million, with less than a quarter directed to vaccine research.91 The Stop TB Working Group on New TB Vaccines has estimated that over $3000 million will be needed to ensure that we get a new TB vaccine into the field by 2015.8
CONCLUDING REMARKS The challenges facing developers of new TB vaccines are considerable. Regardless, significant progress in the development of new vaccines has been made over the past two decades and continues to be made. Even when new TB vaccines are developed and shown to be superior to BCG in animal studies, the task of translating these laboratory findings into clinical practice and public health policy, and ultimately impacting on the burden of TB infection and disease, is daunting. Nevertheless we are optimistic that the goal of getting a more effective vaccine to those who most need one before 2015 is realizable.
tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367:1173–1180. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393:537–544. Brennan MJ, Morris SL, Sizemore CF. Tuberculosis vaccine development: research, regulatory and clinical strategies. Expert Opin Biol Ther 2004;4:1493–1504. World Health Organization. Global Plan to Stop TB 2006–2015. WHO/HTM/STB/200635. Geneva: World Health Organization, 2006. Ginsberg AM. What’s new in tuberculosis vaccines? Bull World Health Organ 2002;80:483–488. McShane H, Hill A. Prime-boost immunisation strategies for tuberculosis. Microbes Infect 2005;7: 962–967.
11. Kaufmann SH, McMichael AJ. Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med 2005;11:S33–44. 12. Skeiky YA, Sadoff JC. Advances in tuberculosis vaccine strategies. Nat Rev Microbiol 2006;4:469–476. 13. Koch R. Fortstzung uber ein Heilmittel gegen Tuberculose. Deutsche Med Wochenschr 1891;17: 101–102. 14. Taylor JL, Turner OC, Basaraba RJ, et al. Pulmonary necrosis resulting from DNA vaccination against tuberculosis. Infect Immun 2003;71:2192–2198. 15. Wiker HG, Harboe M. The antigen 85 complex: a major secretion product of Mycobacterium tuberculosis. Microbiol Rev 1992;56:648–661. 16. Mahnel H, Mayr A. [Experiences with immunization against orthopox viruses of humans and animals using vaccine strain MVA]. Berl Munch Tierarztl Wochenschr 1994;107:253–256.
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Tuberculosis vaccines 17. Stickl H, Hochstein-Mintzel V, Mayr A, et al. [MVA vaccination against smallpox: clinical tests with an attenuated live vaccinia virus strain (MVA)]. Dtsch Med Wochenschr 1974;99:2386–2392. 18. Cosma A, Nagaraj R, Buhler S, et al. Therapeutic vaccination with MVA-HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals. Vaccine 2003;22:21–29. 19. Harrer E, Bauerle M, Ferstl B, et al. Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther 2005; 10:285–300. 20. Goonetilleke NP, McShane H, Hannan CM, et al. Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara. J Immunol 2003;171:1602–1609. 21. Williams A, Hatch GJ, Clark SO, et al. Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis. Tuberculosis (Edinb) 2005;85:29–38. 22. Verreck F. Personal communication to H. McShane. 2007. 23. McShane H, Pathan AA, Sander CR, et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med 2004;10:1240–1244. 24. Pathan AA, Sander CR, Fletcher HA, et al. Boosting BCG with Recombinant Modified Vaccinia Ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials. PLoS ONE 2007;2:e1052. 25. McShane H. Personal communication, 2007. 26. Ibanga HB, Brookes RH, Hill PC, et al. Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design. Lancet Infect Dis 2006;6:522–528. 27. Hawkridge A. Phase one trial of Modified Vaccinia Ankara tuberculosis vaccine in adults in a high TB prevalence setting in South Africa. In: Proceedings of Tuberculosis Vaccines for the World Conference, Vienna, Austria, 19–21 April 2006. 28. Horwitz MA, Harth G. A new vaccine against tuberculosis affords greater survival after challenge than the current vaccine in the guinea pig model of pulmonary tuberculosis. Infect Immun 2003;71:1672–1679. 29. Horwitz MA, Harth G, Dillon BJ, et al. Recombinant bacillus Calmette-Guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc Natl Acad Sci USA 2000;97:853–13,858. 30. Hoft DF. Results of the 1st phase I trial of a recombinant BCG TB vaccine (rBCG30). In: Proceedings of 40th Tuberculosis and Leprosy Research Conference; Seattle, WA, 28–30 July 2005. 31. Orme IM. Mouse and guinea pig models for testing new tuberculosis vaccines. Tuberculosis (Edinb) 2005;85:13–17. 32. Reed S, Lobet Y. Tuberculosis vaccine development; from mouse to man. Microbes Infect 2005;7:922–931. 33. Irwin SM, Izzo AA, Dow SW, et al. Tracking antigen-specific CD8 T lymphocytes in the lungs of mice vaccinated with the Mtb72F polyprotein. Infect Immun 2005;73:5809–5816. 34. Skeiky YA, Alderson MR, Ovendale PJ, et al. Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J Immunol 2004;172:7618–7628. 35. Brandt L, Skeiky YA, Alderson MR, et al. The protective effect of the Mycobacterium bovis BCG vaccine is increased by coadministration with the Mycobacterium tuberculosis 72-kilodalton fusion polyprotein Mtb72F in M. tuberculosis-infected guinea pigs. Infect Immun 2004;72:6622–6632. 36. Morrison R. Personal communication to O. OforiAnyinam, 2007.
37. Leroux-Roels I, Lerroux-Roels G, Clement F, et al. Safety and immunogenicity of the Mtb72f/ASO2A tuberculosis vaccine in PPD-negative Belgian adults. In: Proceedings of Tuberculosis Vaccines for the World Conference, Vienna, Austria, 19–21 April 2006. 38. Spertini F, Audran R, Lurati F, et al. Safety and immunogenicity of the Mtb72f/ASO2A tuberculosis vaccine in PPD-positive Swiss adults. In: Proceedings of Keystone Conference: Tuberculosis: from Lab Research to Field Sites; Vancouver, Canada; 20–25 March 2007. 39. Vogels R, Zuijdgeest D, van Rijnsoever R, et al. Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. J Virol 2003;77:8263–8271. 40. Kostense S, Koudstaal W, Sprangers M, et al. Adenovirus types 5 and 35 seroprevalence in AIDS risk groups supports type 35 as a vaccine vector. AIDS 2004;18:1213–1216. 41. Radosevic K, Wieland CW, Rodriguez A, et al. Protective immune responses to a recombinant adenovirus type 35 tuberculosis vaccine in two mouse strains: CD4 and CD8 T-cell epitope mapping and role of gamma interferon. Infect Immun 2007;75: 4105–4115. 42. Skeiky Y. Personal communication, 2007. 43. Fourie PB, Ellner J, Johnson JL. Whither Mycobacterium vaccae—encore. Lancet 2002;360: 1032–1033. 44. Von Reyn CF, Arbeit RD, Yeaman G, et al. Immunization of healthy adult subjects in the United States with inactivated Mycobacterium vaccae administered in a three-dose series. Clin Infect Dis 1997;24:843–848. 45. Von Reyn CF, Marsh BJ, Waddell R, et al. Cellular immune responses to mycobacteria in healthy and human immunodeficiency virus-positive subjects in the United States after a five-dose schedule of Mycobacterium vaccae vaccine. Clin Infect Dis 1998;27:1517–1520. 46. Johnson D, Waddell RD, Pelton SI, et al. Randomised trial of intradermal Mycobacterium vaccae or intradermal hepatitis B immunisation in children with HIV infection. Vaccine 1999;17:2583–2587. 47. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999;354:116–119. 48. Waddell RD, Chintu C, Lein AD, et al. Safety and immunogenicity of a five-dose series of inactivated Mycobacterium vaccae vaccination for the prevention of HIV-associated tuberculosis. Clin Infect Dis 2000;30: S309–315. 49. Mwinga A, Nunn A, Ngwira B, et al. Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial. Lancet 2002;360:1050–1055. 50. Flynn JL. Lessons from experimental Mycobacterium tuberculosis infections. Microbes Infect 2006;8:1179–1188. 51. Orme IM. Preclinical testing of new vaccines for tuberculosis: a comprehensive review. Vaccine 2006;24:2–19. 52. Flynn JL. Immunology of tuberculosis and implications in vaccine development. Tuberculosis (Edinb) 2004;84(1–2):93–101. 53. Kaufmann SH. New issues in tuberculosis. Ann Rheum Dis 2004;63(Suppl 2):ii50–ii56. 54. Agger EM, Rosenkrands I, Olsen AW, et al. Protective immunity to tuberculosis with Ag85BESAT-6 in a synthetic cationic system IC31. Vaccine 2006;24:5452–5460. 55. Freidag BL, Melton GB, Collins F, et al. CpG oligodeoxynucleotides and interleukin-12 improve the efficacy of Mycobacterium bovis BCG vaccination in mice challenged with M. tuberculosis. Infect Immun 2000;68:2948–2953. 56. Langermans JA, Doherty TM, Vervenne RA, et al. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT-6. Vaccine 2005;23(21):2740–2750.
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57. Martin E, Kamath AT, Triccas JA, et al. Protection against virulent Mycobacterium avium infection following DNA vaccination with the 35-kilodalton antigen is accompanied by induction of gamma interferon-secreting CD4(þ) T cells. Infect Immun 2000;68:3090–3096. 58. Santosuosso M, McCormick S, Zhang X, et al. Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infect Immun 2006;74: 4634–4643. 59. Hovav AH, Mullerad J, Davidovitch L, et al. The Mycobacterium tuberculosis recombinant 27-kilodalton lipoprotein induces a strong Th1-type immune response deleterious to protection. Infect Immun 2003;71:3146–3154. 60. Hope JC, Thom ML, Villarreal-Ramos B, et al. Vaccination of neonatal calves with Mycobacterium bovis BCG induces protection against intranasal challenge with virulent M. bovis. Clin Exp Immunol 2005;139:48–56. 61. Buddle BM, Wedlock DN, Denis M, et al. Identification of immune response correlates for protection against bovine tuberculosis. Vet Immunol Immunopathol 2005;108:45–51. 62. Chen L, Wang J, Zganiacz A, et al. Single intranasal mucosal Mycobacterium bovis BCG vaccination confers improved protection compared to subcutaneous vaccination against pulmonary tuberculosis. Infect Immun 2004;72:238–246. 63. Goter-Robinson C, Derrick SC, Yang AL, et al. Protection against an aerogenic Mycobacterium tuberculosis infection in BCG-immunized and DNAvaccinated mice is associated with early type I cytokine responses. Vaccine 2006;24:3522–3529. 64. Ha SJ, Park SH, Kim HJ, et al. Enhanced immunogenicity and protective efficacy with the use of interleukin-12-encapsulated microspheres plus AS01B in tuberculosis subunit vaccination. Infect Immun 2006;74:4954–4959. 65. Bennekov T, Dietrich J, Rosenkrands I, et al. Alteration of epitope recognition pattern in Ag85B and ESAT-6 has a profound influence on vaccineinduced protection against Mycobacterium tuberculosis. Eur J Immunol 2006;36:3346–3355. 66. van Pinxteren LA, Cassidy JP, Smedegaard BH, et al. Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells. Eur J Immunol 2000; 30:3689–3698. 67. Giri PK, Verma I, Khuller GK. Enhanced immunoprotective potential of Mycobacterium tuberculosis Ag85 complex protein based vaccine against airway Mycobacterium tuberculosis challenge following intranasal administration. FEMS Immunol Med Microbiol 2006;47:233–241. 68. Watanabe Y, Watari E, Matsunaga I, et al. BCG vaccine elicits both T-cell mediated and humoral immune responses directed against mycobacterial lipid components. Vaccine 2006;24:5700–5707. 69. Comstock GW. Identification of an effective vaccine against tuberculosis. Am Rev Respir Dis 1988; 138:479–480. 70. Black GF, Weir RE, Floyd S, et al. BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies. Lancet 2002;359:1393–1401. 71. Davids V, Hanekom WA, Mansoor N, et al. The effect of bacille Calmette-Guerin vaccine strain and route of administration on induced immune responses in vaccinated infants. J Infect Dis 2006;193:531–536. 72. Hanekom WA. The immune response to BCG vaccination of newborns. Ann NY Acad Sci 2005;1062:69–78. 73. Hoft DF, Worku S, Kampmann B, et al. Investigation of the relationships between immune-mediated inhibition of mycobacterial growth and other potential surrogate markers of protective Mycobacterium tuberculosis immunity. J Infect Dis 2002;186:1448–1457. 74. Marchant A, Goetghebuer T, Ota MO, et al. Newborns develop a Th1-type immune response to
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Mycobacterium bovis bacillus Calmette-Guerin vaccination. J Immunol 1999;163:2249–2255. Weir RE, Black GF, Nazareth B, et al. The influence of previous exposure to environmental mycobacteria on the interferon-gamma response to bacille Calmette-Guerin vaccination in southern England and northern Malawi. Clin Exp Immunol 2006;146:390–399. Smith SM, Brookes R, Klein MR, et al. Human CD8þ CTL specific for the mycobacterial major secreted antigen 85A. J Immunol 2000;165: 7088–7095. Murray RA, Mansoor N, Harbacheuski R, et al. Bacillus Calmette Guerin vaccination of human newborns induces a specific, functional CD8þ T cell response. J Immunol 2006;177:5647–5651. Hawkridge AJ, Hanekom W, Geiter L, et al. Results from a randomised controlled trial comparing intradermal and percutaneous administration. Int J Tuberc Lung Dis 2006;10:S13. Cobelens FG, Egwaga SM, van Ginkel T, et al. Tuberculin skin testing in patients with HIV infection: limited benefit of reduced cutoff values. Clin Infect Dis 2006;43(5):634–639.
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80. Farhat M, Greenaway C, Pai M, et al. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10:1192–1204. 81. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: part I. Latent tuberculosis. Expert Rev Mol Diagn 2006; 6:413–422. 82. Mahomed H, Hughes EJ, Hawkridge T, et al. Comparison of Mantoux skin test with three generations of a whole blood IFN-gamma assay for tuberculosis infection. Int J Tuberc Lung Dis 2006;10:310–316. 83. Enarson PM, Enarson DA, Gie R. Management of tuberculosis in children in low-income countries. Int J Tuberc Lung Dis 2005;9:1299–1304. 84. Fifteen year follow up of trial of BCG vaccines in south India for tuberculosis prevention. Tuberculosis Research Centre (ICMR), Chennai. Indian J Med Res 1999;110:56–69. 85. Rook GA, al Alliyah R. Cytokines and the Koch phenomenon. Tubercle 1991;72:13–20.
86. Hesseling AC, Marais BJ, Gie RP, et al. The risk of disseminated Bacillus Calmette-Guerin (BCG) disease in HIV-infected children. Vaccine 2007;25:14–18. 87. World Health Organization. Global advisory committee on vaccine safety, 29–30th November 2006. Weekly Epidemiol Rep 2006; 82:2–8. 88. Guleria I Teitelbaum R, McAdam RA, et al. Auxotrophic vaccinesfor tuberculosis. Nat Med 1996;2:334–337. 89. Moyo S, Hawkridge T, Mahomed H, et al. Determining causes of mortality in children enrolled in a vaccine field trail in a rural area in the western Cape Province of South Africa. J Paed Child Health 2007;43:178–183. 90. Joffe S, Cook EF, Cleary PD, et al. Quality of informed consent: a new measure of understanding among research subjects. J Natl Cancer Inst 2001;93:139–147. 91. Kaufmann SHE, Parida SK. Changing funding patterns in tuberculosis. Nat Med 2007;13:299–303.
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12
Pathology and pathogenesis of tuberculosis Juanita Bezuidenhout and Johann W Schneider
Tuberculosis is a mycobacterial infection that is usually pulmonary and may lead to severe destruction and lung dysfunction. It is a chronic disease, often associated with some form of underlying immune deficiency, such as malnutrition or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). It may be seen in adults and children, depending on age at infection. In developing countries with a high annual risk of infection and a high proportion of the population less than 14 years of age children may constitute 20% of the TB case load. With the advent of HIV/AIDS the profile of TB has changed, especially in adults, and it is now frequently found in multiple extrapulmonary sites often with a more severe course than isolated pulmonary TB. The pathogenesis and macroscopic and microscopic morphology lie at the heart of the clinical manifestations and complications of TB. A clear understanding of the disease and its morphological manifestations in the various organs can be obtained only by understanding the pathogenesis and impact of the infection on the body.
BASIC CONCEPTS AND DEFINITIONS DEFINITION OF A GRANULOMA A granuloma comprises a microscopic aggregation of epithelioid (activated) macrophages, usually surrounded by a collar of lymphocytes (Fig. 12.1).1 Lymphocytes may be abundant or sparse, but they are always present. The epithelioid macrophages may occur in tight groups, or may be loosely associated. Although granulomas may display characteristic histological features in specific diseases, the various subtypes of granulomas are not pathognomonic of a particular disease and additional investigations are always required to determine the exact cause of the granulomatous disease. This will be discussed further in Chapter 21.
THE CELLS INVOLVED IN GRANULOMA FORMATION Antigen-presenting cells and T-lymphocytes are the main cell types involved in an immunogenic granuloma.
Antigen-presenting cells Antigen-presenting cells (macrophages and dendritic cells) are specialized to capture and process microbial and other antigens, present them to lymphocytes, and provide signals that stimulate proliferation and differentiation of lymphocytes.2
Macrophages The activated macrophage produces a wide range of chemical mediators that drive and orchestrate chronic inflammation.3 It forms part of the mononuclear phagocyte system that comprises blood monocytes and tissue macrophages arising from a common bone marrow precursor. Tissue macrophages are scattered in connective tissue or clustered in organs such as the liver (Kupffer cells), spleen, lymph nodes (sinus histiocytes), and lungs (alveolar macrophages). They originate from blood monocytes (with a half-life of about 1 day) that migrate into various tissues where they transform into macrophages with a half-life of months. This whole process is regulated by a variety of growth and differentiation factors, cytokines, adhesion molecules, and cellular interactions.3 Macrophages are primarily phagocytic cells, but once activated they become larger with an epithelioid appearance and display increased lysosomal enzyme levels and metabolism that enhance their efficiency to phagocytose and kill ingested organisms. The simultaneous increased expression of major histocompatibility complex (MHC) class II molecules on the cell surface facilitates antigen presentation, because CD4þ lymphocytes recognize antigens only in the presence of MHC class II expression. Several growth factors that stimulate fibroblast proliferation and collagen synthesis are also secreted. After activation the macrophage secretes a wide variety of biologically active products.4 In a haematoxylin–eosin-stained slide epithelioid cells have abundant pale-pink cytoplasm with indistinct cell borders, creating the impression of merging into one another. The cell has a vesicular nucleus, often with a distinct nucleolus. Epithelioid cells frequently fuse to form multinucleated giant cells of various configurations. These multinucleated giant cells are usually seen at the periphery of a granuloma, but can be present anywhere in the granuloma (Fig. 12.1). Dendritic cells Dendritic cells play an important role in antigen capture and the induction of T-cell responses, especially in naı¨ve T cells.5 They are present in lymphoid organs, the skin, the gastrointestinal and respiratory tracts, and most parenchymal organs. Dendritic cells have spine- or finger-like projections of their cell membranes, resulting in a vastly increased surface area of each cell. These cells capture protein antigens and transport them to the draining lymph nodes. During this journey the dendritic cells mature and become extremely efficient in presenting antigens to naı¨ve T cells.6
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BASIC SCIENCE Antigen presenting cell
Receptor Antigen Receptor
IL-12
CD4 + T-lymphocyte Activated macrophage (epithelioid macrophage)
IL-2 IFN-g
TNF Blood vessel Monocyte CD4 + T-lymphocytes
Granuloma Multinucleated giant cell
A
Epithelioid macrophage
Fig. 12.1 (A) A schematic illustration of granuloma formation during the delayed type hypersensitivity (DTH) reaction.39 After capture of the antigen, antigen-presenting cells present the antigen to the CD4þ lymphocytes, while producing interleukin (IL)-12, which stimulates Th1 differentiation. The proinflammatory cytokines tumour necrosis factor (TNF)-a and interferon (IFN)-g recruit and stimulate monocytes to transform into activated epithelioid macrophages, resulting in granuloma formation. (B) Microscopic appearance of a well-formed granuloma containing epithelioid macrophages, with a rim of lymphocytes and Langhans giant cells. (C) A granuloma with central caseous necrosis apparent as amorphous pink material.
Lymphocytes Lymphocytes are the only cells in the body capable of specifically recognizing and distinguishing different antigens.7 They are therefore responsible for both the specificity and memory that are the defining characteristics of the adaptive immune response. Lymphocytes that have not been stimulated by antigens are called naı¨ve
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lymphocytes and are small cells, measuring 8–10 mm in diameter. Once stimulated they become larger, with more cytoplasm, organelles, and cytoplasmic RNA. The lymphocytes involved in the cell-mediated adaptive immune response are CD3þ T cells, usually of the T-helper type (CD4þ). Once activated they differentiate into effector and memory cells.7,8
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PATHOGENESIS OF DELAYED-TYPE HYPERSENSITIVITY AND GRANULOMA FORMATION A detailed description of the immunopathogenesis of the granuloma can be found in Chapter 8. There are five distinct phases of adaptive immunity, namely:9,10 1. recognition of antigens; 2. activation of lymphocytes; 3. effector phase (elimination of antigens); 4. decline (return to resting state); and 5. memory. The current model for granuloma formation is based on the delayedtype hypersensitivity (DTH) reaction, as epitomized by the tuberculin reaction.11 With the first exposure of a person to tubercle bacilli, naı¨ve CD4þ T cells recognize captured peptides derived from these bacilli in association with class II molecules on antigenpresenting cells. This initiates the differentiation of these T cells into sensitized Th1 cells. Some of these Th1 cells enter the circulation and remain in the T-cell memory pool for years.8,12 On subsequent intracutaneous injection of tuberculin, the DTH process is initiated by these sensitized Th1 cells, following antigen presentation by macrophages.2,13 In a previously sensitized person, a response appears on site within 8–12 hours after injection (Mantoux test), in the form of reddening and induration. This reaches a peak within 24–72 hours and thereafter recedes. The redness and induration are due to vasodilation with perivascular cuffing of predominantly CD4 (helper) T-lymphocytes around small veins and venules.8,13 An increase in vascular permeability results in the escape of plasma proteins and fluid, causing dermal oedema and fibrin deposition, leading to induration. With persistence of the antigen, the lymphocytic infiltrate is largely replaced by macrophages over the next 2–3 weeks. These macrophages undergo morphological transformation to epithelioid cells and thus a granuloma is formed14 (Fig. 12.1B).
ANTIGEN CAPTURE, PROCESSING, AND PRESENTATION Microorganisms stimulate the innate immune response and induce the secretion of inflammatory cytokines in an effort to kill the organisms. Innate immunity against intracellular organisms may limit bacterial growth, but usually fails to eradicate the organisms; adaptive cell-mediated immunity is required for eradication. This process starts with the capturing of an antigen by an antigenpresenting cell.6,7,15 Once the protein antigen is captured and phagocytosed by the antigen-presenting cells, it is converted to a peptide and then displayed as a peptide–MHC II complex on the surface of the antigen-presenting cells, for recognition by T cells.7
ACTIVATION, PROLIFERATION, AND DIFFERENTIATION OF LYMPHOCYTES During this process the naı¨ve lymphocytes are activated. This results in a clonal expansion of antigen-specific lymphocytes and the differentiation of these cells into effector cells and memory cells. Some of these cells re-enter the systemic circulation and migrate to the site of infection. Here the cells again encounter the antigen and respond to eliminate the antigen.15
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Effector phase In cell-mediated immunity, the main effector function of the CD4þ cells is to stimulate the microbiocidal activities of macrophages and other leucocytes. Memory phase Memory T cells are an expanded population of T cells specific for an antigen that can respond rapidly to subsequent encounters with the same antigen, differentiate into effector cells, and eliminate the antigen. The mechanisms of memory cell generation are not known.
PATHOGENESIS OF TUBERCULOSIS Based on whether it is the first time a patient is infected, TB is divided into a primary and secondary type. Previously primary TB was called ‘childhood’ type, but over the years more adults presented for the first time with TB and the terminology was therefore changed to ‘primary TB’, indicating that a person is infected by TB for the first time. Secondary TB is usually seen in adults, subsequent to primary infection in childhood and a third type, ‘progressive-primary’, follows directly on primary TB. Figure 12.2 summarizes the typical spectrum of events that may follow primary and secondary TB, respectively.
PRIMARY TUBERCULOSIS This phase occurs in a previously unexposed host. The lungs are typically the initial site of contact between the host and Mycobacterium tuberculosis organisms, but less commonly other organs including the skin, oral cavity, and gastrointestinal tract may be involved. The initial phases of primary TB have seldom been seen in the human lung, and our understanding of the early pathogenesis is based solely on experimental animal models. In primary pulmonary TB the organism is inhaled and, usually in the periphery of the lung, is phagocytosed and innate immunity initiated. The phagocytosed organism is transported to the hilar lymph nodes and presented to naı¨ve T cells, stimulating the process of activation, proliferation, and differentiation of these T cells. If the organism is not killed, the process of adaptive immunity takes control and a DTH response commences at the primary site of infection. Initially very little reaction can be seen and small numbers of neutrophils and exudate surround the organisms. In the following days macrophages collect to engulf the organisms in an attempt to eradicate the infection. If this is unsuccessful, granuloma formation ensues. The macrophages first form microscopic aggregates that may distort the normal lung architecture. They become activated and develop into epithelioid cells, acquiring abundant pale-pink cytoplasm with indistinct cell borders, a vesicular nucleus, and often a distinct nucleolus. These changes represent the change from phagocytic to secretory function that enhances the microbiocidal properties of macrophages, but unfortunately can also induce necrosis of lung tissue. The macrophages may fuse to form multinucleated giant cells. Interspersed between and surrounding the macrophages are lymphocytes. This collection of macrophages, giant cells, and lymphocytes form the granuloma. After a few weeks, the granuloma can be macroscopically visible as a small nodule. At first it is grey in colour, but eventually turns yellow as it enlarges. On closer examination at this stage, necrosis is evident in the centre of the granuloma. Adjacent granulomas
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M. tuberculosis Ghon focus PRIMARY TB Poor immune status Ghon complex
PROGRESSIVE PRIMARY TB
Good immune status
FIBROSIS = latency
Reactivation or reinfection
Haemoptysis, haemorrhage
SECONDARY TB
Destroy bronchial walls Cavitation = ‘open’ TB
APICAL LUNG LESIONS Endotracheal Laryngeal
Break through pulmonary vein
P R - heart SWALLOW
Pulmonary arteries
L - heart
Both lungs
Intestinal TB Bronchogenic dissemination
TB bronchopneumonia
Systemic circulation
TB pleuritis + effusion
Fibrous pleuritis, empyema
Pulmonary military TB
Liver, bone marow, spleen, adrenal, CNS, uro-genital GIT, skin, lymph nodes
Systemic miliary TB
Single organ involvement
Break into pulmonary arteries
Segment of lung
Fig. 12.2 A summary of the typical spectrum of events that may follow primary and secondary TB, respectively. CNS, central nervous system; GIT, gastrointestinal tract.
often develop at this stage, and can also undergo necrosis and coalesce with later confluence of necrosis and more extensive tissue damage. The necrosis seen in TB is usually described as caseous, because of its crumbly, cheesy appearance. It is formed due to a combination of coagulative and liquefaction necrosis. The primary granulomatous reaction characteristically occurs in the peripheral part of the lung close to the pleura in virtually any part of the lung. Classically, this lesion is called the Ghon focus. In most patients infected in this manner the infection is contained, usually by fibrosis. Subsequent calcium salt deposition may occur. The calcium salts are usually deposited diffusely throughout the necrosis, but in certain cases may be deposited in a concentric fashion. The subsequent area of pulmonary calcification can be detected on chest radiograph about 9–16 months after recovery from primary TB. In isolated cases these calcifications may undergo ossification after several years. Dissemination of organisms from the primary infected lung tissue to the hilar lymph nodes may lead to granulomatous lymphadenitis. The subsequent hilar lymphadenopathy and Ghon focus are then referred to as a Ghon complex.5,16 Organisms may survive the initial immune reaction and persist for years as viable bacilli within the healed Ghon focus and hilar lymph nodes.
PROGRESSIVE PRIMARY TUBERCULOSIS AND CONSEQUENCES In a small number of patients, usually due to immune suppression and most often in young children under 2 years of age, active disease develops immediately following primary infection. This
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process is called progressive primary TB and often leads to a disseminated form of TB. Progressive granulomatous inflammation and necrosis of lung tissue result in erosion of infected debris into a bronchus or a blood vessel with consequent tuberculous bronchopneumonia or miliary TB (see below), respectively. Airway obstruction, segmental pulmonary TB, bacteraemia and miliary TB, and pulmonary haemorrhage may complicate primary TB.
Obstruction In cases where hilar lymph nodes are massively enlarged, they may compress and obstruct a large bronchus and lead to collapse of the distal pulmonary lobe or segment. Partial bronchial obstruction may result in a valve effect with air-trapping and overdistension of a lobe or segment. Respiratory distress, secondary bacterial infection and pneumonia, or bronchiectasis may be life threatening and require surgical intervention to alleviate the obstruction. Enlargement of paratracheal lymph nodes may compress the trachea and lead to stridor. On occasion a necrotic lymph node may rupture into a bronchus, causing acute obstruction and asphyxia. Involvement of the bronchus and oesophagus may lead to a broncho-oesophageal fistula. Segmental tuberculosis More commonly, progressive granulomatous inflammation and necrosis affect the relevant lung segment, leading to segmental TB. Rupture of a lymph node with extensive necrosis into a segmental bronchus results in infected necrotic debris being distributed throughout the airways, causing expansion of the inflammatory response. Macroscopically the affected area is pale
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Pathology and pathogenesis of tuberculosis
grey. On microscopy an exudate with macrophages and interstitial lymphocytes can be seen. Numerous small granulomas that may undergo necrosis are also present. In time organization by fibrosis may transpire, which may cause obstruction, or, in rare cases, a bronchial diverticulum.
Bacteraemia and miliary tuberculosis Early in primary TB, a mycobacterial bacteraemia frequently occurs. Usually the organisms are contained by macrophages, but may cause changes akin to the Ghon focus in various organs. In some cases granulomatous angiitis develops. Progressive caseous necrosis leads to ulceration of the blood vessel intima and further release of infected debris into the blood vessel. The organisms now have the opportunity to spread haematogenously, causing systemic miliary TB. This is often a complication of hilar lymph node involvement in primary TB, as the lesions in the hilar lymph nodes are often much bigger than the pulmonary component and the adjacent pulmonary veins are large, providing easy access. Macroscopically miliary TB consists of countless numbers of minute yellow–white nodules less than 2 mm in size that can be seen in all affected organs. It most commonly involves the liver, spleen, bone marrow, lungs, and meninges. The most likely reason for this distribution is that these organs have numerous phagocytic cells in their sinusoidal walls. Even though minute in size, these miliary tubercles are just as capable of undergoing necrosis and microscopically have the same appearance as any other granuloma. This is usually an aggressive form of the disease with a fulminant course, especially if the central nervous system is also involved, causing tuberculous meningitis.5 Haemorrhage Occasionally rupture into the aorta may occur, with massive haemorrhage and sudden death. In adults progressive primary TB may present as a bacterial pneumonia, usually in the lower and mid-lobes. Hilar lymphadenopathy and pleural effusions are often present, but cavitation is seldom seen. The organisms may also spread haematogenously or lymphatically, resulting in devastating disease when meningitis or miliary TB develops. Any of the changes that occur in secondary TB may also occur in progressive primary TB.
the bacteria and progressive and often extensive caseous necrosis and tissue destruction develop.17
Course of secondary tuberculosis The extent of granulomatous inflammation, necrosis, and tissue destruction depends on many factors and the subsequent course of the disease is thus variable:
Organization and healing of localized inflammation by fibrosis, scarring, and calcification results in a fibro-calcified nodule. Progression of the inflammatory process as caseating granulomas with local destruction of pulmonary tissue and cavitation facilitates growth of organisms due to the favourable oxygen tension and an alkaline pH (Fig. 12.3). Encapsulation and localization of pulmonary cavities by fibrosis and scarring is a frequent outcome and assists to limit progressive disease. Occasionally, infective material may disseminate to other anatomical regions or organs by means of one or more pathogenic mechanisms.17 M. tuberculosis bacilli favour extrapulmonary organs such as the kidneys, meninges, and skeletal metaphyses that are very well vascularized with relatively high oxygen tension.
Dissemination of M. tuberculosis organisms can happen in one or more of the following ways.
Rupture into a bronchus The caseating granulomatous inflammation may erode bronchi with subsequent release of infective caseous material into the airways (Fig. 12.4). The infective material may be coughed up and spread in the following way(s):
SECONDARY (ADULT-TYPE) TUBERCULOSIS Some patients become reinfected with M. tuberculosis or experience reactivation of dormant disease in the Ghon focus or complex. Latent M. tuberculosis infection is present in one-third of the world’s population. Less than 10% of infected individuals, however, develop active disease. The remainder generate an effective immune response, which allows containment of the bacilli within granulomas. The bacilli persist for long periods of time in this dormant state, and there is no transmission of infection. Reactivation of the dormant infection and the onset of active disease will follow immunosuppression for whatever reason and may lead to the transmission of disease to a new host. The clinical and morphological pictures of these events are similar. Granulomatous inflammation in secondary TB occurs most often in the lungs, but it may be widely disseminated, depending on a large variety of factors. M. tuberculosis is a strict aerobic organism, and due to higher oxygen tension and poor lymphatic drainage in the apices of the lungs, the organism favours these areas. In secondary TB the granulomatous inflammation fails to contain
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It can spread proximally along the airways and affect the trachea, larynx, and the rest of the upper respiratory and digestive tract. The infective material can be inhaled, and spread distally throughout other parts of the lungs, causing tuberculous bronchopneumonia in especially the lower lobes of the lungs. Sometimes a whole lower lobe may be involved by rapidly developing confluent tuberculous bronchopneumonia. On histology, numerous acid-fast bacilli can be identified. The infected debris can be swallowed with subsequent intestinal TB, usually in the region of the distal ileum or ileocaecal junction, as this is where the lymphoid tissue of the gastrointestinal tract is present in the form of Peyer’s patches.
Rupture into pulmonary artery The caseating granulomas may spread into a branch of the pulmonary artery, leading to the following:
The pulmonary artery haemorrhages into a pulmonary cavity or larger airway, resulting in haemoptysis. Usually, tissue destruction occurs slowly, causing obliterative endarteritis of the blood vessels with occlusion of blood vessel lumina before penetration of the blood vessel wall occurs. Rapid progression of granulomatous arteritis can lead to an aneurysm of the blood vessel wall (Rasmussen’s aneurysm) that may rupture and lead to sudden massive and often fatal haemorrhage. Distal spread of the infective material through a segment of the pulmonary artery will cause localized pulmonary miliary TB in the lung parenchyma supplied by that branch of the pulmonary artery.
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Fig. 12.3 Stages of cavity formation. (A) Extensive confluent areas of necrotizing granulomatous inflammation in the upper lobe, with lymph node involvement around the bronchus. Note the size of the lymph nodes and the prospect of bronchus compression. (B) Early cavity formation with adjacent tuberculous bronchopneumonic changes. (C) Extensive cavity formation is apparent.
Rupture into lymphatics The infective agent may spread through the lymphatics to lymph nodes, causing granulomatous lymphadenitis. Further lymphatic spread can lead to:
retrogressive dissemination through other lymphatics to other areas of the lung, or to other organs; and spread to both lungs via the right heart and back to the lungs through the pulmonary arteries, causing diffuse pulmonary miliary TB (Fig. 12.5).
Rupture into pulmonary veins The organisms may spread into the pulmonary veins, again resulting in:
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haemoptysis; and spread to the systemic circulation via the pulmonary veins and the left heart, leading to widely disseminated granulomas in
many organs, especially the kidneys, adrenal glands, bone marrow, meninges, liver, and spleen.
Morphology of typical pulmonary tuberculosis The lungs in established secondary pulmonary TB have a typical macroscopic appearance. The disease is usually bilateral, with one side often less affected than the other. The upper lobes show large cavities and smaller cavities are often present in the apices of the lower lobes. The cavities often contain caseous material, but may also be empty following the release of the necrotic content into the adjacent communicating bronchi. These cavities can be quite large and may measure up to several centimetres in diameter. The cavity walls contain fibrosis and often the remnants of a bronchial wall or branches of the pulmonary arteries. Histological examination of a cavity wall reveals different zones. The cavity itself is surrounded by a rim of caseous material flanked by organizing granulomatous inflammation and variable fibrosis and scarring
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Fig. 12.4 Bronchopneumonic TB. (A) A low magnification of a lung section with granuloma formation surrounding bronchioles. (B) Rupture into the bronchus is clearly illustrated by the erosion of the respiratory epithelium and the underlying necrotic granuloma. (C) The patchy, bronchopneumonic nature of the process in the lung.
towards the periphery of the wall. Ziehl–Neelsen stains usually reveal acid-fast bacilli in the necrotic material or on the edge of necrosis adjacent to the granulomatous inflammation. Satellite granulomas may occur in the adjacent lung tissue. When there is communication between a cavity and a bronchus infective material is coughed up and released into the environment as a droplet aerosol with the potential for transmission of the organisms. Cavitation is usually absent or much less pronounced in the lower lobes. Hilar lymph nodes are less frequently involved than in primary TB, but microscopic examination will often show residual granulomatous lymphadenitis.
Local complications of secondary pulmonary tuberculosis
Advanced secondary pulmonary TB leads to an extensive loss of lung parenchyma with subsequent diminished lung capacity and progressive respiratory failure. Large cavities with thick, fibrotic walls often persist and may develop an epithelial lining. This lining may be of respiratory type, but more often it comprises squamous metaplasia, simple or stratified, with or without keratinization. The cavity may contain keratin, mimicking an epidermoid cyst. In rare cases, squamous carcinoma may develop in the cyst wall.
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or opposite effusion should raise the possibility of miliary TB.19 Primary pleural TB usually resolves without treatment. However, especially in young adults, it correlates with an increased risk of developing into other forms of TB, usually within 5–10 years. Full therapy of primary pleural TB is therefore justified. Local complications that may ensue include focal or diffuse fibrosis, a large caseous lesion that may rupture into the lung, creating a pulmonary– pleural fistula or spontaneous pneumothorax, paravertebral abscess, and osteitis of the ribs.
Fig. 12.5 (A) Disseminated miliary tubercles can be seen in the lung, with (B) a close-up of tubercles in the inset, as well as in the liver and spleen.
The environment of the cavity, especially when not communicating with a bronchus, is conducive to secondary bacterial infection, with subsequent abscess formation. Occasionally fungal colonization, especially by Aspergillus flavus, results in a ball of fungi known as an aspergilloma. Bronchiectasis is a common complication of destructive pulmonary TB and can be complicated by the usual problems associated with bronchiectasis. Progression of pulmonary disease often involves the pleura by means of serous effusions, tuberculous empyema, or massive obliterative fibrous pleuritis.17
Spread via the systemic circulation can lead either to individual organs being affected or to miliary TB, depending on the immune status of the patient and the virulence of the organism. Organs often affected include the kidneys, brain, liver, spleen, adrenals, and testes. The respective chapters on organ TB provide more detail pertaining to the relevant organ-specific pathology and clinicopathological features.
PLEURAL TUBERCULOSIS Primary pleural effusion, as a presenting feature of TB, usually occurs in adolescents and adults. It occurs on the same side as the primary Ghon complex, suggesting that a subpleural tuberculous focus or lymph node has extended into the pleural space.18 Bilateral
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Pathogenesis of primary pleural tuberculosis The current hypothesis for the pathogenesis of primary tuberculous pleural effusion is that a subpleural caseous focus in the lung ruptures into the pleural space 6–12 weeks after a primary infection.19 Mycobacterial antigens enter the pleural space and elicit a delayed hypersensitivity reaction and an accumulation of fluid. It appears that the DTH reaction results in an increased permeability of pleural capillaries to serum proteins, leading to increased oncotic pressure in the pleural fluid and the development of a pleural effusion.20 In primary pleural effusions, typical TB granulomas occur on both the visceral and the parietal pleural surfaces. These granulomas tend to follow the lymphatics in the visceral pleural surface and focal or diffuse pleural fibrosis may follow. Impaired clearance of proteins from the pleural space has been reported in human tuberculous effusions.20 Clearance of proteins and fluid from the pleural space occurs via lymphatics in the parietal pleura. Access to the lymphatics is through openings in the parietal pleura called stomata.21 In tuberculous pleuritis, with diffuse involvement of the parietal pleura, damage to or obstruction of the stomata could be an important mechanism leading to accumulation of pleural fluid. It appears thus that tuberculous pleurisy is due to the release of isolated mycobacterial antigens into the pleural space, eliciting a delayed hypersensitivity reaction rather than to direct tuberculous infection of the pleura.22 On histological examination, acid-fast bacilli are demonstrated in only 5–18% of cases.23 However, the diagnosis can be confirmed in more than 95% of patients with the performance of a combination of culture of pleural fluid and tissue, and histology of pleural tissue.24 Typical granulomas with caseous necrosis are also present in pleural tissue.
THE EFFECT OF HIV ON TUBERCULOSIS A detailed discussion of the effect of HIV on TB will be found in Chapter 10. Increased nosocomial and community exposure to M. tuberculosis may play a role in the increased risk of contracting TB in HIV-infected patients, but HIV-associated impairment of one or more immunological mechanisms plays an important role.25–28 These mechanisms include impairment of pulmonary innate immune defences, impairment of cellular recruitment and establishment of the cell-mediated granulomatous response to recent M. tuberculosis infection, and functional impairment of established granulomas containing latent M. tuberculosis infection. HIV-1 infects macrophages and CD4þ T cells essential in granuloma formation in TB. Coinfection will therefore impair cell-mediated immune responses to M. tuberculosis infection. Several possible levels of impairment exist.29–34 Tuberculosis and HIV-1 coinfection is also likely to be associated with extensive virus-induced and activation-induced cell loss and with the suppression of lymphocyte regeneration and maturation.35,36 HIV may also block
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the ability of the host to mount an effective proliferative T-lymphocyte response to M. tuberculosis.37 The risk of developing TB disease following infection in HIV-infected individuals is no longer 10% lifelong but close to 10% per year.
In 1993 Lucas et al.39 described three histological stages of cellular immune response that correlate with depletion of the peripheral blood CD4þ lymphocyte count, namely:
THE EFFECT OF HIV ON GRANULOMATOUS INFLAMMATION The changes described above, as well as the progressive immunosuppression associated with the development of AIDS, result in failure of epithelioid differentiation of macrophages, and lack of Langhans giant cells and caseous necrosis. Tuberculous hypersensitivity-type granulomas are not considered immunologically quiescent structures, but rather have a continual level of mononuclear cell death and cell replacement by active recruitment.38 It is therefore possible that HIV-1 infection affects granuloma function via two processes:
systemic depletion of the mononuclear cells required for the ongoing maintenance and functioning of granulomas; and the effects of HIV-1-infected cells (either lymphocytes or macrophages) trafficking into the granuloma itself.
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In immunocompetent individuals with HIV-1 infection, tuberculous granulomas are characterized by abundant epithelioid macrophages, Langhans giant cells, peripherally located CD4þ lymphocytes, and a paucity of bacteria. In individuals with moderate HIV-associated immunodeficiency, Langhans giant cells are not seen, epithelioid differentiation and activation of macrophages are absent, there is CD4þ lymphocytopenia, and acid-fast bacilli are more numerous. In individuals with advanced HIV-associated immunosuppression and AIDS, there is a striking paucity of granuloma formation with little cellular recruitment, very few CD4þ lymphocytes, and even larger numbers of acid-fast bacilli.
It is therefore apparent that HIV-1 coinfection weakens the granulomatous host response to M. tuberculosis and affects the ability of established granulomas to contain M. tuberculosis, resulting in increased reactivation of latent mycobacteria (Fig. 12.6).
A
C
D
Fig. 12.6 The effect of HIV on granuloma formation. (A) A loose collection of inflammatory cells, vaguely resembling a granuloma, can be seen. (B) On high magnification of this area a few isolated epithelioid macrophages are visible. (C) A high magnification of a confluent area of inflammation with numerous neutrophils and some lymphocytes, but no recognizable epithelioid macrophages. (D) A Ziehl–Neelsen stain of the areas highlights the vast number of acid-fast bacilli present in this biopsy.
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THE EFFECT OF TUBERCULOSIS ON TISSUE The effect of TB on tissue varies enormously, depending on the extent of involvement and also the organs involved (Fig. 12.7). In some cases, especially when tissue destruction has not yet occurred, and treatment is early and effective, tissue may heal without any signs of residual damage. More often, one or more of the following will occur.
DESTRUCTION OF TISSUE
Caseating necrosis, associated with granulomatous inflammation, has a very destructive effect, often resulting in loss of function of the organ affected.
Tissue destruction occurs, especially in the lung, leading to fibrosis and distortion of lung tissue. Impairment of lung function will follow, depending on the extent of fibrosis. Destruction of tissue centred around the bronchi will result in bronchiectasis, with all its complications.
Destruction of blood vessel walls will cause haemorrhage, and, depending on the size of the vessel, the haemorrhage may be insignificant or devastating. In the adrenals TB is one of the causes of chronic primary insufficiency, due to destruction of the adrenal cortex and medulla. The breast is sometimes involved in TB and usually a fibrocaseous mass with numerous sinuses develops. In those cases where fibrosis develops, the mass may be clinically indistinguishable from carcinoma. In the kidney TB may form either a single mass, usually in the parenchyma, or multiple smaller nodules, resembling abscess formation. In the case of long-standing TB, pyelonephrosis develops due to rupture of the mass into the pelvis. Complete destruction of the renal pelvis may ensue. Involvement of the vertebral column is relatively frequent, also in children. Osteomyelitis causes extensive destruction of vertebral bodies, which is complicated by collapse. This condition is also known as Pott’s disease. In children, tuberculous arthritis occurs, with destruction of cartilage and subsequent fibrosis.
Fig. 12.7 Potential complications of TB. (A) A fibrinous pericarditis is demonstrated. On histology, numerous granulomas with caseous necrosis are evident. (B) Massively enlarged lymph nodes in the mesentery are demonstrated. This may lead to functional bowel obstruction. (C) Enlarged, necrotic lymph nodes can be seen around the main bronchi. It is apparent that obstruction is imminent and necrosis through the bronchus wall may follow.
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Granulomatous endometritis is an unusual, but not uncommon, cause of infertility in females. Numerous small granulomas form throughout the endometrium and ulceration with haemorrhage may develop. If this occurs during pregnancy, congenital TB may occur. Numerous other organs, including the epididymis, skin, gastrointestinal tract, and central nervous system, are also affected. For a discussion on the organ pathology of TB, please refer to the appropriate organ-specific chapters.
the extensive fibrosis may lead to further tissue destruction with dire consequences.
SPACE-OCCUPYING LESIONS Granulomas may enlarge and, depending on the organ, this may have a space-occupying effect.
In the brain, tuberculomas develop, mainly supratentorial, but may occasionally affect the cerebellum, basal ganglia, and brainstem. Although children frequently present with convulsions as the first sign, other symptoms and signs of a spaceoccupying lesion may develop. In the prostate, enlarging granulomas may clinically mimic benign prostate hyperplasia. Only on microscopic examination can the granulomas be seen and the diagnosis suggested.
FIBROSIS Extensive fibrosis is typical of organizing granulomatous inflammation associated with TB and tends to surround granulomas in an attempt to contain the organism within granulomas. Unfortunately
REFERENCES 1. Kumar V, Abbas A, Fausto N. Acute and chronic inflammation. In: Kumar V, Abbas AK, Fausto N (eds). Robbins and Cotran Pathologic Basis of Disease, 7th edn. Philadelphia: Elsevier Saunders, 2005: 47–86. 2. Beutler B. Innate immunity: an overview. Mol Immunol 2004;40:845–859. 3. Flynn JL. Immunology of tuberculosis and implications in vaccine development. Tuberculosis (Edinb) 2004;84:93–101. 4. Allen EA. Tuberculosis and other mycobacterial infections of the lung. In: Thurlbeck W, Churg A (eds), Pathology of the Lung, 2nd edn. New York: Thieme Medical, 1995: 229–265. 5. Hart DN. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 1997;90:3245–3287. 6. Sallusto F, Lanzavecchia A. The instructive role of dendritic cells on T-cell responses. Arthritis Res 2002; 4(Suppl 3):S127–S132. 7. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med 2000;343:1020–1034. 8. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol 2003;111(2 Suppl):S442–459. 9. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med 2000;343:338–344. 10. Abbas AK, Lichtman AH, Prober JS. Effector mechanisms of T cell-mediated immune reactions. In: Abbas AK, Lichtman AH, Prober JS (eds). Cellular and Molecular Immunology, 4th edn. Philadelphia: Saunders, 2000: 278–296. 11. Heath WR, Carbone FR. Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 2001;19:47–64.
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In body cavities, organization through fibrosis results in adhesions. Depending on the site and extent of the adhesions, signs and symptoms may develop: ○ In tuberculous meningitis, obstructive hydrocephalus, with all its sequelae may develop. ○ In the pleura the fibrosis may be followed by loculated zones of empyema. ○ In the pericardium, a restrictive pericarditis develops. ○ In the peritoneum bowel obstruction with its complications may result. In hollow organs it may lead to obstruction: ○ In the fallopian tubes infertility may be ascribed to complete, or partial, obstruction of the lumina. ○ In the small bowel, where TB is present in the Peyer’s patches, ulceration and haemorrhage of the mucosal surface occurs early with circumferential granuloma formation and mural fibrosis later, culminating in intestinal obstruction.
One of the complications of TB that used to be very common, but currently is seldom seen, is amyloidosis. This is a condition associated with long-standing chronic diseases, but is at present uncommon. For the handling, processing, interpretation, fine needle aspiration technique and differential diagnosis of specimens, please refer to Chapter 21.
12. Alam R, Gorska M. Lymphocytes. J Allergy Clin Immunol 2003;111(2 Suppl):S476–485. 13. Sinigaglia F, D’Ambrosio D. Regulation of helper T cell differentiation and recruitment in airway inflammation. Am J Respir Crit Care Med 2000;162 (4 Pt 2):S157–160. 14. Algood HM, Chan J, Flynn JL. Chemokines and tuberculosis. Cytokine Growth Factor Rev 2003;14: 467–477. 15. Miceli MC, Parnes JR. Role of CD4 and CD8 in T cell activation and differentiation. Adv Immunol 1993;53:59–122. 16. Husain AN, Kumar V. In: Kumar V, Abbas AK, Fausto N (eds). Robbins and Cotran Pathologic Basis of Disease, 7th edn. Philadelphia: Elsevier, 2005: 711–772. 17. Hasleton PS. Pulmonary bacterial infection. In: Hasleton PS (ed.). Spencer’s Pathology of the Lung, 5th edn. New York: McGraw-Hill, 1996: 189–255. 18. Stead WW, Eichenholz A, Stauss HK. Operative and pathologic findings in twenty four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous. Am Rev Respir Dis 1955;71:473–502. 19. Leckie WJH, Tothill P. Albumin turnover in pleural effusions. Clin Sci 1965;29:339–352. 20. Harley RA. Pathology of pleural infections. Semin Respir Infect 1988;3:291–297. 21. Wang NS. The preformed stomas connecting the pleural cavity and the lymphatics in the parietal pleura. Am Rev Respir Dis 1975;111:12–20. 22. Ellner JJ, Barnes PF, Wallis RS, et al. The immunology of tuberculous pleurisy. Semin Respir Infect 1988;3:335–342. 23. Reese O Jr, Mclean RL, Raaen TD. Acid-fast bacilli in pleural biopsy specimens. Arch Intern Med 1961;108:438–441.
24. Diacon AH, Van de Wal BW, Wyser C, et al. Diagnostic tools in tuberculous pleurisy: a direct comparative study. Eur Respir J 2003;22:589–591. 25. Di Perri G, Cruciani M, Danzi MC, et al. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 1989;2:1502–1504. 26. Dooley SW, Villarino ME, Lawrence M. Nosocomial transmission of tuberculosis in a hospital unit for HIV-infected patients. JAMA 1992;267:2632–2635. 27. Centers for Disease Control and Prevention. Tuberculosis outbreak among persons in a residential facility for HIV-infected persons, Florida and New York. MMWR Morb Mortal Wkly Rep 1991;40:585–591. 28. Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002;4:635–646. 29. Polyak S, Chen H, Hirsch D, et al. Impaired class II expression and antigen uptake in monocytic cells after HIV-1 infection. J Immunol 1997;159:2177–2188. 30. Zembala M, Pryjma J, Plucienniczak A, et al. Modulation of antigen-presenting capacity of human monocytes by HIV-1 gp120 molecule fragments. Immunol Invest 1994;23:189–199. 31. Ieong MH, Reardon CC, Levitz SM, et al. Human immunodeficiency virus type 1 infection of alveolar macrophages impairs their innate fungicidal activity. Am J Respir Crit Care Med 2000;162:966–970. 32. Baldwin GC, Fleischmann J, Chung Y, et al. Human immunodeficiency virus causes mononuclear phagocyte dysfunction. Proc Natl Acad Sci USA 1990;87:3933–3937. 33. Imperiali FG, Zaninoni A, La Maestra L, et al. Increased Mycobacterium tuberculosis growth in HIV-1infected human macrophages: role of tumour necrosis factor-alpha. Clin Exp Immunol 2001;123:435–442.
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34. Kallenius G, Koivula T, Rydgard KJ, et al. Human immunodeficiency virus type 1 enhances intracellular growth of Mycobacterium avium in human macrophages. Infect Immun 1992;60:2453–2458. 35. Clark DR, de Boer RJ, Wolthers KC, et al. T cell dynamics in HIV-1 infection. Adv Immunol 1999;73:301–327. 36. Lawn SD, Rudolph D, Wiktor S, et al. Tuberculosis and HIV infection are independently associated with
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elevated serum concentrations of tumour necrosis factor receptor type 1 and b-microglobulin, respectively. Clin Exp Immunol 2000;122:79–84. 37. Lawn SD, Rudolph D, Coulibaly D, et al. Lack of induction of interleukin-2-receptor alpha expression in patients with tuberculosis and human immunodeficiency virus coinfection: implications for pathogenesis. Trans R Soc Trop Med Hyg 2001;95; 449–452.
38. Lawn SD, Butera ST, Folks TM. Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection. Clin Microbiol Rev 2001;14: 753–777. 39. Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993;7:1569–1579.
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The natural history of Mycobacterium tuberculosis infection in adults Dermot Maher
INTRODUCTION Our understanding of the natural history of TB goes back at least to the tenth century when Avicenna (also known as Ibn Sina) described the contagious nature of pulmonary TB in his book Qanun fi’l-Tibb (The Canon of Medicine).1 Nine hundred years later, Koch confirmed Avicenna’s description with his identification of the tubercle bacillus and its causative role in TB.2 Although the pace of scientific discoveries concerning the natural history of TB has sped up since Koch’s seminal discovery in 1882, much still remains to be discovered. As indicated by G. Bacelli in 1882, ‘Il bacillo non e´ ancora tutta la tuberculosi’ (‘The bacillus is not yet all there is to tuberculosis’).3 Tubercle bacilli are a necessary, but not a sufficient, cause of TB. Tuberculosis can only occur following infection with Mycobacterium tuberculosis, but occurs in a small minority of those infected. The risk of M. tuberculosis infection is largely exogenous in nature, determined by the characteristics of the source case, environment, and duration of exposure. In contrast, the risk of TB following M. tuberculosis infection is largely endogenous, determined by the individual’s immune status. This chapter describes the sequence of events that constitute the natural history of M. tuberculosis infection in adults: the transmission of infection, the process of becoming infected, and the pathogenesis of TB as one of the consequences of becoming infected. A good grasp of the natural history of M. tuberculosis infection underpins our understanding of TB epidemiology and control, as well described by Rieder.4
INFECTION WITH M. TUBERCULOSIS TRANSMISSION OF INFECTION The transmission of M. tuberculosis is almost exclusively by the airborne route. The most important source of infection is the patient with pulmonary TB who is coughing. Coughing produces droplets – as does talking, sneezing, spitting or singing – that may contain tubercle bacilli.5 As the droplets expelled into the air evaporate, some form droplet nuclei, which are infectious particles of respiratory secretions usually less than 5 mm in diameter containing one or a few tubercle bacilli. A single cough can produce 3,000 droplet nuclei and they can remain suspended in the air for several hours. Whereas larger particles either fall to the ground or, if inhaled, are trapped either
in the nose or in the mucociliary system of the tracheobronchial tree, droplet nuclei are so small that they avoid the defences of the bronchi and penetrate into the terminal alveoli of the lungs where infection begins.6 Since the particles containing tubercle bacilli on the clothing, bedcovers, or belongings of a TB patient cannot be dispersed in aerosols, they do not play a significant part in infection.7
CHARACTERISTICS OF AN INFECTIOUS PATIENT Patients with extrapulmonary TB do not generally constitute a source of infection, unless by direct inoculation. The production of airborne infectious droplets is by people with respiratory tract TB. Those who produce the most tubercle bacilli are the most infectious. The number of tubercle bacilli found in sputum specimens reflects infectiousness.8 Studies of the close contacts of patients with culture-proven pulmonary TB showed that a higher proportion of contacts of sputum smear-positive cases than of smearnegative source cases were infected.9–11 The most potent sources of infection are therefore patients with sputum smear-positive pulmonary TB. Classical contact tracing has also shown the importance of patients with sputum smear-positive pulmonary TB as sources of secondary cases of TB. For example, in a 2-year contact followup study in Finland, among the 609 contacts of 134 culture-proven source cases, four developed TB, all of them among contacts of the 69 source cases with heavily sputum smear-positive TB.12 The use of molecular fingerprinting techniques has also shed light on the relative importance of sputum smear-positive and sputum smear-negative source cases in generating clusters of secondary cases of cultureproven TB sharing identical DNA fingerprints and therefore assumed to have arisen from recent transmission. A study in San Francisco, USA, found that, of 183 secondary cases, the number attributed to infection by sputum smear-positive and sputum smear-negative source cases was 151 (83%) and 32 (17%), respectively, and the relative transmission rate from sputum smear-negative compared with sputum smear-positive source cases was 0.22.13 Patients with sputum smear-positive pulmonary TB are therefore also the most potent source cases of secondary TB.
RISK OF INFECTION Risk of infection depends on the extent of an individual’s exposure to droplet nuclei and on susceptibility to infection.
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Exposure to droplet nuclei Two factors determine an individual’s risk of exposure: the concentration of droplet nuclei in contaminated air and the length of time spent breathing that air. The extent of an individual’s exposure to droplet nuclei is determined by the proximity and duration of contact with an infectious source case, since the concentration of droplet nuclei to which the person is exposed depends on proximity, and the length of time spent breathing the contaminated air depends on duration of contact. The concentration of droplet nuclei depends on the number of infectious droplets expelled and the volume of air into which they are expelled. Risk of exposure is therefore much greater in an enclosed poorly ventilated space indoors than outdoors. Ventilation dramatically dilutes the concentration of droplet nuclei and is therefore the most important environmental measure to decrease risk of infection among exposed persons. The simplest and least expensive way of ventilating a room or hospital ward is to maximize natural ventilation through open windows.14 Since the concentration of droplet nuclei in contaminated air falls very quickly outdoors, and direct sunlight kills tubercle bacilli in 5 minutes (although they can survive in the dark for long periods of time), transmission generally occurs indoors. The risk of infection of a susceptible individual is therefore high with close, prolonged, indoor exposure to a person with sputum smear-positive pulmonary TB. These are the conditions generally thought of as constituting ‘close contact’. A contact tracing study in The Netherlands, with the contact tracing ‘net’ cast very widely, showed that the closer the contact of a susceptible individual to an infectious source case, the greater the chance of infection.15 The number of cases of infection in a particular exposure group (defined by closeness to the source case) is the product of the risk and the number of people in the group. Thus, exemplifying the Rose axiom, there is a larger number of cases of infection in the large group of distant, low-risk contacts than in the small group of close, high-risk contacts.16 Conventional contact tracing generally identifies the close, high-risk contacts and therefore identifies a minority of the contacts infected by a source case. The extent of an individual’s exposure to infection determines not only risk of infection but also affects the risk of disease, since those with greater intensity of exposure are at greater risk of developing disease. For example, in the micro-outbreak of TB described among the crew members of the US submarine Byrd, the presence of one man with TB resulted in 139 M. tuberculosis infections among the 308 crew, with six out of the seven cases of active TB occurring in men who were sleeping in the same cabin and working closely together.17 Susceptibility to infection The risk of M. tuberculosis infection is largely exogenous in nature, determined by the characteristics of the source case, environment, and duration of exposure. It has been difficult to separate the influence of the genetic and exogenous (socio economic and environmental) factors that determine susceptibility to infection. A study in the USA of nursing home residents with apparently the same risk of exposure found a higher risk of infection among black than white residents, suggesting the role of genetic factors in determining susceptibility.18 Susceptibility to infection is affected by the ability of macrophages to phagocytose and destroy the bacilli that reach the terminal alveoli and begin the process of implantation and infection.19 Since several genes are involved in this process, the study of human genomics has the potential to increase our
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understanding of differences between individuals and populations in their susceptibility to infection.20 Some exogenous factors that may cause increased susceptibility to infection by impairing the local immune response in the respiratory tract, e.g. silicosis and inhalation of smoke from cooking fires and industrial pollution, have been suggested. Long-term cigarette smoking causes disruption and injury of the respiratory tract endothelial cells (peribronchial inflammation, abnormal vascular and epithelial permeability) and decreased mucociliary clearance of inhaled particles that may favour infection by inhaled pathogens such as M. tuberculosis.21 In practice it has been difficult to separate the possible influence of these exogenous factors on susceptibility to infection versus progression of infection to disease. Human immunodeficiency virus (HIV) may increase susceptibility to infection with M. tuberculosis. The evidence for this mainly depends on comparisons in hospital outbreaks of the outcome of exposure to source cases of TB, with higher rates of development of TB in HIV-infected than in HIV-uninfected patients exposed. The assumption is that the secondary cases have primary TB, so the higher rates of TB in HIV-infected people reflect higher rates of M. tuberculosis infection and therefore increased susceptibility to infection with M. tuberculosis.
PATHOGENESIS OF TUBERCULOSIS PRIMARY INFECTION Primary infection occurs in persons without previous exposure to tubercle bacilli. Droplet nuclei inhaled into the lungs and small enough to avoid the mucociliary defences of the bronchi lodge in the terminal alveoli. Non-specifically activated alveolar macrophages ingest the inhaled bacilli. If the bacilli are virulent enough to withstand the proteolytic enzymes in the macrophage phagolysosomes, they multiply and initiate infection. About 2–4 weeks after infection, cell-mediated immunity results in the formation of granulomas which usually constrain the spread of the bacilli. A granuloma is an aggregation of macrophages activated by cytokines produced by CD4þ T-lymphocytes. The initial focus of infection in the lungs is the Ghon focus. Lymphatics drain the bacilli to the hilar lymph nodes. The Ghon focus and related hilar lymphadenopathy form the primary complex. The development of the primary complex is asymptomatic. The development of the immune response (delayed hypersensitivity and cellular immunity) about 4–6 weeks after the primary infection is indicated by a positive tuberculin skin test and occasionally by clinical hypersensitivity reactions (e.g. erythema nodosum, phlyctenular conjunctivitis, dactylitis).
OUTCOMES OF PRIMARY INFECTION The balance between host immunity and bacillary multiplication determines what happens next. In most cases, the immune response stops the multiplication of bacilli. A calcified nodule visible on chest radiography is a common outcome of successful immune containment of infection with killing of bacilli. The immune response in a few cases is not strong enough to prevent multiplication of bacilli, and progression from infection to disease occurs within a few months. Primary TB results from local bacillary multiplication and spread in the lung or spread in the blood from the primary complex throughout the body, with seeding of bacilli in
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The natural history of Mycobacterium tuberculosis infection in adults Outcome of primary infection No clinical disease positive tuberculin skin test (indicating latent infection) (usual outcome: 90% of cases)
Primary complex
Hypersenitivity reactions e.g. erythema nodosum phlyctenular conjunctivitis dactyllitis Pulmomary and pleural complications e.g. tuberculous pneumonia hyper inflation and collapse/consolidation pleural effusion Disseminated disease e.g. lymphadenopathy (usually cervical) meningitis percarditis miliary disease
Fig. 13.1 Outcomes of primary infection with M. tuberculosis.
various tissues and organs. In some cases dormant bacilli may persist and cause disease on later reactivation. Figure 13.1 summarizes the possible outcomes of primary infection with M. tuberculosis.
PROGRESSION OF M. TUBERCULOSIS INFECTION TO DISEASE Once infected with M. tuberculosis, a person stays infected for many years, probably for life. The vast majority (90%) of people without HIV infection who are infected with M. tuberculosis do not develop TB. In these healthy, asymptomatic, but infected individuals, the only evidence of infection may be a positive tuberculin skin test. In contrast to the risk of M. tuberculosis infection largely determined by exogenous factors, the risk of TB following M. tuberculosis infection is largely endogenous, determined by the individual’s immune status. A significant improvement in our understanding of M. tuberculosis latency is necessary to be able to answer the question why some people with latent M. tuberculosis infection develop TB and others do not. As Bishai22 has put it, ‘understanding how M. tuberculosis lies quiescent for years if not decades, how the immune system fails to detect and eradicate it, and the nature of the stimuli for its reactivation remain nearly as uncertain today as in Robert Koch’s time.’ About 5–10% of people infected with M. tuberculosis develop TB in their lifetime, mostly within 5 years of infection.23 Various physical or emotional stresses may trigger progression of infection to disease. The most important trigger is weakening of immune resistance, especially by HIV infection. The chance of developing disease is greatest shortly after initial infection and then steadily lessens as time goes by.
PRIMARY, POST-PRIMARY, AND RECURRENT TUBERCULOSIS A first episode of TB may be primary (i.e. occurring through progression of primary infection) or post-primary (i.e. occurring after a latent period of months or years after primary infection, either through reactivation of the dormant tubercle bacilli acquired from a primary infection or by reinfection). A recurrent episode of TB may occur through relapse (reactivation) or reinfection.
13
Primary tuberculosis Progression of primary infection may result in pulmonary and pleural complications, e.g. tuberculous pneumonia, hyperinflation and collapse/consolidation, pleural effusion, and disseminated disease, e.g. lymphadenopathy (usually cervical), meningitis, pericarditis, and miliary disease. Since most people infected with M. tuberculosis are infected in childhood, primary TB mainly occurs in childhood. Since HIV dramatically increases the risk of rapid progression of M. tuberculosis infection to disease, adults with HIV infection who become infected with M. tuberculosis often develop primary TB. The incidence of primary TB is therefore higher in countries with high HIV prevalence. Post-primary tuberculosis Post-primary TB occurs after a latent period of months or years after primary infection. It may occur either by reactivation of the dormant tubercle bacilli acquired from a primary infection or by reinfection. Reactivation means that dormant bacilli persisting in tissues for months or years after primary infection start to multiply. This may be in response to a trigger, such as weakening of the immune system by HIV infection. Reinfection means a repeat infection in a person who has already previously had a primary infection. The immune response of the patient results in a pathological lesion that is characteristically localized, often with extensive tissue destruction and cavitation. Post-primary TB usually affects the lungs but can involve any part of the body. The characteristic features of post-primary pulmonary TB are the following: extensive lung destruction with cavitation; positive sputum smear; upper lobe involvement; and usually no intrathoracic lymphadenopathy. Patients with these lesions are the main transmitters of infection in the community. Table 13.1 shows the main forms of postprimary TB. Recurrent tuberculosis A recurrence of TB is a second episode of TB occurring after a first episode had been considered cured. Recurrent TB may be due to relapse (reactivation) or reinfection.24
Table 13.1 The main forms of post-primary tuberculosis Pulmonary TB e.g. Cavities Upper lobe infiltrates Fibrosis Progressive pneumonia Endobronchial disease Extrapulmonary TB Common Pleural effusion Lymphadenopathy (usually cervical) Central nervous system (meningitis, cerebral tuberculoma) Pericarditis (effusion/constrictive) Gastrointestinal (ileocaecal, peritoneal) Spine, other bone and joint
Less common Empyema Male genital tract (epididymitis, orchitis) Female genital tract (tuboovarian, endometrium) Kidney Adrenal gland Skin (lupus vulgaris, tuberculids, miliary)
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COINFECTION WITH M. TUBERCULOSIS AND HIV HIV infection increases the risk of progression to active TB in both people with recently acquired and those with latent M. tuberculosis infection (for which HIV infection is the most powerful known risk factor for reactivation).25,26 This risk increases with increasing immunosuppression. As HIV infection progresses, CD4þ T-lymphocytes steadily decline in number and function and therefore the ability to restrict tubercle bacilli to a few infected macrophages decreases. The impact of HIV on the outcome of primary infection is an increased risk and speed of progression to primary TB through local and disseminated bacillary spread. The tuberculin skin reaction is also suppressed. HIV infection increases not only the risk but also the speed of progression of latent M. tuberculosis infection to disease. Overall, compared with an individual not infected with HIV, a HIV-infected individual has a 10 times increased risk of developing TB. HIV also increases the rate of recurrent TB, which may be due to either endogenous reactivation (true relapse) or exogenous reinfection.27–29
NATURAL HISTORY OF UNTREATED TUBERCULOSIS Nowadays it would be unethical to study the natural history of untreated TB. However, a study of TB in a rural population in South India, carried out during the 1960s, found that five out of
REFERENCES 1. Ahmed M. Ibn Sina (Avicenna)—Doctor of doctors. [online] Available at URL:http://www.ummah.net/ history/scholars/ibn_sina 2. Koch R. Die aetiologie der tuberculose. Berl Klin Wochenschr 1882;19:221–230. 3. Quoted in: Bloom BR (ed.). Tuberculosis: Pathogenesis, Protection and Control. Washington, DC: ASM Press, 1994. 4. Rieder HL. Epidemiologic Basis of Tuberculosis Control. Paris: International Union against Tuberculosis and Lung Disease, 1999. 5. Loudon RG, Roberts RM. Droplet expulsion from the respiratory tract. Am Rev Respir Dis 1966;95: 435–442. 6. Sonkin LS. The role of particle size in experimental air-borne infection. Am J Hyg 1951;53:337–354. 7. American Thoracic Society. Infectiousness of tuberculosis, a statement of the ad hoc committee on treatment of tuberculosis patients in general hospitals. Am Rev Respir Dis 1967;96:837. 8. Toman K. Tuberculosis Case-Finding and Chemotherapy: Questions and Answers. Geneva: World Health Organization, 1979. 9. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954;69:724–732. 10. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975;50:90–106. 11. Van Geuns HA, Meijer J, Styblo K. Results of contact examination in Rotterdam, 1967–1969. Bull Int Union Tuberc 1975;50:107–121.
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10 untreated patients with sputum smear-positive pulmonary TB died within 5 years, three self-cured, and two remained ill with chronic, infectious TB.30 As a rule of thumb in TB epidemiology, this finding is embodied in practically every conceptual model – qualitative or quantitative – of the way TB affects populations.31,32
THE CYCLE OF TRANSMISSION In the absence of HIV infection, about 10% of people infected with M. tuberculosis will develop active TB (whether from progression of recent infection or from reactivation), of whom about onehalf will be infectious (usually with sputum smear-positive pulmonary disease).33 Thus, only one in 20 people infected with M. tuberculosis develops infectious TB, and each infectious case in its turn needs to infect about 20 people in order to generate one further infectious case. This is the situation of stable TB incidence (i.e. the case reproduction number is 1). Key determinants of the case reproduction number are the number of people infected by an infectious case, and the proportion of people infected with M. tuberculosis who develop active TB. Any factors which increase the number of people infected by an infectious case (e.g. lack of or inadequate antituberculosis treatment) or which increase the proportion of people infected with M. tuberculosis who develop active TB (e.g. HIV infection) will push the case reproduction number above 1, with consequent increasing TB incidence. The primary stratagem of TB control is to reduce the average number of people infected by each infectious case so that the case reproduction number is less than 1.
12. Liippo KK, Kulmala K, Tala EOJ. Results of tuberculosis contact tracing by smear grading of index cases. Am Rev Respir Dis 1993;148:235–236. 13. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999;353:444–449. 14. World Health Organization. Guidelines for the Prevention of Tuberculosis in Health Care Facilities in Resource-Limited Settings. Geneva: World Health Organization, 1999. 15. Veen J. Microepidemics of tuberculosis: the stone-in-the-pond principle. Tuberc Lung Dis 1992;73:73–76. 16. Rose G. Sick individuals and sick populations. Int J Epidemiol 1985;14:32–38. 17. Houk VN, Rent DC, Baker JH, et al. The Byrd study, an analysis of a micro-outbreak of tuberculosis in a closed environment. Arch Environmental Health 1968:16;26. 18. Stead WW, Senner JW, Reddick WT, et al. Racial differences in susceptibility to infection by M. tuberculosis. N Engl J Med 1990;322:422–427. 19. Schluger NW, Rom WN. The host immune response to tuberculosis. Am J Respir Crit Care Med 1998;157:679–691. 20. Davies P, Grange J. The genetics of host resistance and susceptibility to tuberculosis. Ann NY Acad Sci 2001;953:151–156. 21. Aubry MC, Wright JL, Myers JL. The pathology of smoking-related lung diseases. Clin Chest Med 2000;21:11–35. 22. Bishai WR. Rekindling old controversy on elusive lair of latent tuberculosis (Commentary). Lancet 2000;356:2113–2114. 23. Comstock GW, Cauthen GM. In: Reichman LB, Hershfield ES (eds). Tuberculosis. A Comprehensive
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
International Approach, Vol. 66. New York: Marcel Dekker, 1993: 23–48. Lambert M-L, Hasker E, Van Deun A, et al. Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 2003;3:282–287. DiPerri G, Cruciani M, Danzi MH, et al. Nosocomial epidemic of active tuberculosis in HIV infected patients. Lancet 1989;2;1502–1504. Rieder HL, Cauthen GM, Comstock GW, et al. Epidemiology of tuberculosis in the United States. Epidemiol Rev 1989;11:79–98. Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003;37:101–112. Daley CL. Tuberculosis recurrence in Africa: true relapse or re-infection? Lancet 1993;342:756–757. Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001;358:1687–1693. National Tuberculosis Institute, Bangalore. Tuberculosis in a rural population of South India: a five-year epidemiological study. Bull World Health Organ 1974;51:473–488. Styblo K. Epidemiology of Tuberculosis, 2nd edn. The Hague: Royal Netherlands Tuberculosis Association, 1991: 1–136. Dye C. India’s leading role in tuberculosis epidemiology and control (editorial). Indian J Med Res 2006;123:481–484. Sutherland I. Recent studies in the epidemiology of tuberculosis, based on the risk of being infected with tubercle bacilli. Adv Tuberc Res 1976;19:1–63.
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14
The natural history of tuberculosis infection and disease in children Ben J Marais and Peter R Donald
BACKGROUND During the twentieth century major advances occurred in the diagnosis and treatment of TB. Although the most important advance in the diagnosis of adult TB occurred with the detection of Mycobacterium tuberculosis by direct sputum microscopy, this offered little diagnostic value to children with paucibacillary disease. However, the tuberculin skin test (TST) allowed diagnosis of M. tuberculosis infection and more accurate TB diagnosis became possible as chest radiography became more widely available after the First World War. Therefore, from 1920 the tools for diagnosing M. tuberculosis infection and disease were widely available in developed countries, enabling them to document the evolution of disease in children. The first anti-TB drugs were introduced after the Second World War, and the most effective drug, isoniazid (INH), only became widely available in the early 1950s. Studies of childhood TB conducted during the period from 1920 to 1950 offer a picture of the natural history of TB in children, which can no longer be obtained. During this time, TB was still a major public health problem in many Western countries, and diseased children were frequently admitted to child sanatoria, where they were observed for prolonged periods of time. Numerous prospective observation studies were conducted, with meticulous long-term follow-up of patients providing detailed descriptions of disease presentation and progression. Active screening and prospective disease surveillance of household contacts documented primary infection (TST conversion) and progression to active disease. Two recent reviews summarized the results of these seminal prechemotherapy studies, conducted between 1920 and 1950.1, 2 They included all major studies published in the English literature; major studies were defined as those reporting on more than 1,000 children and with a follow-up period of more than 10 years.3–16 Three exceptions were made: 1. Avrid Wallgren’s findings were included as, although he reported on only 100 exposed children who became infected under close observation, he described the classic time-table of primary TB and based his conclusions on a lifetime of personal experience and careful observation.11–13 2. Tobias Gedde-Dahl included 3,138 children, but the study was interrupted after 8 years of follow-up due to the Second World War.6 The study’s contribution is important, because it provides the only accurate description of active community surveillance.
3. Edith Lincoln reported on 964 children, who were followed for up to 25 years and the study provided unique descriptions of the clinical signs and symptoms that develop during disease progression.15 The studies reviewed included both community and hospital-based cohorts, which reduces selection bias and ensures representation of the whole disease spectrum. The combined studies represent an impressive body of evidence that clarifies some important epidemiological concepts, although it fails to describe the influence of human immunodeficiency virus (HIV) infection.
CLINICAL EPIDEMIOLOGY Table 14.1 provides a brief description of the individual studies and Table 14.2 summarizes the key findings and major limitations.
EXPOSURE TO INFECTION The Mantoux TST, using 5 tuberculin units (TU) and an induration cut-off of 10 mm, was identified as the optimal way to diagnose M. tuberculosis infection.8,9 The induration induced by Bacillus Calmette–Gue´rin (BCG) vaccination was usually less than 10 mm, compared with the response after natural infection with M. tuberculosis, which usually exceeded 10 mm.7 BCG-induced delayed hypersensitivity responses diminished with time. The waning of the TST response varied depending on the timing of the BCG vaccination and the specific strain used. TST reversion occurred in less than 0.5% of children after natural M. tuberculosis infection, although temporary inhibition of TST responses did occur; this was mainly associated with severe malnutrition, viral illnesses, or extensive TB.6,8–10 The probability of infection was influenced by the infectivity as well as the proximity and duration of contact with the source case. Household exposure to a sputum smear-positive source case posed the greatest infection risk. Following prolonged household contact with a sputum smear-positive source case, 60–80% of children became infected.5,8–10 Household exposure to a sputum smearnegative source case posed a reduced, but still appreciable, risk; when the source case was smear-negative, 30–40% of children became infected.6,9,10 The majority of children who became infected did so within 3 months of symptom onset in the adult source case, but infection was frequently delayed in household contacts under 2 years of age if the primary caregiver was not the
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Table 14.1 Description of the original studies and individual study designs documenting the clinical epidemiology of childhood pulmonary tuberculosis Individual study reference
Time frame
Study type
Study population
Opie E, McPhedran FM, Putnam P (1935), Henry Phipps Institute, Philadelphia, PA, USA3
1907–1934, follow-up period of 1–27 years
Retrospective descriptive, outpatient based
Pope AS, Sartwell MD, Zacks D (1939), State Department of Public Health (Chadwick Clinics), Boston MA, USA4 Brailey M (1940), Johns Hopkins (Harriet Lane Clinic), Baltimore, MD, USA5
1924–1939, follow-up period of 5–15 years
Prospective TST survey, school based
Gedde-Dahl T (1951), Kinn District, Bergen, Norway6
1937–1944, follow-up period of 1–8 years
Retrospective descriptive, outpatient based Prospective TST survey, community based
Bentley FJ, Grzybowski S, Benjamin B (1954), High Wood Hospital for Children, Brentwood, Essex, UK7
1901–1952, notification data used
Davies PDB (1961), Brompton Hospital, London, UK8
1930–1954, follow-up period of 1–25 years
Miller FJW, Seal RME, Taylor MD (1963), Royal Victoria Infirmary, Newcastle upon Tyne Children’s Sanatorium, Stannington, Northumberland, UK9
1. 1947–1954 2. 1951–1961 Follow-up period of 1–10 years
Retrospective descriptive, outpatient based Retrospective descriptive, outpatient based
Zeidberg LD, Gass RS, Dillon A, et al. (1963), Tennessee Department of Public Health, USA10
1931–1955, follow-up period of 1–24 years
1928–1937, follow-up period of 1–10 years
Audit of TB notifications Mathematical deductions
Prospective community cohort study
Children < 15 years from 1,000 families with an adult source case Mortality data for the city of Philadelphia 400,330 school children 6–16 years TB notification data for Boston 1383 children < 15 years from 285 families with an adult source case Mortality data for Baltimore 6,739 people of all ages 3,138 children < 15 years
UK national TB notification data British MRC national TST survey
2377 children < 15 years in household contact with an adult source case 1. Children < 7 years from 1,000 families with an adult source case 2. 1,500 children < 5 years in household contact with an adult source case
1746 children < 15 years from 828 families with an adult source case Tennessee mortality data
Data collection methods
Adult source cases were selfselected Annual clinical follow-up of all source case contacts Annual CXR (if available) TST survey (Von Pirquet) CXR done if TST positive Annual CXR if the initial CXR was abnormal All children from tuberculous households screened Old tuberculin TST (0.1 or 1 mg) Annual CXR if TST positive Annual community-based TST survey (Von Pirquet) Documented TST conversion/ matriculation Annual CXR once TST positive Reviewed TB notifications for the whole UK and for London (1901–1952) Reviewed TST surveys D’Arcy Hart (1929), Prophit (1944), British MRC (1950) Included all asymptomatic household contacts Different TSTs were compared Annual CXR 1. 1,000 family study Household contacts < 7 years Annual CXR+TST (until positive) 2. Household contact study Household contacts < 5 years Annual CXR+TST (until positive) Voluntary inclusion of all household contacts Detailed questionnaire and physical examination Old tuberculin TST (0.1 or 1 mg), 6–12 monthly CXR
TST, tuberculin skin test; CXR, Chest radiograph; MRC, Medical Research Council. Adapted from Marais BJ, Gie RP, Schaaf HS et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:278–285.
source case.5 This observation suggests that the limited social contact of very young children reduces their likelihood of becoming infected, unless the caregiver is the source case.5 Infection rates peaked during winter months, but it was uncertain whether this was due to the increased crowding and reduced ventilation brought about by the cold winter months, or whether viral upper respiratory tract infections may have increased the vulnerability of children to become infected.9 Similar findings were documented in the 1990s in the Western Cape Province of South Africa; although the exact reasons underlying the seasonal variation observed remains uncertain.17 The vast majority of very young children were infected by a household source case, although additional caregivers, especially
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grandparents or extended family members who took care of the children during the day, were also important.5,7,9 The majority of older children with a positive TST reported no household contact with source case, and were therefore likely to have been infected in the community.4,5,9,11 As it is a public health priority to identify and treat all sputum smear-positive cases as quickly as possible to limit disease transmission, prudent public health policy should encourage active case finding amongst household contacts of very young children (< 3 years of age) with proven infection or disease. This type of ‘reverse’ contact tracing can be expanded to children of all ages in low-prevalence areas, where household exposure remains the most likely source. These studies provide the scientific basis for current contact investigation practices, which focus on children less than
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Table 14.2 Summary of key findings and major limitations of the original studies, documenting the clinical epidemiology of childhood pulmonary tuberculosis Citation
Features
Key findings
Major limitations
Opie et al.3
First to focus on families and children
Pope et al.4
TST positivity school survey
Brailey5
Focus on children < 2 years of age. Racial comparison
GeddeDahl6
TST conversion community survey
Bentley et al.7
TB disease and mortality specified per age group. Concept of relative contribution
Davies8
Long-term follow-up. Persistence of TST conversion
Miller et al.9
Comprehensive literature review
Zeidberg et al.10
Long-term follow-up in the community
Sputum-positive exposure increased the frequency and severity of disease in childhood contacts The lifetime risk for the development of cavitating disease depended on the age at primary infection, increasing significantly after 10 years of age Only 30% of infected school children had household contact with a known source case Cavitating pulmonary TB was seen only in children older than 10 years of age Infected children < 2 years of age indicated an active household source case The majority of household contacts infected within 3 months of symptom onset in the adult source case No racial difference in infection following exposure Definite racial difference in disease and mortality following infection The rate of TB infection and TB-related mortality was increased in urban areas Radiological abnormalities were visible in 75% of children following primary TB infection The ARI was not constant; varied between different age groups The majority (90%) of TB-related radiological abnormalities not detected in routine clinical practice The risk of disease and death following infection was the highest during infancy The relative contribution of TB to age-specific all-cause mortality was the lowest during infancy TB contributed significantly to all-cause mortality throughout childhood The Mantoux skin test outperformed other TSTs A positive TST response persisted for > 20 years Exposure to a sputum smear-positive vs a smear-negative source case doubled the risk of infection Infection after exposure to a sputum smear-positive source case doubled the risk for disease and death Clarified the confusion surrounding different TST techniques and doses Described the importance of cultural influences and the extended family Viral respiratory infections might have contributed to the seasonal variation in TB infection Identified critical periods of risk for disease development (infancy, puberty) Documented a drastic reduction in TB-related disease and mortality over the 24-year study period in black patients
Tuberculin skin test not recorded Age groups poorly defined Limited CXR availability Sputum positivity not specified (smear or culture)
Tuberculin skin test conversion not recorded Selective follow-up (only those with initial chest radiograph abnormalities were followed) Documented cavitating disease only Public health entry point selected the poor Response to high dose (1 mg) tuberculin, used in a small minority of patients, is not specific for M. tuberculosis infection Sputum positivity not specified (smear or culture) Socioeconomic differences were not evaluated
Pre-school children were selectively represented (only contacts and symptomatic cases included) Results from this isolated community may be difficult to generalize Response to high-dose (100 TU) tuberculin, used in 24% of subjects in the British MRC survey, is not specific for M. tuberculosis infection Relied exclusively on TB notification data for disease and mortality analysis
Majority of patients were already infected at study entry Selected only asymptomatic children at study entry, in order to ensure clinical uniformity
Few deductions were made from own studies Validity of quoted studies were not evaluated Relied extensively on notification data
Age at primary infection was not documented Entry criteria were adapted during the study A controversial finding, not supported by mortality data or results from other studies reviewed, was the delayed progression of disease reported in children infected between 1 and 15 years of age
ARI, annual rate of infection; TST, tuberculin skin test; CXR, chest radiograph; MRC, Medical Research Council; TU, tuberculin units. Adapted from Marais et al.1
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5 years of age in most developing countries (although reverse contact tracing is not advocated) and all household contacts in most industrialized countries. The risk of infection following household exposure was reduced under good socioeconomic conditions, and in American studies there were no racial differences in the rate of infection following household exposure.5,7,10 An interesting observation rarely taken into consideration was that the annual risk of infection (ARI) was not constant across age groups; there were clearly identifiable periods when infection rates increased.5,7,9 These age periods seemed to correlate with times of widening social contact; with increased mobility after 2 years of age, with school entry at 5–7 years of age, and with school exit at 15–20 years of age.7,9 The age-specific infection rate was found to be the single most important public health indicator of disease prevalence and active transmission within a given community.7,9,10
INFECTION TO DISEASE MORBIDITY With active contact tracing and regular radiographic screening, suggestive chest radiograph changes were noted in 50–60% of children following TST conversion.1,4,6–8 When comparing observations from prospective surveillance with routine notification data, it was calculated that only 5–10% of children in whom chest radiograph abnormalities were expected were ultimately notified. This implied that the majority of radiographic signs were transient and passed undetected in routine clinical practice.5,7 Nearly all disease manifestations developed within the first year following primary infection, identifying the first year following exposure as the time period of greatest risk.1,3–5,7 Specific time- and age-related disease patterns are discussed under ‘Clinical Disease Manifestations’.
MORTALITY The highest risk for TB-related mortality following primary infection (5–10%) occurred during infancy.3,5–7,9,10 This risk declined to 1% between 1 and 4 years of age, with the lowest levels (< 0.5%) maintained in the age group 5–14 years, before rising to more than 2% after 15 years of age.7,9 In children less than 10 years of age the majority of deaths occurred within the first year following primary infection, but, in older children who frequently developed adult-type cavitary disease, mortality lagged further behind.3,5–7,9,10 The relative TB-related mortality best describes the impact of TB on all-cause mortality within a specific age group.7 TB contributed significantly to all-cause mortality in all age groups, except in infancy.5,7 This contradiction is explained by the relatively small number of infants infected and the high rate of mortality from other causes.5,7,10 Although the relative contribution of TB to all-cause mortality is low in infancy, this does not detract from the important observation that, if infected, infants are at high risk of severe disease and death. Black children suffered double the TB-related mortality and four times the all-cause mortality compared with white children, but in the Tennessee study the TB-related mortality in black children declined by 80% within 20 years.5,9,10 In addition, a 10-fold decline in TB-related mortality occurred in Britain between 1900 and 1950, without a comparable decrease in TB infection.7,9 These dramatic declines in TB-related disease and mortality, documented within a single generation and without a comparable decrease in infection, emphasize the considerable influence of socioeconomic
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improvement.7,10 The nature versus nurture issue is complex, but the findings from these old studies suggest that improvement in the environment, rather than genetic selection, probably contributed most to the dramatic reduction in TB prevalence witnessed in the developed world during the twentieth century.18 Notification data often provide unreliable information due to under- or over-reporting of disease and inaccurate cause of death identification. In order to gain a better understanding of the crucial transition from infection to disease, it is important to look at studies that followed exposed children who became infected and/or diseased longitudinally and that described the clinical disease manifestations that occurred in sufficient detail.
CLINICAL DISEASE MANIFESTATIONS The optimal way to define risk and to describe exact disease entities is by prospectively following a cohort of children with recent primary infection for subsequent disease development and death. A number of studies from the pre-chemotherapy era achieved this. A brief description of each individual study is provided in Table 14.3. In order to facilitate the comparison and combination of results from different studies, a uniform template was developed to classify disease according to the disease descriptions and concepts of pathology derived from the pre-chemotherapy literature (Table 14.4). It is important to note that more than one disease entity may coexist at the same time or develop during the course of disease. Table 14.5 summarizes the key findings and major limitations.
‘TIME-TABLE OF CHILDHOOD TB’ Avrid Wallgren summarized the sequence of pathology following primary M. tuberculosis infection as the so-called ‘time-table of childhood TB’.11 Pulmonary infection occurs when a few TB bacilli, contained in a small infectious aerosol droplet, reaches a terminal airway and succeeds in establishing infection. A localized inflammatory process occurs within the lung and this is called the primary (Ghon) focus. From the Ghon focus, bacilli drain via lymphatics to the regional lymph nodes. The Ghon focus with associated tuberculous lymphangitis and involvement of the regional lymph nodes is called the primary (Ghon) complex. From the regional lymph nodes bacilli enter the systemic circulation directly or via the lymphatic duct. This occult haematogenous spread occurs during the incubation period, before adequate immune responses contain the disease. After dissemination, bacilli may survive in target organs for prolonged periods. The future course of the disease at each of these sites depends on the dynamic balance between host immunity and the pathogen.19
Phase 1 occurred 3–8 weeks after primary infection.11,13 The end of the initial asymptomatic incubation period was heralded clinically by hypersensitivity reactions such as initial fever, erythema nodosum, a positive TST response, and formation of the primary complex visible on chest radiograph.11,13 Phase 2 occurred 1–3 months after primary infection.13 This period followed the occult haematogenous spread that occurred during incubation, and represented the period of highest risk for the development of tuberculous meningitis (TBM) and disseminated (miliary) TB in young children.11,13 However, these disease entities may occur after any time interval; haematogenous dissemination frequently acted as
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14
Table 14.3 Description of original studies and individual study designs documenting the natural history of childhood intrathoracic tuberculosis Individual study reference
Time frame
Study type
Study population
Data collection methods
Wallgren A (1935, 1938, 1948), Children’s Hospital, Gothenburg and the Karolinska Medical Institute, Stockholm, Sweden11–13
1930-1950, followup period not specified
Prospective descriptive, hospital based Personal experience
100 newly infected children. All children with TB seen on referral
Brailey M (1940), Johns Hopkins (Harriet Lane Clinic), Baltimore, MD, USA14
1928-1937, followup period of 1–10 years
Retrospective descriptive, outpatient based
285 families with 1,383 children < 15 years 40% white 60% black
Gedde-Dahl T (1951), Kinn District, Bergen, Norway6
1937-1944, followup period of 1– 8 years
Prospective TST survey, community based
6,739 people 3,138 children < 15 years
Bentley FJ, Grzbowski S, Benjamin B (1954), High Wood Hospital for children, Brentwood, Essex, UK7
1942–1952, followup period of 5–10 years
Davies PDB (1961), Brompton Hospital, London, UK8
1930–1954, followup period of 2–25 years
Retrospective descriptive, outpatient based
Lincoln EM, Sewell EM (1963), Bellevue Hospital, New York City, NY, USA15
1930–1960, followup period of 10–25 years
Prospective descriptive, hospital based
Sanatorium patients 954 < 15 years 50% white 25% black 25% Puerto Rican
Miller FJW, Seal RME, Taylor MD (1963), Royal Victoria Infirmary, Newcastle upon Tyne and Children’s Sanatorium at Stannington, Northumberland, UK16
1. 1941–1951 2. 1951–1961 Follow-up period of 1–10 years
1. Children < 7 years from 1,000 families with an adult source case 2. 1,500 children < 5 years in household contact with an adult source case
1. Sanatorium patients 1,049 children < 16 years 2. Death investigation 100 consecutive TB deaths notified in children 2,377 children < 15 years
Retrospective descriptive, hospital based Literature review
Retrospective descriptive, outpatient based Literature review
Children observed after household exposure Meticulous documentation of signs/ symptoms following infection In addition, Wallgren drew from vast personal experience All children from tuberculous households TST (old tuberculin at 0.1 or 1 mg) Annual CXR if TST positive Annual community-based TST survey (Von Pirquet) Documented TST conversion Annual CXR if TST positive Successive referrals admitted over a 10-year period Observation and CXR in hospital Review CXR 5–10 years after hospital discharge
All asymptomatic household contacts Different TSTs compared Annual CXR 70% follow-up achieved Children referred with evidence of recent (uncalcified) TB Observation and CXR in hospital Hospitalized for extended periods with careful documentation of disease progression Annual CXR after discharge 90% follow-up achieved 1. 1,000 family study Household contacts < 7 years Annual CXR+TST (until positive) 99 TST converted 2. Household contact study Household contacts < 5 years Annual CXR+TST (until positive) 72 TST converted
TST, tuberculin skin test; CXR, chest radiograph; TB, tuberculosis. Adapted from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis – a critical review of the literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402.
the final terminal pathway following uncontrolled disease progression in the absence of treatment.15,16 Phase 3 occurred 3–7 months after primary infection.13 This was the period of secondary airway involvement due to diseased lymph nodes in children less than 5 years of age, while large reactive pleural effusions also occurred during this time period, but mostly in children older than 5 years of age.13,15,16 Phase 4 lasted until the primary complex was calcified, 1– 3 years after primary infection, and represented the period of osteoarticular TB in children under 5 years of age, and adulttype disease in adolescents.12–19 As a general rule the risk of disease progression following primary infection had passed by the time calcification appeared.14–19 However, in adolescent
children adult-type disease sometimes had a delayed clinical onset, occurring after the appearance of calcification.8,16 Phase 5 occurred after calcification was complete, more than 3 years after primary infection. By this time the highest risk period has passed, although some of the very late manifestations of TB, including pulmonary reactivation, were rarely observed.7,16
The features of the classic time-table first described by Wallgren were later confirmed and expanded by observations from other studies. It is important to point out that the timeline reflected in Fig. 14.1 summarizes common clinical patterns of disease and does not represent dogmatic rules regarding the course of TB in children; also that the vast majority (> 90%) of disease manifestations occurred in the first 6–12 months following primary infection.7,8,16
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Table 14.4 Disease classification of childhood intrathoracic tuberculosis used as template Pulmonary infection Pulmonary disease
Tuberculosis infection uncomplicated by clinical symptoms (other than self-limiting, viral-like illness) or radiological abnormalities (other than the primary complex). The primary complex includes the Ghon focus with associated TB lymphangitis and affected regional lymph nodes. Tuberculosis infection complicated by marked clinical symptoms or additional radiological abnormalities apart from the primary complex. Pulmonary disease includes a diverse spectrum of pathology, described as separate disease entities.
Separate disease entities Ghon focus with/without cavitation Lymph node disease Complicated by airway involvement
—With obstruction —With collapse/ hyperinflation —With allergic consolidation —With bronchopneumonic consolidation —With caseating consolidation Pleural disease
—With effusion —With empyema Adult-type disease
Haematogenous spread
—With disseminated (miliary) disease
Progressive parenchymal caseation surrounding the Ghon focus represents poor organism containment. The caseated area may discharge into a bronchus, resulting in the formation of a cavity with possible endobronchial spread. Regional lymph node enlargement forms part of the primary complex, but the presence of marked clinical symptoms differentiates lymph node disease from pulmonary infection. With pulmonary infection, affected regional lymph nodes attach to the bronchus, but rarely progress to clinical or radiological disease. If disease progression follows this ‘lympho-bronchial involvement’, the affected bronchus may become partially or totally obstructed as a result of nodal compression, inflammatory oedema, polyps, granulomatous tissue, or caseous material extruded from ulcerated lymph nodes. Parenchymal disease may result from aspiration of caseous material. Variation in the degree of airway obstruction, dose and virulence of the bacilli aspirated and the immune status of the host determines the degree of pathology. Airway obstruction occurs because of enlarged matted nodes encircling and compressing an airway, together with associated inflammation or additional processes described above. Complete airway obstruction leads to resorption of distal air and collapse, while partial airway obstruction may cause a ball-valve effect with hyperinflation of the segment or lobe supplied. Nodal perforation into an airway with endobronchial aspiration of allergic products causes an acute hypersensitivity response (epituberculosis) with dense consolidation. Nodal perforation into an airway with endobronchial aspiration of live bacilli causes local areas of caseation surrounding the airways, resulting in patchy consolidation. Nodal airway obstruction with perforation and endobronchial aspiration of live bacilli causes extensive parenchymal caseation, resulting in dense expansile consolidation of the affected lobe. Pleural involvement occurs after direct spread of bacilli from a subpleural parenchymal or lymph node focus, or from haematogenous spread. Variation in the dose and virulence of bacilli that enter the pleural space and the immune status of the host determines the degree of pathology. The presence of caseous material in the pleural space triggers a hypersensitivity inflammatory response with the accumulation of serous straw-coloured fluid, containing few TB bacilli. Active caseation in the pleural space causes thick loculated pus, containing many TB bacilli. Excessive local containment may cause parenchymal destruction and resultant cavity formation. Tubercle bacilli flourish in these cavities from where they disseminate to other parts of the lung via endobronchial spread. Endobronchial spread occurs directly from these infected cavities and is not dependent on lympho-bronchial breakthrough, as with bronchial disease. TB bacilli may enter the blood stream via pulmonary lymphatic drainage, from affected regional lymph nodes or directly from the parenchymal focus. Haematogenous spread is a condition of infinite gradation, depending on the frequency, dose, and virulence of the bacilli released as well as host immunity. During occult spread bacilli are seeded into susceptible organs, while the child remains asymptomatic. Following invasion of the blood stream, TB bacilli lodge in small capillaries, where they may progress to form tubercles, visible on chest radiograph as typical even-sized, miliary lesions (< 2 mm) or atypical lesions of differing size.
Adapted from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis – a critical review of the literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402.
INTRATHORACIC MANIFESTATIONS PULMONARY INFECTION Pulmonary infection was usually identified after active contact tracing or presentation of children by anxious parents.7,15,16 Pulmonary infection was associated with TST conversion and non-specific, self-limiting, viral-like, respiratory symptoms.11–13,16 Enlarged regional lymph nodes on chest radiograph were the hallmark of pulmonary infection with or without a visible Ghon focus.6,7,15,16 Following primary infection, 50–70% of children showed these radiological signs, irrespective of symptoms.6,8,16 Good quality anteroposterior and lateral radiographic views were required for optimal visualization of enlarged regional lymph nodes.15,16 The Ghon focus showed no predilection for any specific part of the lung.7,15,16 The regional lymph
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nodes affected depended on the anatomical location of the Ghon focus; a Ghon focus in the apex of the lung affected the ipsilateral paratracheal nodes,7,16 a Ghon focus in other parts of the right lung caused right-sided hilar adenopathy, and a Ghon focus in the left lung usually caused bilateral hilar adenopathy.7,16 Paratracheal nodes reflected a Ghon focus in the apex, spread from hilar glands, or haematogenous spread.7 It occurred more frequently in children under 2 years of age and showed a consistent trend to increased haematogenous spread, even with correction for age.7 During the first 3–4 months the lymph nodes were in a phase of ‘full activity’, vaguely defined, cloudy and homogeneous.7 Over the following months the radiological signs of ‘activity’ regressed, the shadow became denser and better defined.7 With serial radiographs, 40% of lesions cleared within 6 months, a further 30% within 1 year, and the remaining 30% persisted up to 4 years.7,16 Calcification
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The natural history of tuberculosis infection and disease in children
Table 14.5 Summary of key findings and major limitations of the original studies that documented the natural history of childhood intrathoracic tuberculosis Citation
Age groups
Unique feature
Key findings
Major limitations
Wallgren11–13
2 groups: < 3, 3–14 years
Meticulous observation Detailed description of symptoms and signs following primary infection Relevant age groups Racial differences
TST conversion in the community
Brailey14
5 groups: < 1, 1–2, 2–4, 5–9, 10–14 years
3 groups: < 5, 5–9, 10–14 years
4 groups: < 1, 1–4, 5–9, 10–15 years
4 groups: < 1, 1–4, 5–9, 10–14 years
Lincoln et al.15
4 groups: < 1, 1–4, 5–9, 10–14 years
Miller et al.16
5 groups: < 1, 1–2, 2–4, 5–9, 10–14 years
GeddeDahl6
Bentley et al.7
Davies8
First dedicated childhood TB study in UK
UK study with longest follow-up period
Detailed description of disease progression Relevant age groups Comprehensive literature review
Age at primary infection and time since infection were major determinants of risk for disease development. It also influenced the type of disease manifestation Host immunity was influenced by age and considered to be of crucial importance Documented the time-table of disease In all children < 2 years and in black children < 5 years segmental lung lesions predominated Black children suffered increased morbidity and mortality Enlarged nodes were visible on CXR in the vast majority of recently infected children All CXR changes apart from cavitation and calcification seen within 1 year after infection Described the slow rate of radiological regression with lymph adenopathy Suggested a focus on high-risk groups: < 2 years and > 10 years of age Progression of disease documented even after calcification became visible Risk of cavitating disease dependent on age at primary infection (> 10 years) Documented disease progression together with the signs, symptoms and outcome associated with specific disease entities
Informative illustrations of lymph drainage and TB lung pathology Re-emphasized high-risk groups following primary infection (< 2 years and adolescents) Cavitary disease may follow primary infection, reinfection or reactivation
Study methodology not specified Observations illustrated with case studies Guidelines provided very dogmatic
Public health entry point selected the poor Type of segmental lesion not specified Socioeconomic differences not evaluated Pre-school children were poorly and selectively represented Isolated community Excessive pre-selection occurred due to referral and long waiting periods Disease progression was not well documented Selected only asymptomatic children at study entry, to ensure clinical unity Majority of children were already infected at study entry Study inclusion was selective (symptomatic children with CXR evidence of recent infection) Limited racial subanalysis Cavitation with visible calcification was accepted as proof of reactivation. Validity of studies quoted were not evaluated
TST, tuberculin skin test; CXR, chest radiograph. Adapted from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis – a critical review of the literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402.
0 0 1 Infection
I
II 2
III 3 4 Months
IV 6
8 Time
10
12
V 2
Years
3
4
13
Fig. 14.1 Phase of disease, adapted from the time-table of TB described by Wallgren.13
Phase of disease adapted from the time-table of tuberculosis described by Wallgren 0 Incubation phase I Hypersensitivity phase II Phase of miliary tuberculosis and tuberculous meningitis II Phase of segmental lesions in children < 5 years and pleural effusion in those > 5 years IV Phase of osteo-articular tuberculosis in children < 5 years and adult-type disease in those >10 years V Phase of late manifestations including pulmonary re-activation Not all these disease manifestations (phases) are equally common and while hypersensitivity is a nearly universal phenomenon following primary infection, the late manifestations are extremely rare. Table 6 provide an indication of how common the most important of these disease manifestations are in specific age groups. The vast majority of complications occur in the first 3 12 months following primary infection.
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Table 14.6 Age-specific risk for disease development following primary infection
50
Age at primary infection (years)
Risk of disease following primary infection in immune-competent children (dominant disease entity indicated in brackets)
40
<1
No disease 50% Pulmonary disease (Ghon focus and/or lymph node) 30–40% TBM or miliary disease 10–20% No disease 70–80% Pulmonary disease (Ghon focus and/or lymph node) 10–20% TBM or miliary disease 2–5% No disease 95% Pulmonary disease (lymph node) 5% TBM or miliary disease 0.5% No disease 98% Pulmonary disease (lymph node, pleural effusion or adult-type) 2% TBM or miliary disease < 0.5% No disease 80–90% Pulmonary disease (pleural effusion or adult-type) 10–20% TBM or miliary disease < 0.5%
5–10
> 10
TBM, tuberculous meningitis. Adapted from Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis – a critical review of the literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402.
developed in 20–50% of infected children with visible lymph node involvement.7,8,16 Calcification usually occurred between 12 and 24 months, but was sometimes delayed up to 4 years after primary infection.7,16 Calcification in young children tended to be more extensive and developed earlier (within 6–12 months) than in older children.7,16 In general, calcification was an indication of clinical quiescence, but not a guarantee thereof.15,16 The disappearance of calcification was rare and attributed to either resorption or bronchial escape of a pneumolith.16 The prognosis of pulmonary infection was generally favourable and the risk depended mainly on the age at the time of primary infection (Table 14.6).11–16
PULMONARY DISEASE Host immunity was considered to be the major determinant of risk for disease development following infection.11 Infants with immature immune systems were at highest risk, 11–16 with pulmonary disease developing in 30–40% and TBM and/or disseminated miliary disease in 10–20% (Fig. 14.2).14–16 The risk decreased considerably in the second year of life, but stayed significant with 10–20% of infected children developing pulmonary disease and a further 2–5% TBM or miliary disease.15,16 The risk decreased to less significant levels in the age group 2–5 years, before reaching its lowest level at 5–10 years of age.14–16 Lymph node disease with/without airway involvement predominated in children under 5 years.7,8,15,16 Disease occurred less frequently in children aged 5–10 years; pleural effusion became more common throughout this period,16–19 but lymph node disease was mainly restricted to the younger group and adulttype disease to the older group (> 7–8 years of age).15,16 Black children had an increased risk of developing complicated lymph node disease across all age groups.14 Primary infection during adolescence
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Disseminated
30 20 10 0
<1
1 to 2
2 to 5 Age in years
5 to 10
10 to 15
Fig. 14.2 Age-related risk of progression to active disease following primary M. tuberculosis infection.
Frequency of disease manifestation
2–5
PTB
%
1–2
Age-related risk
(1) 0
1
(2) 2
(3) 4
6
8 10 Age in years
(4) 12
14
16
(1) Complicated Ghon focus and/or disseminated disease (2) Uncomplicated Ghon focus and/or lymph node disease Complicated lymph node disease (3) Pleural effusion (4) Adult-type disease Adapted from Marais BJ et al.
Fig. 14.3 Age-related manifestations of intrathoracic TB in immunecompetent children.
(> 10 years of age) was associated with a high risk (10–20%) of developing adult-type disease.7–9,11–16 A summary of the age-related disease patterns described are demonstrated in Fig. 14.3.
GHON FOCUS WITH/WITHOUT CAVITATION A Ghon focus complicated by cavitation was rare. It occurred predominantly in infancy.14–16 Clinical symptoms of Ghon focus cavitation included weight loss, fatigue, fever, and chronic cough, and in these immune immature infants the underlying mechanism is probably poor disease containment.15,16 In those with cavitation of the Ghon focus, disease quickly progressed to death in the majority of cases and the few who survived the initial illness ultimately died from TB or TB-associated complications.15,16 Cavitation following primary infection was not uncommon during adolescence,7–9,12,15,16 but in this age group the parenchymal breakdown probably reflects excessive rather than poor disease containment;19 this is discussed under ‘Adult-Type Disease’.
CHAPTER
The natural history of tuberculosis infection and disease in children
LYMPH NODE DISEASE Enlarged regional lymph nodes, visible on chest radiograph, usually caused symptoms associated with airway inflammation and/or obstruction, but massive caseating nodes were often associated with persistent fever and excessive weight loss.16 The subcarinal nodes were most commonly involved, but any of the hilar or paratracheal group of nodes may be involved.16
Complicated by airway involvement Airway involvement was indicated by different degrees of obstruction and/or secondary parenchymal disease. Airway involvement occurred predominantly in children under 5 years of age and it occurred more frequently in younger children and boys, 7,8,15,16 as well as black children.14 The airways most frequently affected were those supplying the right upper lobe (anterior segment), the right middle lobe, and the left upper lobe.16–19 The airways most frequently affected in combination were those of the right middle and lower lobes, indicating involvement of the bronchus intermedius.16–19 Rebound enlargement of segmental lesions, attributed to immune reconstitution, were described after cessation of high-dose steroid treatment.19 The spectrum of airway pathology demonstrated on bronchoscopy included the following: no visible involvement, obstruction from external compression, endobronchial breakthrough with caseous drainage, granulation tissue with polyps, and fistula formation.7,15 A very rare sequel was the expectoration of a pneumolith after perforation of a calcified lymph node into an airway.15,16 Symptoms varied according to the degree of airway irritation and obstruction. Infants frequently developed a persistent cough, sometimes mimicking pertussis.15,16 With disease progression the cough became more prominent, often brassy or bi-tonal with associated large airway wheeze or stridor.11,15,16 With collapse/hyperinflation Collapse and hyperinflation were mostly a radiological diagnosis with minimal clinical symptoms unless large lung segments collapsed, or hyperinflation caused symptoms related to pressure on surrounding structures.7,16 With ‘allergic’ consolidation (epituberculosis) This represented a type of hypersensitivity response to dead TB organisms and TB antigens that were aspirated (or in experimental animal studies, deposited) into a particular part of the lung. The onset of symptoms could be dramatic, with a high fever, acute respiratory symptoms, and signs of consolidation.15 Chest radiography revealed a densely consolidated segment or lobe with minimal volume change.15,16 Consolidation resolved completely within months with no permanent sequellae.15 With bronchopneumonic consolidation Bronchopneumonic consolidation was rare. Symptoms were not well described, but depended on the extent of involvement. On chest radiograph patchy infiltration usually involved more than one lobe of a single lung, reflecting airway spread.7 Bilateral patchy infiltration was mostly due to protracted disease or due to haematogenous spread with an atypical slowly progressive course.7 With caseating consolidation Children with caseating consolidation were ill, with a high undulating fever, chronic cough, and sometimes even haemoptysis.15 On chest radiograph dense lobar consolidation was visible, usually with volume increase (expansile), with or without areas of breakdown. Mycobacterium tuberculosis cultures were positive in more than 80% of cases.7,15,16
14
Secondary bacterial infection often complicated the picture.7,16 Bronchoscopy showed total airway obstruction and surgical re-establishment of airway patency together with penicillin gave dramatic symptomatic relief.15,16 Following resolution of the consolidation, non-collapsing parenchymal bullae appeared with extensive fibrotic scarring in the surrounding lung tissue.7,15 Without intervention the prognosis was poor, with frequent haematogenous spread terminating in disseminated (miliary) TB and/or TBM.7,15 If resolution occurred, the end result of bronchopneumonic or caseating consolidation was a contracted, fibrotic area and contracted segments were often impossible to visualize on later chest radiographs.7,15 Bronchiectasis was a common sequel to peribronchial caseation.7,8,15,16 Airway damage ranged from saccular bronchiectasis to bronchial stenosis.15,16 Most children with bronchiectasis remained asymptomatic on long-term follow-up.7,8,15,16 Apical lesions hardly ever caused complications, but large basal bronchiectatic lesions did predispose to future suppurative disease.7,8,15,16 Surgery was indicated only when a bronchiectatic lobe caused recurrent symptomatic disease.15,16 Very rarely, massive fibrosis and contraction of a whole lung (chronic fibroid lung) caused mediastinal shift and also resulted in severe scoliosis.7,15
PLEURAL DISEASE With effusion Localized pleurisy overlying a peripheral Ghon focus was common.15 Limited adhesions developed between the visceral and parietal pleura, but this did not cause symptoms or lung function abnormality.15 Effusions were rare in children under 5 years of age and most common in adolescent boys.7,8,15,16 A seasonal variation was observed with the lowest incidence during late summer and autumn, accounted for by reduced primary infection in the preceding summer months.7 Pleural effusion had a characteristic clinical course, starting with an acute pleuritic pain in the chest, accompanied by a high fever in the absence of acute illness, an ill-defined loss of vigour, and a dry cough.7,8,15,16 The TST was usually highly reactive.7,15 On chest radiography the size varied from small effusions obliterating only the costophrenic angle to massive fluid collections that caused opacification of a whole lung with mediastinal shift to the opposite side.7,15 In most cases, a third to a half of the lung was obliterated with a clear meniscus sign.7 With fluid in the pleural space it is nearly impossible to exclude lesions in the underlying lung.7,15 Localized interlobular effusions required radiological differentiation from segmental lesions.16 A unilateral effusion, ipsilateral to the parenchymal focus, indicated direct spread to the pleural space from a subpleural focus. Bilateral effusions indicated haematogenous spread or bilateral primary foci.15,16 Pleural fluid was a straw-coloured exudate with high protein content and lymphocyte predominance, 15,16 although the amount of polymorphonuclear cells depended on the acuteness of onset.16 Direct microscopy was negative, but culture yields were as high as 70% with immediate inoculation.15 In children the prognosis of effusion was generally good. The high fever showed gradual defervescence over 3–4 weeks,7,15 while the fluid collection resolved more slowly over 3–6 months.7,16 Obliteration of the costophrenic angle and slight pleural thickening remained permanently.7,15,16 The main complication described was future adult-type disease, which was not a complication of the effusion per se, but reflected the risk associated with primary infection at an older age.7,8,15,16 Rarely, extensive pleural fibrosis caused contraction of the affected hemithorax with scoliosis.7,14 Bilateral
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effusions were associated with a higher risk for haematogenous spread and future adult-type disease.7,15,16
With empyema The presence of caseating empyema was indicated by a persistent high swinging fever and a loculated pleural collection on chest radiograph.16 Aspiration was difficult because of thick pus. Tubercle bacilli were usually visible on microscopy.16 Caseating empyema was rare and the prognosis was variable with slow disease progression and death or slow resolution with pleural calcification and fibrosis.16 ADULT-TYPE DISEASE Adult-type disease resulted after primary infection, endogenous reactivation, or exogenous reinfection.16 All these processes operated in the same community at the same time.15 Adult-type disease was most common after recent primary infection in children over 10 years of age.7,8,12,14–16 The interval from primary infection to adult-type disease was widely variable (3 months to 20 years) and depended mostly on the child’s age at the time of primary infection.7,8,15,16 The shortest time intervals and highest risk followed primary infection during adolescence, especially in girls of perimenarchal age.15,16 Disease started off with minimal symptoms such as cough, loss of appetite, and fatigue.15 With disease progression typical TB symptoms of chronic cough, chest pain, lethargy, anorexia, and weight loss became evident.7,8,15,16 Children with advanced disease became anaemic, and developed an oscillating fever and haemoptysis.15 A frequent complaint, even in the absence of fever, was night sweats.15 On chest radiograph an initial rounded homogeneous shadow, 2–3 cm in diameter situated in the vicinity of the clavicle was typical, followed by parenchymal breakdown and cavity formation.15,16 Cavities did not contain a fluid level and were characteristically surrounded by inflammation.16 Bilateral disease was common, mainly involving the apical segments of the upper lobes; lower lobe involvement was far less frequent.16 Previous radiographic appearances were non-predictive and highly variable, ranging from no visible abnormality detected to a densely calcified primary complex.7 A correlation existed between those lesions that represented primary infection in the older age group, such as pleural effusion, and adult-type disease.7,8,15,16 The prognosis of adult-type disease was poor, with 50–60% mortality within 5–10 years.7,8,15,16 These children were sputum smear-positive and could transmit infection.
HAEMATOGENOUS SPREAD During incubation and occult spread, bacilli seed to susceptible organs, especially the spleen, bone, kidney, and cerebral cortex and possibly to the apices of the lungs (Simon foci).11,15,16 The age at the time of infection and the time since infection were the major determinants of risk for the development of ‘metastatic’ disease. Infection under 2 years of age carried a significant risk of serious disease, even if the radiograph was considered normal.7,16 TBM was present in over 30% of children who presented with TB before 2 years of age.7,16 The risk of TBM after 3 years of age was extremely low and those who did develop TBM had significant preceding symptoms.15,16
With disseminated (miliary) disease Infants were most vulnerable to develop disseminated (miliary) disease.11,15,16 The symptoms included prolonged pyrexia, lassitude, anorexia, and weight loss.7,15,16 Children appeared acutely ill with minimal physical signs apart from tachypnoea and
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hepatosplenomegaly.7,15 Radiological mottling followed 7–21 days after febrile onset, starting as barely visible nodules that slowly progressed to large poorly defined patches.15 The initial miliary lesions were often difficult to visualize with 30–40% of autopsy-proven miliary lesions missed on chest radiograph before death.6 Bone marrow biopsy and ophthalmoscopy were useful diagnostic aids.7 The reported presence of choroidal tubercles varied widely, from 13% to more than 50%.7,8,15,16 The majority of children were TST-positive and, in those children with an initial negative TST, skin test conversion occurred within 1–4 months when effective treatment became available.15 The prognosis of disseminated (miliary) disease was poor. Clinical progression with persistent fever increased irritability and weight loss frequently terminated in TBM.15,16 The majority died within 6 months, but chronic forms were occasionally seen where children eventually died from ‘toxaemia’, malnutrition, or amyloidosis.15 Typical even-sized miliary mottling pointed to an acute invasion of the blood stream. Protracted release of bacilli from a chronic focus, e.g. a matted lymph node mass or rarely a skeletal lesion, also occured.15 The symptoms of protracted seeding were similar to acute invasion, but were initially more intermittent, presumably corresponding to periods of bacilli or toxic product release.15 This repetitive seeding was sometimes manifested by successive crops of papulonecrotic tuberculids (skin manifestation).15 Chest radiograph images revealed large hilar lymph node masses with mottling of variable size, and eventually progression did occur with either acute or chronic deterioration.15,16
PRINCIPLES OF DISEASE DYNAMIC BALANCE The clinical manifestation of an infectious disease depends on the balance that exists between the pathogenicity of the organism and the immune competence of the host. In tuberculosis, an important dynamic dimension is added to this balance, because initial organism containment rarely ensures organism eradication.19,20 Persistence of dormant bacilli inside sequestered foci (latent infection) provides an ‘ever-present’ risk of reactivation whenever the balance shifts in favour of the organism. In addition to the risk of reactivation following previous primary infection, high levels of transmission implies an additional risk of reinfection in highburden settings.21,22 The delicate and dynamic balance established between the pathogen and the host may be influenced by numerous variables (Fig. 14.4). Pathogen
Host immunity Dynamic balance
Pathogen Infecting dose (limited) Virulence Persistence (Preferential growth in lung apices)
Host immunity Innate immunity including local defences Acquired immunity (Pronounced lymphadenopathy <5 years) (Excessive tissue necrosis >10 years)
*Adapted from Marais BJ et al. Diversity of disease manifestations in childhood pulmonary tuberculosis19
Fig. 14.4 Factors underlying different manifestations of pulmonary TB. Adapted from Marais BJ, Donald PR, Gie RP, et al. Diversity of disease manifestations in childhood pulmonary tuberculosis. Ann Trop Paediatr 2005;25:79–86.
CHAPTER
The natural history of tuberculosis infection and disease in children
THE PATHOGEN Variables related to the pathogen include the number of organisms inhaled (size of the infecting dose), the virulence of these organisms, and their ability to resist eradication (persistence). With M. tuberculosis infection, variation in the infecting dose seems negligible. Lung deposition studies indicate that only the tiniest aerosol droplets, containing fewer than five bacilli, are likely to reach the terminal airways and establish a pulmonary focus of infection.23–25 Larger droplets are either not inhaled (since they are less likely to remain suspended in the air), or they are deposited in the proximal airways where infection is effectively resisted.24,25 Epidemiological evidence and experimental evidence from laboratory animals suggest that the intensity of exposure influences the risk of both infection and disease.26,27 It is well established that variables such as the duration of exposure and the number of infectious particles in the ambient air influence the risk of infection. However, natural infection in humans seems a fairly uniform event with little variation in the infecting dose, being ascribed to a single aerosol droplet containing fewer than five bacilli. Other variables, including multiple infections or increased virulence of the infecting organisms, may explain the increased tendency to progress to disease following high-intensity exposure, such as household exposure to a sputum smear-positive source case. Primary infection is usually visualized as a single parenchymal (Ghon) focus,2 but exposure to multiple infective doses may increase the likelihood that a single infective dose is ultimately successful in establishing infection and/or disease. Variation in the virulence of the infecting organisms may offer another explanation, as the phenotypic virulence may differ according to the sputum smear status of the source case, while the proximity of the source case will determine the influence of environmental factors such as exposure to ultraviolet irradiation or drying.24,25 Genetic variation in organism virulence is well documented, 28,29 but it is unlikely that strain differences can explain the consistent epidemiological finding that household contacts of sputum smear-positive source cases are more likely to progress to disease following infection. Persistence describes the ability of the pathogen to evade eradication and to remain dormant for extended periods of time. Several mechanisms which may enable M. tuberculosis to persist both intracellularly (inside macrophages) and extracellularly (inside the caseous centres of granulomas) have been described.30,31 The presence of dormant M. tuberculosis bacilli is not harmful to the host unless circumstances favour their reactivation, which explains why progressive immune compromise poses such a high risk of reactivation disease.
HOST IMMUNITY Total host immunity includes a combination of both innate and acquired immune responses, together with local pulmonary defences, which seem more important than was previously appreciated. Compromised organism clearance, decreased mucosal immunity, and a favourable microenvironment at the point of organism deposition may all contribute to an increased risk of infection and disease. The importance of these local pulmonary influences is demonstrated by the comorbidity that exists between pulmonary TB and silicosis,32 or tobacco smoking.33,34 The protection provided by the innate immune response seems limited, because bacilli grow unrestrained within naı¨ve macrophages and occult haematological dissemination occurs frequently during
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the first 4–6 weeks, following primary infection.11,19,35 Acquired cellular immunity is of crucial importance to contain the organism and prevent uncontrolled disease progression.11,19,35 In the absence of immune compromise, age is the dominant variable that determines the effectiveness of acquired cellular immunity to contain the organism. This is illustrated by the striking age-related risk to develop TB following primary infection and by the age-related differences seen between particular disease manifestations (Figs 14.2 and 14.3).19,36 Apart from the age and immune status of the child, the time since infection is another important variable that influences the particular disease manifestation, as illustrated by the time-table of TB in children (Fig. 14.1). To improve our understanding of the mechanisms that underlie the different manifestations of childhood TB, as described in the pre-chemotherapy literature and confirmed by more recent reports,37 requires a renewed focus on the ontogeny of the host immune response towards infection with M. tuberculosis.19 The knowledge gained may be essential for directing future research in the field of TB prevention, vaccine development, and treatment.
SUMMARY Clinicians and researchers have limited access to the important prechemotherapy literature that documented the natural history of TB in children. Since the discovery of safe and effective treatment, conducting studies on the natural history of disease became unethical and therefore these historic disease descriptions remain invaluable today. The pre-chemotherapy literature provides a strong body of evidence; multiple studies followed large cohorts of children for prolonged periods of time and carefully documented the development of disease following primary infection with M. tuberculosis. In summary, the natural history of disease demonstrates three central concepts that are important to consider when addressing current and/or future challenges in the field of childhood TB: 1. the need for accurate case definitions; 2. the importance of risk stratification; and 3. the diverse spectrum of disease pathology, which necessitates accurate disease classification.36,38
CASE DEFINITION Accurate case definition revolves mainly around the ability to differentiate primary infection from active disease. Primary infection is believed to occur when a previously uninfected child inhales an infectious aerosol droplet; a localized pneumonic process (the Ghon focus) forms at the site of organism deposition. Initially (for the first 4–6 weeks), unrestrained multiplication occurs within the Ghon focus and bacilli drain via local lymphatics to the regional lymph nodes and beyond. Occult dissemination occurs frequently during this early proliferative phase before cell-mediated immunity is fully activated. Bacteriologic cultures collected at this time may be positive; Arvid Wallgren demonstrated that M. tuberculosis can be recovered from recently infected children who are not diseased. Therefore, with active contact tracing and aggressive screening that includes the collection of mycobacterial cultures in asymptomatic children it is not unexpected that some positive cultures will be found in recently infected children who are not diseased. This illustrates the overlap that exists between recent primary infection and
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case definitions of disease that rely exclusively on bacteriology. It is important to consider this overlap when case definitions are formulated for research purposes, particularly within the contact setting, although it is less relevant in everyday practice where there is no reason to obtain cultures from completely asymptomatic children. Uncomplicated hilar adenopathy remains the most common disease manifestation in children and is usually regarded as the hallmark of primary TB. However, the pre-chemotherapy literature documented transient hilar adenopathy in the majority of children following recent primary pulmonary infection, of whom only a small minority progressed to disease. The natural history of disease illustrates that progression to disease is indicated by the onset of persistent, non-remitting symptoms, while the complete absence of symptoms usually indicates good organism containment. By convention, asymptomatic hilar adenopathy is currently treated as active disease, but, in terms of pathophysiology, microbiology, and natural history, asymptomatic hilar adenopathy is more indicative of recent primary infection than active disease. This indicates that radiologic signs should be interpreted with caution in the absence of clinical data. The entity of so-called ‘asymptomatic childhood TB’, where the case definition rests exclusively on radiographic criteria, is a case in point. In reality, differences in patient selection may result in the use of different functional case definitions even though the definitions appear similar on paper. In non-endemic areas where active contact tracing is diligently enforced, more children with transient radiological signs indicative of recent primary infection will be identified, and those with active disease will be diagnosed at an earlier, less advanced stage. Active contact tracing is rarely enforced in endemic areas and children usually present to healthcare facilities with suspicious symptoms and more advanced disease. Unlike asymptomatic contacts in whom visible radiologic signs probably indicate recent primary infection only, radiologic signs in symptomatic children indicate active disease. From a research perspective it is important to be aware of these differences, as inconsistent case definitions may confound the scientific interpretation of results. In everyday practice, distinguishing between the signs and symptoms of recent primary infection and active disease is less relevant in high-risk children (< 3 years of age and/or immune compromised) in whom infection more frequently (and sometimes more rapidly) progresses to disease.
RISK STRATIFICATION The natural history of disease demonstrates that age is the most important variable that determines the risk of progression to disease following primary M. tuberculosis infection in immune-competent children (Fig. 14.2). Infants are at highest risk; the risk drops but stays appreciable in the second year of life, to reach its lowest level in children infected between 5 and 10 years of age. Children with HIV infection and/or other forms of immune compromise, such as severe malnutrition, seem to experience a similar high risk as very young (< 2 years of age) immune immature children.39–42 The vast majority (> 95%) of children who progress to disease do so within 12 months of primary infection, and therefore it seems prudent to categorize all children < 3 years of age and/or immune-compromised children as high risk. Because of the frequency and rapidity with which disease progression may occur, exposure to and/or infection with M. tuberculosis warrants preventive chemotherapy in this high-risk group.
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Immune-competent children 3 years of age are at low risk of progression to disease following primary infection. However, as the vast majority of children in endemic areas become infected after 2– 3 years of age, these low-risk children still contribute a significant percentage of the total disease burden.43 In addition, although these children are at low risk of progression to disease, latent infection with M. tuberculosis poses a small risk of future reactivation disease. In non-endemic areas, where transmission rates are low and eradicating the pool of latent infection is an achievable aim, the provision of preventive therapy to these low-risk children is warranted. In endemic areas, where the majority of disease in immune-competent adults results from ongoing transmission and not from reactivation,44 the provision of preventive therapy following exposure and/or infection becomes less relevant. The major diagnostic challenge in this low-risk group is the differentiation between latent infection and active disease. Fortunately, the natural history of disease demonstrates that active disease is accompanied by persistent, non-remitting symptoms and disease progression is usually slow, which provides a window of opportunity for symptom-based diagnosis.
DISEASE DIVERSITY Childhood TB is often reported as a single disease entity, although it represents a diverse spectrum of pathology, and one of the obstacles has been the lack of standard descriptive terminology. Accurate disease classification is important, because of its prognostic significance and to facilitate scientific communication and optimal case management. Within the Ghon focus containment is usually successful, but disease progression may result from either poor or ‘excessive’ containment.19,36 Poor containment and unrestrained organism proliferation may cause progressive parenchymal damage, with ultimate breakdown of the Ghon focus. Infants and severely malnourished and/or HIV-infected children, who have poor cellmediated immune responses, are most vulnerable to this type of cavitation.2,19,39,45 These are also the groups at greatest risk of disseminated (miliary) disease. In contrast, immune-competent adolescents seem to mount an ‘excessive’ (damaging) immune response in an attempt to contain the organism. The exact immune mechanisms underlying adult-type disease remain uncertain, but it is a striking observation that it only emerges as children enter into puberty. It is important to remember that children with adult-type disease are frequently sputum smearpositive,46,47 and that they do contribute to disease transmission, particularly in congregate settings such as schools. Complications that arise from affected lymph nodes are most common in children < 5 years old, due to exuberant lymph node enlargement and small airway size. Radiologic signs vary from segmental or lobar hyperinflation with partial obstruction and a check-valve effect, to segmental or lobar collapse with total obstruction and resorption of distal air. The pathology that results when a diseased lymph node erupts into an airway and caseous material is aspirated depends on the dose and virulence of the bacilli aspirated. The pathology may range from transient parenchymal consolidation, resulting from a pure hypersensitivity response to dead bacilli and/or toxic products, to an expansile pneumonic process with progressive caseating pneumonia, which frequently leads to parenchymal destruction and cavity formation within the affected lobe. Thus cavitary disease in children may result from three distinct pathologic processes:
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The natural history of tuberculosis infection and disease in children
1. poor containment at the site of organism deposition (very young and/or immune-compromised children); 2. aspiration of live bacilli when a diseased lymph node erupts into an airway, with destructive caseating pneumonia in the distal segment or lobe (children < 5 years of age); and 3. from adult-type disease (mainly children > 10 years of age). In conclusion, the natural history of disease identifies two major challenges regarding the diagnosis of TB in childhood. The first challenge is to identify any untreated infection (primary or reinfection), with a
REFERENCES 1. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:278–285. 2. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis — a critical review of the literature from the prechemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402. 3. Opie E, McPhedran FM, Putnam P. The fate of children in contact with tuberculosis: the exogenous infection of children and adults. Am J Hyg 1935;22:644–682. 4. Pope AS, Sartwell MD, Zacks D. Development of tuberculosis in infected children. Am J Public Health 1939;29:1318–1325. 5. Brailey M. A study of tuberculous infection and mortality in the children of tuberculous households. Am J Hyg 1940;31:Sec A1–43. 6. Gedde-Dahl T. Tuberculous infection in the light of tuberculin matriculation. Am J Hyg 1952;56:139–214. 7. Bentley FJ, Grzybowski S, Benjamin B. Tuberculosis in Childhood and Adolescence. The National Association for the Prevention of Tuberculosis. London: Waterlow, 1954:1–253. 8. Davies PDB. The natural history of tuberculosis in children. Tubercle 1961;42(suppl):1–40. 9. Miller FJW, Seal RME, Taylor MD. Tuberculosis in Children. London: Churchill, 1963: 79–163. 10. Zeidberg LD, Gass RS, Dillon A, et al. The Williamson County tuberculosis study: a twentyfour-year epidemiologic study. Am Rev Resp Pulm Dis 1962;87:1–41. 11. Wallgren A. Primary pulmonary tuberculosis in childhood. Am J Dis Child 1935;49:1105–1136. 12. Wallgren A. Pulmonary tuberculosis—relation of childhood infection to disease in adults. Lancet 1938;1:5973–5976. 13. Wallgren A. The time-table of tuberculosis. Tubercle 1948;29:245–251. 14. Brailey M. Prognosis in white and colored tuberculous children according to initial chest x-ray findings. Am J Public Health 1943;33:343–352. 15. Lincoln EM, Sewell EM. Tuberculosis in Children. New York: Mc Graw-Hill, 1963:1–315. 16. Miller FJW, Seal RME, Taylor MD. Tuberculosis in Children. London: Churchill, 1963: 163–275, 466-587. 17. Schaaf HS, Nel ED, Beyers N, et al. A decade of experience with Mycobacterium tuberculosis culture from children: a seasonal influence on incidence of childhood tuberculosis. Tuberc Lung Dis 1996;77:43–46.
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high degree of sensitivity and specificity in immune-compromised children, as this would identify children at high risk of disease progression who may benefit from preventive chemotherapy. The second challenge is to identify active disease as early as possible so that these children can be treated appropriately to reduce the high morbidity and mortality associated with childhood TB. It seems important to incorporate the lessons learnt from the natural history of disease in order to develop a rational and well-focused approach to childhood TB that will improve service delivery to children in high-burden settings with limited resources.
18. Grange JM, Gandy M, Farmer P, et al. Historical declines in tuberculosis, nature, nurture and the biosocial model. Int J Tuberc Lung Dis 2001; 5:208–212. 19. Marais BJ, Donald PR, Gie RP, et al. Diversity of disease manifestations in childhood pulmonary tuberculosis. Ann Trop Paediatr 2005;25:79–86. 20. Rich A. The Pathogenesis of Tuberculosis, 2nd edn. Springfield, IL: CC Thomas, 1951: 314–880. 21. Van der Spuy GD, Warren RM, Richardson M, et al. Use of genetic distance as a measure of ongoing transmission of Mycobaterium tuberculosis. J Clin Microbiol 2003;41:5640–5644. 22. Van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999,341:1174–1179. 23. Riley RL. Airborne infection. Am J Med 1974;57:466–475. 24. Balasubramanian V, Wiegeshaus EH, Taylor BT, et al. Pathogenesis of tuberculosis: pathway to apical localization. Tuberc Lung Dis 1994;74: 168–178. 25. Dannenberg AM. Immune mechanisms in the pathogenesis of pulmonary tuberculosis. Rev Infect Dis 1989;11(Suppl 2):S369–S378. 26. Rieder HL. The Epidemiologic Basis of Tuberculosis Control. Paris: International Union against Tuberculosis and Lung Disease, 1999. 27. Converse PJ, Dannenberg AM, Estep JE, et al. Cavitary tuberculosis in rabbits by aerosolized virulent tubercle bacilli. Infect Immunol 1996;64: 4776–4787. 28. Lopez B, Aguilar D, Orozco H, et al. A marked difference in pathogenesis and immune response induced by different Mycobacterium tuberculosis genotypes. Clin Exp Immunol 2003;133:30–37. 29. Manabe YC, Dannenberg AM, Tyagi SK, et al. Different strains of Mycobacterium tuberculosis cause various spectrums of disease in the rabbit model of tuberculosis. Infect Immunol 2003;71:6004–6011. 30. Zahrt TC. Molecular mechanisms regulating persistent Mycobacterium tuberculosis infection. Microb Infect 2003;5:159–167. 31. Boom WH, Canaday DH, Fulton SA, et al. Human immunity to M. tuberculosis: T cell subsets and antigen processing. Tuberculosis 2003;83:98–106. 32. Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Resp Crit Care Med 1994;15:1460–1462. 33. Alcaide J, Altet MN, Plans P, et al. Cigarette smoking as a risk factor for tuberculosis in young adults: case control study. Tuberc Lung Dis 1996;77:112–116.
34. Gajalakshmi V, Peto R, Kanaka TS, et al. Smoking and mortality from tuberculosis and other diseases in India: a retrospective study of 43000 adult male deaths and 35000 controls. Lancet 2003;362: 1243–1244. 35. Dannenberg AM. Roles of cytotoxic delayed-type hypersensitivity and macrophage-activating cellmediated immunity in the pathogenesis of tuberculosis. Immunobiology 1994;191:461–473. 36. Marais BJ, Gie RP, Schaaf HS, et al. A proposed radiologic classification of childhood intra-thoracic tuberculosis. Pediatr Radiol 2004;33:886–894. 37. Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of disease in children treated for tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006;10:732–738. 38. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuberculosis—old wisdom and new challenges. Am J Resp Crit Care Med 2006;173: 1078–1090. 39. Palme IB, Gudetta B, Giesecke J, et al. Impact of HIV 1 infection on clinical presentation, treatment, outcome and survival in a cohort of Ethiopian children with tuberculosis. Pediatr Infect Dis J 2002;21(11):1053–1061. 40. Madhi SA, Huebner RE, Doedens L, et al. HIV-1 coinfection in children hospitalised with tuberculosis in South Africa. Int J Tuberc Lung Dis 2000;4:448–454. 41. Hesseling AC, Westra AE, Werschkull H, et al. Outcome of HIV-infected children with cultureconfirmed tuberculosis. Arch Dis Child 2005;90: 1171–1174. 42. Marais BJ, Hesseling AC, Gie RP, et al. The burden of childhood tuberculosis and the accuracy of community-based surveillance data. Int J Tuberc Lung Dis 2006;10:259–263. 43. Shimeles D, Lulseged S. Clinical profile and pattern of infection in Ethiopian children with severe protein-energy malnutrition. East Afr Med J 1994;71:264–267. 44. Weber HC, Beyers N, Gie RP, et al. The clinical and radiological features of tuberculosis in adolescents. Ann Trop Paediatr 2000;20:5–10. 45. Marais BJ, Gie RP, Hesseling AC, et al. Adult-type pulmonary tuberculosis in children aged 10-14 years. Pediatr Infect Dis J 2005;24:743–744. 46. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999;341:1491–1495. 47. Goussard P, Gie RP, Kling S, et al. Expansile pneumonia in children caused by Mycobacterium tuberculosis: clinical, radiological, and bronchoscopic appearances. Pediatr Pulmonol 2004;38:451–455.
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Human tuberculosis due to Mycobacterium bovis and related animal pathogens John M Grange and Alimuddin I Zumla
INTRODUCTION AND HISTORY A zoonosis is a human infectious disease due to a microorganism for which the maintenance host is an animal. In the case of mycobacteria, the zoonosis of major importance is human TB of bovine origin, with the causative organism being Mycobacterium bovis. With the introduction of more discriminating methods for identifying members of the Mycobacterium tuberculosis complex, other species have been found to be of zoonotic importance, principally Mycobacterium caprae, which causes disease in goats. Although disease due to Mycobacterium avium occurs in humans, as described in Chapter 7, this cannot be regarded as a zoonosis as the principal reservoir from which humans are infected is the environment.
BOVINE TUBERCULOSIS A chronic wasting disease of cattle has long been recognized but its relationship to human disease, though suspected, was not at all clear until the late nineteenth century. In the eighteenth century a disease of cattle, now identified as bovine TB, was known in Germany as Perlsucht (pearl disease) because of the characteristic pearl-like granulomas found on the pleura of affected animals. The disease was considered to be a variant of syphilis and legislation to ensure safe disposal of affected carcasses was introduced. The relationship between bovine and human TB was confirmed in a meticulous series of studies, published in 1868, by Jean Antoine Villemin (Fig. 15.1) in which he demonstrated that rabbits inoculated with material from lesions in affected cattle and humans developed an identical TB-like disease.1 He observed, however, that bovine material appeared more virulent. The causative agent of TB was discovered by Robert Koch in 1882 but he did not differentiate between isolates of human and bovine origin. Indeed, Koch believed that all ‘tubercle bacilli’ were identical and urged the development of public health measures to protect the human population from infection from bovine sources. It was therefore in a climate of scepticism that, in 1898, Theobold Smith2 published his findings that tubercle bacilli from humans and cattle differed in small but constant ways. He also found, thereby confirming the observations of Villemin, that bovine isolates were more virulent for the rabbit than human isolates. Although referring to his isolates as the human and bovine tubercle bacilli, Smith warned against the assumption that disease due to these variants was limited to the species from which they were isolated.
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Unfortunately, Robert Koch made this assumption and radically altered his views on the importance of bovine TB control measures. At the British Congress on Tuberculosis held in London in 1901 he stated that ‘the human subject is immune against infection by bovine bacilli or is so slightly susceptible that I do not consider it necessary to take any measures to counteract the risk of infection’. Fortunately, the meeting was attended by several distinguished veterinary surgeons and medical scientists, including Lord Lister, who were certain that Koch was mistaken and were able to convince the British Government to establish a Royal Commission to investigate the matter. The Royal Commissioners undertook a 10-year programme of research which established beyond doubt that, although the human and bovine tubercle bacilli did differ in certain characteristics, humans must, in the words of the Royal Commission’s final report published in 1911, ‘be added to the list of animals notably susceptible to bovine tubercle bacilli’. The Royal Commission also laid the scientific foundations for the test-and-slaughter programmes that were eventually to have such a dramatic effects on the control of TB in cattle and, thereby, on human health.3 The bovine TB eradication schemes rank among the most successful campaigns ever waged against an infectious disease and the great debt owed to the scientists employed by the Royal Commission as well as to the veterinary profession in general should never be forgotten.
TUBERCULOSIS IN CATTLE AND OTHER MAMMALS As discussed in Chapter 6, M. bovis is a member of the M. tuberculosis complex and, although having very close, over 99%, genetic similarity with M. tuberculosis, it differs in several important features, notably the broad range of mammals susceptible to disease. Tuberculosis in cattle is almost always acquired by inhalation and the lung is the primary focus of disease. Tuberculin conversion occurs before the development of detectable lesions and such animals are said to be non-visibly lesioned (NVL) and are generally regarded as being non-infectious. Subsequently, granulomatous lesions containing large numbers of acid-fast bacilli develop in the lungs and the mediastinal and subpleural lymph nodes. The latter have a pearl-like appearance and, as mentioned earlier, this condition has been termed pearl disease. Dissemination to other organs may occur and, although TB mastitis occurs in only around 1% of overtly diseased cattle, this is important as a cause of transmission of infection to humans.
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Human tuberculosis due to Mycobacterium bovis and related animal pathogens
15
BOVINE TUBERCULOSIS IN THE DEVELOPING NATIONS A World Health Organization survey conducted in 1998 showed that information on the occurrence and prevalence of bovine TB in developing countries is rather fragmentary, as summarized in Table 15.1.5 A full account of the distribution of TB in cattle world-wide is beyond the scope of this chapter but detailed surveys covering all countries, and specifically Africa, have been published.6–8 Rights were not granted to include this content in electronic media. Please refer to the printed book.
TUBERCULOSIS IN OTHER ANIMALS The many hosts of M. bovis include feral and wild animals, including those in zoos and game parks, and farmed animals, especially cattle.9 Only a few of the many animals susceptible to TB are maintenance (reservoir) hosts – most are spillover (end) hosts. In addition to cattle, important maintenance hosts of disease are African buffalos, bison, deer, badgers (especially in the UK), the brush tailed possum (in New Zealand), and the elk in Canada.10 It is now appreciated that some closely related strains within the M. tuberculosis complex given separate species names (see Chapter 6) are also primarily pathogens of animals although humans may be infected. These include M. caprae (previously M. bovis subsp. caprae) originally isolated from goats but also from cattle, pigs, captive wild boar, and red deer, and Mycobacterium pinnipedii isolated from seals.11,12
Fig. 15.1 Jean-Antoine Villemin (1827–1892). The first to demonstrate experimentally the transmissibility of TB. Grange JM. Mycobacteria and Human Disease. 2nd edition. London: Arnold. 1996. Page 3.
BOVINE TUBERCULOSIS IN THE INDUSTRIALLY DEVELOPED NATIONS Tuberculosis was once widespread in cattle throughout Europe and the USA but the incidence has been very greatly reduced by the control measures described below. Complete elimination has not been achieved as a result of infection of cattle by wild animals and by humans with TB of bovine origin. In the UK, there is strong evidence that cattle in some regions acquire TB from the badger (Meles meles). Overall, in the UK, the number of tuberculin-positive cattle slaughtered rose from 638 in 1986 to 5,884 in 1998 and 22,571 in 2004, amounting to an increase of around 20% annually. This poses a serious veterinary and public health problem to which there is no easy solution. Although the exact impact of infected badgers on the incidence of bovine TB is not clear, it is noteworthy that the great majority of infected cattle have been detected in regions where diseased badgers have been found. Vaccination or selective culling of infected badgers is considered impractical and widespread culling has met with public opposition, especially as its efficacy has not been determined. Indeed there is some evidence that this strategy may even increase the reactor rate in cattle by extending the territorial range of surviving badgers and, thereby, opportunities for contact with cattle.4
THE NATURE OF ZOONOTIC TUBERCULOSIS Humans acquire TB from animals, notably cattle, by three routes – inhalation, ingestion of derivative products, and traumatic inoculation.
INHALATION As the lung is the main site of TB in cattle, farmers, veterinary surgeons, and other workers in close contact with diseased animals are principally infected by the aerogenous route. In pastoralist communities in developing countries, notably Africa, humans often live in close proximity to their cattle, increasing the risk of aerogenous transmission of disease. Workers in abattoirs are at risk of pulmonary infection by aerosols generated during the handling of diseased animal carcasses.13 Although cattle are the usual source of human infection, tuberculin conversion and, rarely, overt disease have followed exposure to other diseased animals including elk, seals, and zoo animals. In one illustrative case, a seal trainer became tuberculin positive while working with an infected animal, and in another case seven of 24 zoo attendants
Table 15.1 The occurrence of bovine tuberculosis in the developing nations Region
Africa Asia Latin America and Caribbean
Number of countries in region Total
High occurrence
Low and sporadic occurrence
Not reported
No data
Test and slaughter policy
55 36 34
8 1 8
25 16 12
4 10 12
18 9 2
7 7 12
Data taken from 5. Cosivi O, Grange JM, Daborn CJ, et al. Zoonotic tuberculosis due to Mycobacterium bovis in developing countries. Emerg Infect Dis 1998;4:59–70.
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converted to tuberculin reactivity following occupational exposure to a rhinoceros with tuberculous rhinitis over a 6-month period; all received isoniazid preventive therapy and none became ill.14,15 In an outbreak of TB in farmed elk in Alberta, Canada, 81 of 394 people in contact with diseased animals became tuberculin positive but only one developed TB.16 Strains of M. caprae have been isolated from humans, including one isolate from a veterinary surgeon with a recent history of working with tuberculous goats.17 More surprisingly, a third of cases of human TB in Germany, mostly in the south of the country, between 1999 and 2001 and originally thought to be due to M. bovis were found to be due to M. caprae.11 The patients were mostly elderly, and in the same age range as those with disease due to M. bovis and were therefore thought to have disease due to reactivation of infection acquired years or decades ago.
INGESTION OF DERIVATIVE PRODUCTS Town dwellers not exposed directly to animals are at risk of disease if they consume milk containing M. bovis. Although only a small proportion of tuberculous cattle, around 1%, have overt mastitis and excrete tubercle bacilli in their milk, the practice of pooling milk from several animals in churns, or even from several herds in tankers, renders many people prone to infection from a small number of animals. In 1945, M. bovis was isolated from 8% of churn milk samples and from the great majority of samples from 3,000-gal. tankers in the UK.18 In developing countries, milk drawn directly from cows forms an important component of the diet of adults and children. In some communities the milk is soured before consumption by adding fresh milk to some soured milk and storing it for a few days but it is doubtful if it kills mycobacteria to a significant degree.19 Although bovine TB control programmes and pasteurization of milk (see below) have almost eliminated the risk of milk-borne infection in countries where these are applied, importation of milk derivatives from other regions poses a health risk. Between 2001 and 2004, 35 cases of newly diagnosed TB, about 1% of the total, in New York City were due to M. bovis.20 Most patients were of Mexican or South American origin and many reported eating unpasteurized cheese imported from Mexico which could therefore have been a vector of the disease. In this context, M. bovis may survive for up to 100 days in butter and for almost 1 year in certain cheeses prepared from unpasteurized milk.
areas were less likely to develop overt TB after infection than those living in towns and cities.21 It was postulated that the differences in the proportion of those infected developing overt TB (the disease ratio) was due to a higher proportion of those in rural areas being infected with M. bovis. This postulate does not, however, take into account many confounding factors, such as the timing of the initial infection, the infective dose and route of infection, and various factors in the rural environment that might enhance resistance to disease. Human TB due to M. bovis can certainly be as severe as that due to M. tuberculosis, but so can disease due to environmental mycobacteria. Indeed, those infected by the aerogenous route are at risk of developing pulmonary TB which, in its clinical manifestations, is indistinguishable from that caused by M. tuberculosis.22 Another aspect of the pathogenesis of M. bovis is its postulated ability to generate protective immunity against disease due to M. tuberculosis. In the early twentieth century there was a belief, known as Marfan’s Law, that children who developed and recovered from tuberculous lymphadenitis due to consumption of milk were immune to more serious pulmonary TB later in life. Although regarded by some as a highly dubious proposition, it may explain the finding in Burkino Faso that the incidence of human pulmonary TB is five times greater in regions where bovine TB is rare than in regions where it is common, suggesting a protective effect of milk-borne infection.23 In this context, a temporary rise in the incidence of human TB occurred in Scandinavia at the time when bovine TB was controlled, a finding that even led to the suggestion that, by removing natural immunization, bovine TB control schemes had an adverse effect on the prevalence of human TB.24 Ingestion of bacilli, principally in raw milk, leads to implantation in the tonsil or the intestine, usually in the ileocaecal region. Lymphatic spread to the draining lymph nodes results, respectively, in cervical and mesenteric lymphadenopathy. Cervical lymphadenopathy, also known as scrofula, following ingestion of M. bovis usually involves the tonsillar nodes around the angle of the jaw and, less often, the preauricular nodes (Fig. 15.2). This is in contrast to superclavicular
TRAUMATIC INOCULATION Workers handling contaminated carcasses and meat in abattoirs and butchers’ shops are at risk of skin lesions due to traumatic inoculation of bacilli. The resulting lesions, usually on the hands, are termed butchers’ warts and are similar in pathogenesis and appearance to prosectors’ warts acquired by pathologists and anatomists.
PATHOGENESIS AND CLINICAL FEATURES OF ZOONOTIC TUBERCULOSIS It is widely assumed that M. bovis is much less virulent for humans than M. tuberculosis, an assumption never formally proven. One major difficulty in addressing the question of relative virulence is the inability of the tuberculin test to distinguish between latent TB due to the two species. Tuberculin testing surveys in Denmark before bovine TB was eradicated indicated that those living in rural
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Fig. 15.2 Tuberculous cervical lymphadenitis (scrofula) showing enlarged lymph nodes and sinuses around the angle of the jaw.
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lymphadenopathy in the lower part of the neck that sometimes presents as an upward extension of a primary pulmonary complex due, usually, to M. tuberculosis. In the early stages of the disease, the affected lymph nodes are painless and have a firm rubbery texture. Subsequently the nodes undergo central caseous necrosis and become fluctuant on palpation. The necrosis may spread out of the lymph node and through the fascia of the neck, resulting in a superficial abscess. Rupture of the disease process through the skin results in sinus formation and chronic spreading skin lesions with the characteristics of lupus vulgaris – a condition termed scrofuloderma. Involvement of the intestine and mesenteric lymph nodes leads to the various forms of abdominal TB as described in Chapters 39 and 40. Further lymphatic and haematogenous spread may lead to disease in other organs including bones, joints, the central nervous system, and the kidney. As discussed below, the kidney is a frequent site of reactivation disease. The reason for this is unknown, one possibility being that the relatively low oxygen tension may favour the growth of M. bovis which, in contrast to M. tuberculosis, is microaerophilic.25 The clinical and pathological features of renal TB caused by M. bovis are identical to those of disease caused by M. tuberculosis with, in some cases, extensive destructive lesions leading to renal failure.26 Many cases of lupus vulgaris, a very chronic form of skin TB which often involves the face and, if untreated, may lead to gross disfigurement, are caused by M. bovis. In the UK half the cases of lupus vulgaris reported by Griffith in 1932 were caused by M. bovis, and a study of six cases in the late 1960s showed that five were caused by M. bovis and one by an organism with features intermediate between M. bovis and M. tuberculosis.27 Subsequently this form of TB became extremely rare in the UK and a single case reported in 1986, in a 75-year-old woman, was caused by M. bovis.28 These findings suggest, but do not prove, that M. bovis is more likely to cause this form of TB than M. tuberculosis.
CHANGING TRENDS IN THE OCCURRENCE OF ZOONOTIC TUBERCULOSIS IN THE INDUSTRIALLY DEVELOPED NATIONS The bovine TB eradication programmes conducted in many industrially developed nations have made very significant impacts on the epidemiology of zoonotic TB.5,29–33 In the early part of the twentieth century, when bovine TB was common in Europe and North America, most cases of human TB due to M. bovis occurred in young people and were non-pulmonary. Table 15.2 shows that M. bovis was responsible for a high percentage of cases of non-pulmonary TB, particularly in children, with the notable exception of genitourinary disease. At that time, pulmonary disease due to M. bovis was considered a rarity – by 1922 only four cases had been reported in the UK – but more cases were found when actively sought and were relatively more common in rural areas.27 The few cases of TB due to M. bovis seen in the older population in countries that have had effective bovine TB in place for many years are assumed to be predominantly the result of late endogenous reactivation after a long period of latency – a concept supported by spoligotyping, which shows that bacilli isolated from elderly patients are of types not currently seen in cattle.34 The annual number of new cases of human TB due to M. bovis in the
15
Table 15.2 Cases of non-pulmonary tuberculosis reported in England and Wales, 1901–1932, and the percentage of cases caused by M. bovis Type of disease
Number of cases
Cervical node Lupus vulgaris Scrofuloderma Bone/joint Genitourinary Meningitis Other
Percentage of cases caused by M. bovis (%)
126 191 60 553 23 265 23
<5 years of age
5–15 years of age
All ages
91 58 53 30 0 28 33
53 44 43 19 0 25 9
50 49 37 20 17 25 9
UK in the period 1990–2003 varied from 17 to 50 – between 0.5% and 1.5% of cases of TB confirmed by culture.35 Irrespective of the site of primary infection, the lung is the most frequent site of post-primary TB, so that this organ is the commonest site of disease in older patients in countries where primary infection by M. bovis is now very rare.36 The distribution of types of disease in some countries and regions after the completion of their respective bovine control programmes are shown in Table 15.3. In addition, 13 patients (0.95% of all cases of TB) with disease due to M. bovis were seen in a hospital in Madrid, Spain, between 1994 and 1999; the mean age of the patients was 50 years (range 23–83 years) and 10 of the 13 patients, including four who were human immunodeficiency virus (HIV)-infected, had pulmonary disease.37 Genitourinary disease has also become relatively more common. In the years 1975–1980 in the German state of Hessen, where bovine TB had been virtually eradicated by 1961, M. bovis was isolated from 47 of 4498 patients (1%) with pulmonary TB and 23 of 3834 patients with non-pulmonary lesions (0.8%) and, of the latter, 15 had genitourinary TB.38 Since the completion of the bovine TB eradication programmes in the UK, cattle-to-human spread of infection resulting in overt disease has become extremely rare but one illustrative case, confirmed by spoligotyping, has been reported.34
Table 15.3 Type of tuberculosis caused by M. bovis in countries and regions with a low risk of infection from cattle Type of disease
England South-east Ontario, Southern and Wales, England, Canada, Sweden, 1962–1966 1977–1990 1964–1970 1936–1939
Pulmonary Non-pulmonary Genitourinary Lymphadenitis Bone/joint Meningeal Abdominal Other
65 37 25 6 4 2 0 0
94 138 53 39 26 8 8 4
13 18 12 4 1 0 1 0
54 40 12 12 9 4 3 0
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THE OCCURRENCE OF ZOONOTIC TUBERCULOSIS IN THE DEVELOPING WORLD Tuberculosis due to M. bovis is under-recognized and underreported in the developing nations owing to a lack of laboratory facilities for differentiating this species from M. tuberculosis.39 In Tanzania there is a definite relation between the incidence of non-pulmonary TB and the number of cattle owned by the human population in rural regions and in one high-incidence area M. bovis was grown from four of 11 biopsies from patients with cervical lymphadenitis.40 In a further study in the same region, 65 specimens from 457 patients with suspected mycobacterial lymphadenitis were culture positive: seven M. bovis, 27 M. tuberculosis, and 31 environmental mycobacteria.41 Risk factors for disease due to M. bovis were HIV infection and ingestion of raw milk. Studies in other parts of Africa have revealed cases of pulmonary TB due to M. bovis. In Egypt, three surveys on the percentage of such pulmonary cases were, respectively, 0.4%, 5.4%, and 6.4%, and in Nigeria four of 102 cases were caused by M. bovis.42,43 In a further study in Egypt, nine of 20 randomly selected cases of tuberculous peritonitis were caused by M. bovis.44 A report in the year 2000 showed that a third of positive cultures from children living on the USA–Mexico border were M. bovis.45 Most of these children were of Mexican origin and over half had pulmonary disease. Epidemiological studies in Zambia showed that pastoralist families with a case of TB during the previous year were seven times more likely to own herds of cattle containing tuberculin reactors than unaffected families but the cause of the disease in the patients was not confirmed bacteriologically.46 In South America, a conservative estimate is that 2% of cases of pulmonary TB and 8% of nonpulmonary TB cases are due to M. bovis, with higher incidences in areas where the dairy industry is concentrated.5 There is limited information on human TB of bovine origin in Asia. The use of discriminative polymerase chain reaction-based technology in one centre in India has shown that disease due to M. bovis occurs in humans and cattle and that 8.7% and 35.7% of non-pulmonary lesions from humans and cattle, respectively, contained both M. bovis and M. tuberculosis.47 The significance of such apparent mixed infection for transmission of disease between humans and cattle and vice versa requires careful investigation.
THE EPIDEMIOLOGY OF ZOONOTIC TUBERCULOSIS Humans are spillover hosts of M. bovis, which is principally transmitted between animals, either wild or farmed. There is, however, evidence that cycles of animal-to-human, human-to-human, and human-toanimal transmission may occasionally occur. The advent of the HIV/ acquired immunodeficiency syndrome (AIDS) pandemic, by reducing resistance of the human population, could well lead to an increased frequency of human-to-human and human-to-animal transmission, principally by the aerogenous route, with serious public and veterinary health consequences.40,48,49
HUMAN-TO-HUMAN TRANSMISSION: THE IMPACT OF IMMUNOSUPPRESSION Until recently there have been only a few well-documented cases of human-to-human transmission of M. bovis leading to overt disease.50,51 While the apparent rarity of disease due to such transmission has been
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attributed to the presumed lower virulence of M. bovis for humans, it could also be the result of the difficulties in establishing proof, especially as many years may separate the presentation of linked cases. As described in Chapter 10, HIV infection greatly increases the risk of developing active TB after infection by a tubercle bacillus. Thus the advent of the HIV/AIDS pandemic has led to an increase in reports of TB resulting from human-to-human transmission of M. bovis, including some mini-epidemics. In a nosocomial outbreak in Paris, human-to-human transmission of a multidrug-resistant strain of M. bovis resulted in five HIV-infected patients presenting with overt disease within 10 months of exposure to the source case.52 In Spain, 19 profoundly immunosuppressed patients with HIV disease developed TB caused by M. bovis resistant to 11 anti-TB drugs and all the patients died.53
HUMAN-TO-ANIMAL TRANSMISSION There have been several reports of farm workers with open TB due to M. bovis infecting cattle.22,54,55 In North Bavaria, Germany, 49 infected herds were detected between 1973 and 1984 and a human source was found to be the cause in 16 (33%) of these. Exposure to diseased cattle was considered responsible for eight of the other 33 outbreaks but no cause was found for the remainder.56 A case with clear evidence of transmission from cattle to a human and back to cattle has been documented in Switzerland.57 The usual route of transmission of infection from humans to cattle is by cough spray from farm workers with open pulmonary lesions but a substantial minority of workers have genitourinary TB and infect cattle by the apparently common practice of urinating on the hay in cowsheds. In an investigation of 50 cases of infection of cattle by farm workers in Europe, 24 of the source cases were found to have genitourinary TB.58 Between 1968 and 1972, 12 farmers in the German state of Hessen infected 114 cattle in 16 herds.59 Nine of the 12 farmers had genitourinary TB and one of them infected 48 cattle in four herds. Other more unusual activities, including certain traditional customs, could also result in infection of animals. These include the practice of spitting well-chewed tobacco into the mouths of cattle with the aim of restoring appetite and the bizarre but more physiologically sound practice of blowing forcibly into the vagina of a cow to inflate the uterus, thereby causing release of oxytocin which stimulates milk production.48 The effect of HIV disease on the risk of developing overt TB of bovine origin after infection has been mentioned earlier. As a result, it is possible that a high incidence of HIV disease in agricultural communities could result in more cases of human TB of bovine origin and a transmission of the disease back to cattle, with serious public and veterinary health consequences (Fig. 15.3). 40,48,49 Humans can infect cattle with M. tuberculosis by the aerogenous route, resulting in transient tuberculin conversion and, in some cases, small self-limiting lesions in the lungs and mediastinal lymph nodes but very rarely overt disease.55,60 In one case in Slovenia, 16 tuberculin reactors were detected in a previously non-reactive herd and the three strongest reactors were slaughtered.61 The mandibular, mediastinal, and portal lymph nodes were cultured and M. tuberculosis was isolated from one animal and was identical on DNA fingerprinting to a strain isolated from a farm worker with pulmonary TB. Human TB should therefore be excluded as a cause of tuberculin reactivity in previously non-reactive herds, especially in regions where this disease is common in the human population.
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A
15
B
Fig. 15.3 The cycle of infection between cattle and human beings. (A) In a non-immunocompromised community. (B) In a community containing immunocompromised individuals.
PREVENTION OF ZOONOTIC TUBERCULOSIS The risk of infection of the human population has been greatly reduced in many countries by bovine TB control programmes and pasteurization of milk. In early control programmes animals with overt disease were removed from herds and slaughtered, but with limited effect. Following studies by the British Medical Research Council, the importance of removing infected animals before the development of detectable lesions was established and this formed the basis of all subsequent effective eradication programmes.62 At the end of the Second World War, it was estimated that 30–35% of dairy cows in the UK were tuberculin reactors and a compulsory test-and-slaughter programme commenced in 1950. By 1961 the annual reactor rate had dropped to 0.16% and by 1965 it had dropped to 0.06%, with reactors in only 1% of herds. By 1979 only 0.18% of herds contained infected animals and this may be an irreducible minimum owing to infection from wild animals, such as the badger in the UK. The bovine TB control programmes caused a rapid and sharp decline in the incidence of tuberculous cervical lymphadenopathy in children.63 Other forms of the disease also appeared to decline sharply in incidence, but this may in part have been due to a failure or unwillingness of laboratories to discriminate between the types of tubercle bacilli. Physicians in the UK were unwilling to mention M. bovis on notification forms as this led to enquiries from veterinary agencies and breaches of patient confidentiality. Thus, although the Public Health Laboratory Service identified 556 strains of M. bovis isolated from humans in England and Wales between 1977 and 1981, only 125 had been notified by physicians to the health authorities.62 Pasteurization is a process of heat treatment of milk that kills tubercle bacilli and most other non-sporing bacteria. Various different time/temperature combinations, such as heating to 71.7 C for 15 seconds, are used. In regions where bovine TB occurs, and facilities for the formal pasteurization of milk are unavailable, simple boiling of milk before consumption is an effective disease prevention measure.
THERAPY OF ZOONOTIC TUBERCULOSIS With rare exceptions, strains of M. bovis are naturally resistant to pyrazinamide, but susceptibility to other anti-TB agents is similar to that of M. tuberculosis. No specific recommendations for treatment are made in the World Health Organization guidelines on the therapy of TB.64 In practice most patients are likely to be treated with the standard short course of anti-TB regimens as few laboratories in the developing nations differentiate between M. tuberculosis and M. bovis or conduct drug susceptibility tests. If pyrazinamide resistance is identified, this agent may be omitted from the regimen.65 On the other hand, the American Thoracic Society recommends an initial 2-month regimen of isoniazid, rifampicin, and ethambutol followed by a 7-month continuation phase of isoniazid and rifampicin given either daily or twice weekly.66 In a study of 167 patients with TB due to M. bovis in San Diego County, California, the median time to completion of treatment was 3 months longer than for patients with disease due to M. tuberculosis.67 For reasons not clear, although the numbers of patients completing therapy were very similar, mortality among those with disease due to M. bovis (15%) was higher than that in 928 patients with disease due to M. tuberculosis (7%). Drug and multidrug resistance may develop and two miniepidemics in care facilities for patients with HIV disease have been mentioned already.52,53 The management of such cases is the same as that of disease due to drug-resistant M. tuberculosis (Chapters 52 and 53).
CONCLUSIONS Tuberculosis in animals, especially cattle, and human disease resulting from contact with such animals or consumption of derivative products including milk and cheese is a veterinary and public health problem throughout the world. Although bovine TB eradication programmes have been highly successful in eliminating the
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threat to human health in the industrially developed nations, cattle still acquire infection from human attendants and wildlife. In the UK, infection of cattle from badgers is a serious, costly, and increasing problem to which there is no straightforward solution. The contribution of bovine TB to animal and human health in many developing nations is poorly documented owing to a lack of investigational facilities but sporadic investigations indicate that the detected cases in animals and humans are like the tip of an
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iceberg. Although humans are usually spillover or end hosts, with human-to-human or human-to-animal transmission of infection being rare, the advent of the HIV/AIDS pandemic raises the distinct possibility of the establishment of cycles of transmission between humans and animals in pastoralist communities. Accordingly, cooperation between veterinary and medical workers on the problems of TB in animals and the human consequence of such disease needs to be intensified world-wide.
21. Magnus K. Epidemiological basis of tuberculosis eradication. 3. Risk of pulmonary tuberculosis after human and bovine infections. Bull World Health Organ 1966;35:483–508. 22. Magnusson H. The relationship between bovine and human tuberculosis from the veterinary point of view. Acta Med Scand 1941;135:201–239. 23. Rey JL, Villon A, Saliou P. La tuberculose bovine dans le Sahel Voltaique. Correlation avec la tuberculose humaine. Technical Document 6.678. Paris: Organisation de Cooperation et de Coordination pour la lute contre les Grandes Endemies, 1977. 24. Sjo¨gren I, Sutherland I. Studies of tuberculosis in man in relation to infection in cattle. Tubercle 1974;56: 113–127. 25. Grange JM, Yates MD, de Kantor IN. Guidelines for Speciation within the Mycobacterium tuberculosis Complex, 2nd edn. Geneva: World Health Organization, 1996. Publication WHO/EMC/ ZOO/96.4 26. Yaqoob M, Goldsmith HJ, Ahmad R. Bovine genitourinary tuberculosis revisited. Q J Med 1990;74:105–109. 27. Griffith AS. Bovine tuberculosis in man. Tubercle 1937;18:528–543. 28. Wilkins EG, Grifiths RJ, Roberts C. Bovine tuberculosis of the skin. J Infect 1986;12:280–281. 29. Grange JM, Collins CH. Tuberculosis and the cow. J R Soc Health 1997;117:119–122. 30. Grange JM, Yates MD. Zoonotic aspects of Mycobacterium bovis infection. Vet Microbiol 1994;40:137–151. 31. Grange JM. Human disease caused by Mycobacterium bovis and its attenuated derivative, bacillus CalmetteGue´rin (BCG). In: James DG, Zumla A (eds). Granulomatous Disorders. Cambridge: Cambridge University Press, 1999: 161–172. 32. Grange JM. Mycobacterium bovis infection in human beings. Tuberculosis (Edinb) 2001;81:71–77. 33. Moda G, Daborn CJ, Grange JM, et al. The zoonotic importance of Mycobacterium bovis. Tubercle Lung Dis 1996;77:103–108. 34. Gibson AL, Hewinson G, Goodchild T, et al. Molecular epidemiology of disease due to Mycobacterium bovis in humans in the United Kingdom. J Clin Microbiol 2004;42:431–434. 35. de la Rua-Domenech R. Human Mycobacterium bovis infection in the United Kingdom: Incidence, risks, control measures and review of the zoonotic aspects of bovine tuberculosis. Tuberculosis (Edinb) 2006; 86:77–109. 36. Balasubramanian V, Wiegeshaus EH, Taylor BT, et al. Pathogenesis of tuberculosis: pathway to apical localization. Tubercle Lung Dis 1994;75:168–178. 37. Esteban J, Robles P, Soledad Jimenez M, et al. Pleuropulmonary infections caused by Mycobacterium bovis: a re-emerging disease. Clin Microbiol Infect 2005;11:840–843. 38. Salfelder T, Schliesser T, Jungbluth H. Folgerungen aus dem derzeitigen Vorkommen von Mycobacterium bovis bei Mensch und Tier. Fortschr Vet Med 1983;37:141–145. (Summarized in English by Schliesser T. Prevalence of M. bovis in man 20 years after eradication of bovine tuberculosis in cattle. Bull Int Union Tuberc 1986;61(abstract book): 58–59. 39. Ayele WY, Neill SD, Zinsstag J, et al. Bovine tuberculosis: an old disease but a new threat to Africa. Int J Tuberc Lung Dis 2004;8:924–937.
40. Daborn CJ, Grange JM. HIV/AIDS and its implications for the control of animal tuberculosis. Br Vet J 1993;149:405–417. 41. Mfinanga SG, Morkve O, Kazwala RR, et al. Mycobacterial adenitis: role of Mycobacterium bovis, non-tuberculous mycobacteria, HIV infection, and risk factors in Arusha, Tanzania. East Afr Med J 2004;81:171–178. 42. Elsabban MS, Lofty O, Awad WM, et al. Bovine tuberculosis and its extent of spread as a source of infection to man and animals in the Arab Republic of Egypt. In: Proceedings of the International Union against Tuberculosis and Lung Disease Conference on Animal Tuberculosis in Africa and the Middle East, 1992 Apr 28–30, Cairo. Paris: IUATLD, 1992: 198–211. 43. Idigbe EO, Anyiwo CE, Onwujekwe DI. Human pulmonary infections with bovine and atypical mycobacteria in Lagos, Nigeria. J Trop Med Hyg 1986;89:143–148. 44. Nafeh MA, Medhat A, Abdul-Hameed A-G, et al. Tuberculous peritonitis in Egypt: the value of laparoscopy in diagnosis. Am J Trop Med Hyg 1992;47:470–477. 45. Dankner WM, Waecker NJ, Essey MA, et al. Mycobacterium bovis infections in San Diego: a clinicoepidemiological study of 73 patients and a historical review of a forgotten pathogen. Medicine 1993;72:11–37. 46. Cook AJC, Tuchili LM, Buve A, et al. Human and bovine tuberculosis in the Monze district of Zambia—a cross-sectional study. Br Vet J 1996;152:37–46. 47. Prasad HK, Singhal A, Mishra A, et al. Bovine tuberculosis in India: potential basis for zoonosis. Tuberculosis (Edinb) 2005;85:421–428. 48. Daborn CJ, Grange JM, Kazwala RR. The bovine tuberculosis cycle—an African perspective. J Appl Bacteriol 1996;81(Symposium Suppl):27S–32S. 49. Grange JM, Daborn C, Cosivi O. HIV-related tuberculosis due to Mycobacterium bovis. Eur Respir J 1994;7:1564–1566. 50. Sigurdsson J. Studies on the risk of infection with bovine tuberculosis in the rural population. With special reference to pulmonary tuberculosis. Acta Tuberc Scand 1955(Suppl 15):1–250. 51. Kubin M, Heralt Z, Morongova I. Two cases of probable man-to-man transmission of Mycobacterium tuberculosis. Z Erkrank Atmungsorgane 1984;163:285–291. 52. Bouvet E, Casalino E, Mendoza-Sassi G, et al. A nosocomial outbreak of multidrug-resistant Mycobacterium bovis among HIV-infected patients. A case-control study. AIDS 1993;7:1453–1460. 53. Cobo J, Asensio A, Moreno S, et al. Risk factors for nosocomial transmission of multidrug-resistant tuberculosis due to Mycobacterium bovis among HIVinfected patients. Int J Tuberc Lung Dis 2001;5:413–418. 54. Stenius R. Differential by tuberculin testing of infection in cattle due to human, bovine and avian types of tubercle bacilli. Vet Rec 1983;50:633–636. 55. Lesslie IW. Cross infections with mycobacteria between animals and man. Bull Int Union Tuberc 1968;41:285–288. 56. Lutz H. Untersuchungen u¨ber das Auftreten und die Erkennung von Reinfektion mit Mycobacterium bovis in Rinderbestanden in Nordbayern in den Jahren 1973 bis 1984. Inaugural dissertation, Justus Liebig Universita¨t, Giessen, Germany, 1987. 57. Fritsche A, Engel R, Buhl D, et al. Mycobacterium bovis tuberculosis: from animal to man and back. Int J Tuberc Lung Dis 2004;8:903–904.
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Human tuberculosis due to Mycobacterium bovis and related animal pathogens 58. Huitema H. The eradication of bovine tuberculosis in cattle in the Netherlands and the significance of man as a source of infection in cattle. Selected Papers of the Royal Netherlands Tuberculosis Association 1969;12:62–67. 59. Schliesser T. Die Beka¨mpfung der Rindertuberkulose—Tierversuch der Vergangenheit. Prax Pneumonol 1974;28(Suppl):870–874. 60. Krishnaswami KV, Mani KR. Mycobacterium tuberculosis humanis causing zoonotic tuberculosis among cattle. Indian J Public Health 1983;27:60–63. 61. Ocepek M, Pate M, Zolnir-Dovc M, et al. Transmission of Mycobacterium tuberculosis from human to cattle. J Clin Microbiol 2005;43:3555–3557.
62. Collins CH, Grange JM. The bovine tubercle bacillus. J Appl Bacteriol 1983;55:13–29. 63. Meissner G. Tuberkelbacterien von typus bovinus beim Menschen in den Jahren 1953-1957. Tuberk Arzt 1959;13:74–90. 64. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. Geneva: WHO, 2003. Publication WHO/CDS/TB2003.313. 65. O’Donahue WJ, Bedi S, Bittner SJ, et al. Shortcourse chemotherapy for pulmonary infection due to Mycobacterium bovis. Arch Intern Med 1985;145: 703–705.
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66. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Morb Mortal Wkly Rep 2003;52 (RR11):1–77. 67. LoBue PA, Moser KS. Treatment of Mycobacterium bovis infected tuberculosis patients: San Diego County, California, United States, 1994-2003. Int J Tuberc Lung Dis 2005;9:333–338.
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GENERAL CLINICAL FEATURES AND DIAGNOSIS
Clinical features and index of suspicion of tuberculosis in children Stephen M Graham, Ben J Marais, and Robert P Gie
Tuberculosis can present with a wide variety of clinical manifestations in children. The commonest form is pulmonary TB and this can be the most challenging to diagnose. Extrapulmonary TB accounts for around 20–25% of all childhood TB and the commonest forms are TB lymphadenitis, spinal TB, pleural effusion, abdominal TB, miliary TB, and tuberculous meningitis.1–4 The greatest burden of TB in children occurs in highly TB-endemic communities. This is often a resource-limited setting where childhood protein-energy malnutrition and/or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) may also be common. These problems lead to an increased risk of disease and challenges of management. In children at risk for TB infection, it is important to maintain a high index of suspicion for the possibility of TB as a diagnosis in many clinical contexts, especially when the child’s clinical condition fails to respond to recommended first-line care such as antibiotics for pneumonia. This chapter will outline clinical features of TB in children and discuss their diagnostic value in the context of where most cases of childhood TB present. Particular attention is given to the diagnostic approach to suspected pulmonary TB in children and to the diagnosis of sputum smear-negative pulmonary TB including in regions endemic for malnutrition and HIV. Later chapters give detail of the clinical abnormalities associated with pulmonary TB and extrapulmonary TB in children.
INTRODUCTION TO DIAGNOSIS The diagnosis of TB in children is a common clinical challenge that can be successfully overcome in the majority of cases by taking a systematic approach that makes full use of the epidemiological context, clinical information, and relevant investigations. Important factors to consider in all children with suspected TB is the endemic setting as well as the age and immune status of the child.
EPIDEMIOLOGICAL CONTEXT In countries or communities with a very low incidence of TB where childhood TB is normally rare, it is important for the clinician to be alert to the possibility of TB especially in certain groups, such as children of immigrants from TB-endemic countries.4 In this setting, diagnosis is more straightforward. A positive contact history with an infectious pulmonary TB case and suggestive symptoms such as chronic cough or failure to thrive are more specific
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for TB in non-endemic settings. In addition, this is usually in a resource-rich setting where protein-energy malnutrition and HIV infection are rare, and a wider range of investigations is readily available. A history of TB contact is also important in TB-endemic countries or communities but is less sensitive because, when the incidence of infectious TB within the community is high, transmission often occurs through unknown source cases, especially for the older child.5,6 On the other hand, because previous TB exposure and/or infection is not uncommon in older children, a history of recent contact may be less specific. A contact history has become more difficult to interpret in HIV-endemic regions where the majority of sputum smear-positive pulmonary TB cases are also HIV-infected. The children of adults with TB/HIV coinfection are at greater risk for acquiring either or both infections, yet there is considerable overlap in the clinical presentation of TB and HIV in young children. Adults with TB/HIV coinfection are also more likely to develop sputum smear-negative pulmonary TB, in which case the exposure of the children may not be appreciated.
AGE AND CLINICAL PRESENTATION The epidemiology of TB in children in high-TB-endemic countries and the importance of young age as a major risk factor for disease mean that the majority of cases of pulmonary TB present before 5 years of age.1,2,5,7 This adds to the challenge of diagnosis for a number of reasons: 1. symptoms and signs are often less specific than in older children or adults; 2. infants and young children are also at risk for many other infectious diseases of childhood including HIV infection; 3. in poor communities, this is the age group most at risk for protein-energy malnutrition; and 4. it is particularly difficult to obtain specimens for sputum smear and microscopy for acid-fast bacilli (AFB) and culture in infants and young children. Although the risk of developing active disease following TB exposure is much less in older children, they are more likely to be infected owing to their mobility within the community. Therefore, despite children older than 5 years of age being at relatively low risk of developing TB, a considerable number of child cases in endemic areas do occur in this age group. It is not only the difficulty of obtaining sputum samples from young children that makes it difficult to confirm pulmonary TB,
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but young children present with primary TB that is paucibacillary and so the yield from smears for AFB is low even when sputum is available for examination. Older children and adolescents are more able to provide sputum and are also more likely to have sputum smear-positive pulmonary TB.1–4 Age is also important when considering the diagnosis of extrapulmonary TB. Children of less than 2–3 years of age are at greatest risk of severe, disseminated disease following primary TB infection.1 In the pre-Bacillus Calmette–Gue´rin (BCG) era, the risk of miliary TB and TB meningitis were particularly high in this age group and arguably the greatest benefit of routine neonatal BCG immunization has been to reduce the incidence of severe disseminated (miliary) TB.7,8 Other forms of TB, such as pleural effusion, pericardial TB, peritoneal (abdominal) TB, or spinal TB, are more likely to present in children of 3 years and older.1–3 The different presentations with age are likely to be explained by different cellular immune response as the immune system matures with age.
16
Box 16.1 Recommended approach to diagnose tuberculosis in children 1. Careful history including history of TB contact and symptoms consistent with TB. 2. Clinical examination including growth assessment. 3. Tuberculin skin testing. 4. Bacteriological confirmation whenever possible. 5. Investigations relevant for suspected pulmonary TB and suspected extrapulmonary TB. 6. HIV testing in high HIV prevalence areas. From: Guidelines for national tuberculosis programmes on the management of tuberculosis in children. World Health Organization, Geneva, Switzerland. WHO/HTM/TB/2006.371.
with latent TB infection and non-TB-related coincident symptoms from the child with true TB disease.
IMMUNE STATUS AND CLINICAL PRESENTATION The cellular immune response to TB infection affects the likelihood and type of disease presentation in a number of ways. As already implied the effectiveness of the immune response to contain a recent TB infection improves with age as the immune system matures. Infants are at far greater risk for developing disease following infection than school-aged children and are particularly susceptible to disseminated disease. Further, the presentation of pulmonary TB in infants can be more acute and more generalized with a higher bacillary load than in older children.9,10 The presentation of pulmonary TB in children is usually characterized by chronic cough and a lack of respiratory distress but the possibility of pulmonary TB needs to be considered in children, especially infants with acute severe pneumonia not responding to first-line antibiotics.11,12 Children with immunosuppression for other reasons such as HIV infection or severe malnutrition are also at greater risk of disseminated disease if infected with TB.1,3 There are important clinical correlates. The immunodeficient response to TB infection is indicated by a non-reactive response to tuberculin skin test (TST), which is common in TB-infected children with HIV infection, severe malnutrition, or disseminated TB. On the other hand, the same child may become more symptomatic of TB when immune function is restored by antiretroviral therapy (ART) or nutritional rehabilitation. The immune response to TB infection in the immunocompetent child is also relevant to disease presentation. A strong cellular immune response can result in characteristic clinical disease such as in the pathogenesis of TB lymphadenitis or pleural effusion, usually associated with a reactive TST response and more common in older children.
DIAGNOSIS RECOMMENDED APPROACH TO TUBERCULOSIS DIAGNOSIS The approach to the diagnosis of TB in children as recommended in the World Health Organization (WHO) guidelines of 2006 is summarized in Box 16.1.13 The approach is based on clinical experience, expert opinion, and published evidence. Published evidence is generally consistent but interpretation is always limited by a lack of a gold standard for diagnosis to compare definite TB from definitely not TB and the challenge to differentiate the child
CLINICAL FEATURES THAT SUGGEST TUBERCULOSIS Positive tuberculosis contact A child is usually infected with Mycobacterium tuberculosis by a person with pulmonary TB. When seeking a history of TB contact, it is important to determine the closeness of contact and whether the contact is sputum smear-positive, as these are important risk factors for infection (Chapter 5). Close contact is defined as living in the same household as, or in frequent contact with, a source case with sputum smear-positive pulmonary TB. Source cases that are sputum smear negative but culture positive can also infect child contacts but the risk is much lower. The timing of contact is also important as natural history data suggest that the majority of children infected with TB who develop disease will do so within 1 year of infection.5 Therefore a contact history that goes beyond 1 year makes the history less relevant to the clinical presentation of most forms of TB such as pulmonary TB or disseminated disease, at least in HIV-uninfected children. The later presentation of reactivation disease should be considered if there is severe immunosuppression. If there is no known contact with a TB source case it is important to enquire further about anyone in regular contact with the child who has a chronic cough and/or other symptoms suspicious of TB. The presentation of suspected TB in a child can be an opportunity to identify and treat an infectious case in the community and an effort should be made to detect the source case for any child diagnosed with TB.14 Another potential source of infection in some communities is consumption of non-pasteurized milk from cattle infected with Mycobacterium bovis. The usual presentation of M. bovis disease is cervical adenitis or gastrointestinal TB. Persistent cough Pulmonary TB commonly presents with a persistent cough defined as an unremitting cough for more than 21 days that is not improving despite appropriate first-line management. A careful history of the character and duration of the cough is important and helpful.15–17 The characteristic cough of pulmonary TB is persistent and unremitting. Recurrent viral respiratory tract infections and mild asthma, for example, are common causes of cough in children but the cough is usually characterized by an acute onset with steady improvement or a recurrent/relapsing pattern. Table 16.1 lists causes of chronic (persistent or recurrent) cough in children with typical characteristics of their clinical presentation.
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Table 16.1 Characteristics of causes of persistent or recurrent cough in children Causes
Nature of cough
Presence of fever
Typical nutritional assessment
Relevant clinical information
Pulmonary TB
Persistent and unremitting
Variable
Not resolved with antibiotics
Recurrent viral respiratory tract infection Recurrent bacterial pneumonia Asthma Bronchiolitis
Acute onset with delayed recovery or relapse
Recurrent
FTT or malnourished Normal
Recurrent
Pertussis
Acute onset with improvement or relapse Variable. Worse at night Marked at onset with steady improvement Persistent and spasmodic
LIP
Persistent
Not typicala At onset then settles At onset then settles Variablea
Bronchiectasis
Persistent
Variablea
Cystic fibrosis
Persistent
Variablea
Foreign body aspiration Cardiac failure
Persistent Persistent. Worse at night
Not typicala Not typicala
Viral symptoms, e.g. coryza. Not resolved with antibiotics. Improves between episodes
FTT or malnourished Normal Normal
Resolves with antibiotics. Improves between episodes. HIV related Wheeze. Responds to bronchodilators Wheeze. Infant
FTT or malnourished Variable
Not immunized. Subconjunctival haemorrhages
FTT or malnourished FTT or malnourished Normal FTT
HIV-infected. Parotid enlargement, PGL, clubbing. Response to steroids Copious sputum. Clubbing Ethnic group. Copious sputum. Clubbing Choking episode at onset Other signs of cardiac disease
LIP, lymphoid interstitial pneumonitis; FTT, failure to thrive; PGL, persistent generalized lymphadenopathy. Occasionally associated with infection or an increased risk of secondary infection.
a
In TB/HIV-endemic countries, the commonest clinical challenge is to differentiate pulmonary TB from other HIV-related lung disease. This will be addressed in more detail later in the chapter.
Persistent fever Fever is very common in children and is also a variable feature of TB.17 The diagnosis of TB is not usually considered in a febrile child unless the fever is persistent (> 7 days) or other clinical features suspicious of TB are present. It is important that other common causes of fever such as viral respiratory tract infection, malaria, bacteraemia, or focal sepsis have been considered and treated or excluded. Tuberculosis should be considered as a cause of ‘pyrexia of unknown origin’ defined as a daily temperature > 38 C for more than 14 days. Weight loss or failure to thrive Tuberculosis is a debilitating disease that can also cause anorexia and therefore it is unusual for a child with TB disease to thrive. The impact on the nutritional state is affected by the age of the child and type of TB disease. Infants and young children are particularly vulnerable to failure to thrive and malnutrition due to the high caloric demands for rapid growth at that age. This also makes documentation of failure to thrive more sensitive in the younger age group as greater changes are expected over shorter time periods. The importance of conscientiously documenting data on immunization, acute illnesses, and weight gain in a small booklet or growth chart kept by mothers cannot be overemphasized. It is an extremely valuable tool for assessment of the child with suspected TB. Most forms of childhood TB (except TB lymphadenitis) are strongly associated with weight loss and/or failure to thrive.17 The greatest risk of infection or disease for infants and young children is when the mother or primary caregiver has sputum smear-positive pulmonary TB. A diagnosis of TB would be strongly considered if the infant is failing to thrive. It is important
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to keep in mind that in poor communities many infants are at risk of significant malnutrition and mortality if the mother is too sick to adequately care for the baby or the mother dies. This is a common and difficult scenario especially in HIV-endemic countries where TB/HIV coinfection is common in mothers; TB treatment is less effective, maternal comorbidities are common, the infants are at risk of infection with TB and HIV, and there is the likelihood of inadequate care and nutrition. It is difficult to formulate a strict definition of weight loss or failure to thrive for TB diagnosis for the aforementioned reasons. A flat or falling weight that crosses centile lines during the past 3–6 months is the most reliable sign,17 but other causes such as inadequate nutrition and/or episodes of diarrhoea should be considered as well. In poor communities it is common for the weight gain to start to falter around 6 months of age when breast milk alone is not enough for nutritional demands and usual added feeds such as dilute cereal porridge are not sufficient to meet increased demands. The diagnosis of TB and of HIV should be considered in any child who fails to thrive or loses weight despite adequate nutritional rehabilitation, including deworming and iron supplementation as indicated. The cachexia and increased energy demands resulting from TB is more likely to cause marasmus than kwashiorkor, but children with kwashiorkor are extremely vulnerable to develop TB due to immune dysfunction. These children are markedly immunosuppressed, which may suppress some of the clinical and radiological manifestations of TB. Immune reconstitution inflammatory syndrome may also occur on nutritional rehabilitation.
Night sweats Night sweats is a commonly asked-for symptom of TB, especially in adults but also in children. It is a very non-specific symptom and probably only of value if the mother or caregiver spontaneously complains that the child sweats a lot at night. Only if the night sweats are
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severe enough to require a change of clothes, because the clothes are drenched, does the symptom need to be taken seriously. However, night sweats could also be caused by other diseases such as malaria and is therefore of even less value in malaria-endemic regions.
Other symptoms Fatigue is a common symptom of TB though also non-specific.15,17 It is more readily noticeable in children of 3 years or older and may manifest as a decrease in playfulness, activity, or performance at school. Other symptoms such as chest pain or haemoptysis are uncommon but do occur and are more likely to present in older children. Dyspnoea and a raised respiratory rate are not common but may be present especially in young infants.9 Lethargy and/or sleepiness are symptoms of particular concern in very young children in whom the risk of developing TB meningitis is high. The presence of a combination of well-defined symptoms provides added diagnostic value. Cough is a common symptom in children but is more likely to be associated with pulmonary TB if there is also weight loss.16 A recent study of South African children living in a high-burden community found that the combined presence of three well-defined symptoms at presentation (persistent, unremitting cough of over 2 weeks’ duration; objective weight loss, i.e. documented failure to thrive during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children of 3 years of age or older, with clinical follow-up providing additional value.17 CLINICAL EXAMINATION There are no specific examination findings that confirm pulmonary TB. There are clinical signs that strongly suggest extrapulmonary TB such as the typical non-painful asymmetrical often matted cervical lymphadenopathy, sometimes with fistula formation, that occurs with TB lymphadenitis; the non-painful gibbus of spinal TB; or the painless ascites of peritoneal TB. These are outlined in other chapters. Clinical abnormalities associated with pulmonary TB may be absent or are non-specific, but careful clinical examination is worthwhile (see Box 16.2). Note the nutritional state of the child and record weight, temperature and respiratory rate. Examination of the chest is normal in most cases of pulmonary TB but may reveal focal abnormalities such as inspiratory crackles, bronchial breathing, or the reduced air entry and stony dullness suggesting an effusion. In case of obvious abnormalities on auscultation, note whether the child has signs of respiratory distress. The distinctive clinical features of uncomplicated TB pleural effusion are a school-aged child, not acutely ill but complaining of unilateral chest pain with associated stony dullness. It is typical of pulmonary and miliary TB to be associated with considerable focal lung pathology without marked respiratory distress, which is in contrast to the typical presentation of pneumonia due to other pathogens such as Streptococcus pneumoniae in which the child looks more ill and is more breathless. Bacterial pneumonia can also be complicated by a pleural effusion or empyema. Empyema usually occurs at a younger age than TB pleural effusion and children are usually acutely ill. A diagnostic tap is helpful to distinguish empyema from TB pleural effusion although TB can also rarely cause empyema. The finding of wheeze on auscultation is typical of asthma in children or of viral bronchiolitis or pneumonia in infants. Wheeze does occasionally occur with pulmonary TB as a result of airway narrowing by enlarged peribronchial lymph nodes. Take note of the length of history, response to bronchodilators (good response in
16
Box 16.2 Important clinical points in assessment of a child with suspected pulmonary TB 1. Note and record nutritional status – children with pulmonary TB are often thin or undernourished. 2. Think of pulmonary TB if abnormalities on examination of the respiratory system are focal, marked and persistent in the ambulant child not in respiratory distress. 3. Think of pulmonary TB if radiological abnormalities are focal, marked and persistent in the ambulant child not in respiratory distress. 4. Negative tuberculin skin test does not exclude pulmonary TB. 5. Examine for clinical markers of HIV infection. 6. Examine for abnormalities of the cardiovascular system.
those with asthma), and nutritional state of the child. Asthma and bronchiolitis are typically conditions of immunocompetent children and infants of normal nutrition so that, if the child is malnourished, it makes these diagnoses less likely while increasing the possibility of pulmonary TB. Similarly, inspiratory stridor, barking cough, and hoarse voice (or cry) are typically associated with viral laryngotracheitis in children, commonly known as croup. TB involving the larynx or large airways can present with similar signs as croup. Useful features that might help distinguish TB from croup are length of history, persistence of symptoms, and regional lymphadenopathy. Examine for features that suggest HIV infection such as generalized symmetrical lymphadenopathy, digital clubbing, bilateral non-tender parotid swelling, extensive oropharyngeal candidiasis, or typical skin findings such as shingles scarring, extensive fungal infections, molluscum contagiosum, papulo-pruritic eruption, or Kaposi’s sarcoma lesions (Fig. 16.1). Any child in an HIV-endemic setting with suspected pulmonary TB should be offered an HIV test.13 Being HIVinfected increases the risk for TB as well as increasing the possibility of other diagnoses. Clubbing is also a feature of bronchiectasis which is further characterized by a cough productive of copious, purulent, sometimes blood-stained sputum and focal crackles on auscultation. Always examine the cardiac system to exclude pericardial TB but also because cardiac failure can present with persistent cough,
Fig. 16.1 Kaposi of the skin.
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failure to thrive, and fatigue. Congenital heart disease may be diagnosed in the infant and cardiomyopathy or rheumatic heart disease in the older child.
TUBERCULIN SKIN TEST The TST provides important additional information in the assessment of the child with suspected TB. The recommended method is the Mantoux test using either 5 tuberculin units of tuberculin purified protein derivative (PPD) or 2 tuberculin units of PPD RT23. A positive or reactive TST indicates TB infection and is defined as 10 mm diameter of induration when read 48–72 hours after administration in any child irrespective of BCG immunization.13 There is a large amount of data to support this cut-off. It is currently recommended that an induration of 5 mm is significant and be read as positive if the child is HIV-infected or severely malnourished. This recommendation is not based on robust evidence but in practice a reading of 5–10 mm is uncommon. The potential problem of poor specificity (often false-positive) due to BCG immunization or infection with environmental (non-tuberculous) mycobacteria is often mentioned. In practice, a TST of 10 mm should still be considered indicative of TB infection in developing countries where BCG is routinely given during the neonatal period.18 The main limitation of the TST is that it has a low sensitivity (often false-negative), especially in children in whom the diagnosis of TB is already the most difficult, i.e. the child with HIV infection or severe malnutrition. In children with confirmed culture-positive pulmonary TB, the TST is positive in 60–80%. Sensitivity is unknown in children with non-confirmed pulmonary TB but likely to be lower. Some of the other causes of false-negative TST are listed in Table 16.2. There are novel T-cell-based assays that utilize M. tuberculosis-specific antigens in the blood and so are more specific for M. tuberculosis infection than the TST.19 They also show promise as being more sensitive in immunosuppressed children. There are still unanswered questions as to their possible superiority to the TST and they are expensive. More data are needed from different settings of their value and applicability in the routine diagnostic approach to childhood TB.
Box 16.3 Key features suggestive of TB The presence of three or more of the following should strongly suggest a diagnosis of TB:
chronic symptoms suggestive of TB; physical signs highly suggestive of TB; positive tuberculin skin test; and chest radiograph suggestive of TB.
From: Guidelines for national tuberculosis programmes on the management of tuberculosis in children. World Health Organization, Geneva, Switzerland. WHO/HTM/TB/2006.371.
TST, and limitations of sputum examination outlined in the next section mean that CXR is relied upon to make the diagnosis in most parts of the world.4,20,21 The radiological picture depends on how the child presented to the healthcare facility. The majority of children who present through contact screening have hilar lymph node enlargement only. In contrast, children who present because they are symptomatic often (> 50%) have a radiological picture of complicated lymph node disease, pleural disease, or miliary TB.22 The diagnostic accuracy of the CXR depends on the experience of the interpreter and there is only fair to moderate intra- and interobserver agreement.23 More accurate diagnosis requires a good knowledge of the different radiological pictures caused by pulmonary TB in children,24 and these are presented in more detail in Chapter 32 . The use of CXR to diagnose pulmonary TB in HIV-infected children is complicated by other HIV-related lung disease discussed in a later section.25 Lymphoid interstitial pneumonitis (LIP) can cause an image difficult to distinguish on radiological grounds from miliary TB (Figs 16.2–16.4). The chronic radiological changes caused by repeated bacterial infections in an HIV-infected child are easily confused with pulmonary TB as the changes often do not completely resolve after a course of antibiotics.
RADIOLOGICAL FINDINGS The chest radiograph (CXR) is widely used to make the diagnosis of pulmonary TB in children (see Box 16.3). The lack of specificity of suggestive symptoms, the lack of sensitivity and specificity of the Table 16.2 Causes of false-negative tuberculin skin tests Incorrect administration Incorrect interpretation Improper storage of tuberculin Tested too early following infection HIV infection Protein-energy malnutrition Severe TB disease Viral infections (e.g. measles, mumps, varicella) Bacterial infections (e.g. typhoid fever, pertussis, brucellosis) Diseases of lymphoid tissue (e.g. lymphoma, leukaemia, sarcoidosis) Primary immunodeficiencies Neonatal age group Immunosuppressive drugs Chronic renal failure Low protein states
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Fig. 16.2 Chest radiograph of a 4-year-old HIV-infected child with a clinical diagnosis of lymphoid interstitial pneumonitis showing bilateral, diffuse reticulonodular infiltration. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
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Fig. 16.3 Chest radiograph of a 3-year-old HIV-infected child with a clinical diagnosis of lymphoid interstitial pneumonitis showing bilateral adenopathy and reticular infiltration. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
16
and before food (or drink) is taken. This method is not always practical as it requires hospital admission, it is not always well accepted by parents or nursing staff (or the child), and yield from smear is low. For detection using smears, 5,000 – 10,000 bacilli/mL of specimen must be present, whereas a positive culture may result from as few as 10 organisms/mL.4 However, culture of M. tuberculosis is often unavailable and, when it is, the result is not available for 6–8 weeks. It is usually neither practical nor appropriate to wait so long for confirmation before commencing anti-TB therapy if pulmonary TB is strongly suspected. Alternative methods have been employed to obtain sputum. These include nasopharyngeal aspiration, laryngeal swab, bronchoalveolar lavage, and induced sputum using hypertonic saline and chest physiotherapy.26–30 The induced sputum technique shows the most promise for improved yield in young children and can be employed in the outpatient ambulatory setting. Additional studies are needed to compare the feasibility and diagnostic value of these and other sampling methods in different settings.31 Because of the paucibacillary nature of pulmonary TB in young children, there is still a need for culture of sputum specimens to optimize diagnostic yield whatever method of obtaining sputum is employed. Newer diagnostic techniques that might improve accuracy and rapidity of diagnosis are being studied in children and are dealt with in detail in subsequent chapters.32,33
SCORING SYSTEMS
Fig. 16.4 Chest radiograph showing the typical micronodular pattern of miliary TB. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
BACTERIOLOGICAL CONFIRMATION Pulmonary TB is usually not confirmed by culture in children. Sputum smear microscopy for AFB is positive in less than 10–15% of children with probable TB and the yield from culture is around 30–40%.26,27 The yield is higher from older children and adolescents, and in children with advanced intrathoracic disease.4,28 Sputum samples should be obtained whenever possible and can be obtained by expectoration from children older than 6 years of age. The traditional method for obtaining sputum from children unable to provide an adequate sputum sample is by obtaining swallowed sputum from two or three consecutive early-morning gastric aspirate samples before the child is ambulant
As a result of the difficulty of confirming TB in children, there have been a variety of scoring systems proposed to assist the clinician. They usually rely on the key features that suggest TB diagnosis but are not able to be properly validated due to a lack of a gold standard especially for pulmonary TB in children.34 This limits their applicability to being perhaps more useful as a screening tool rather than as a standard diagnostic test but at what cutoff is uncertain. As the score increases, so does specificity but the trade-off is a reduced sensitivity and a good screening tool should have a high sensitivity. The value of these tools is also affected by the setting. They are likely to perform better in the low-TBendemic setting. In contrast, they are not so useful in the HIVendemic setting as the common clinical indicators for assessment of TB are affected by the possibility of coinfection with HIV (Table 16.3).35 Table 16.3 Impact of HIV infection on the value of features commonly used for diagnosis of pulmonary tuberculosis in children Diagnostic feature of pulmonary TB
Impact of HIV infection
Persistent symptoms Sputum smear-positive contact Malnutrition or failure to thrive Positive TST Characteristic CXR abnormalities Satisfactory response to TB treatment
Less Less Less Less Less Less
specific specific or sensitive specific sensitive specific sensitive
TST, tuberculin skin test; CXR, chest radiograph. Adapted from Graham SM, Coulter JBS, Gilks CF. Pulmonary disease in HIV-infected children. Int J Tuberc Lung Dis 2001:5:12–23.
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PULMONARY TUBERCULOSIS IN HIV-INFECTED CHILDREN This chapter has already referred to the important problem of assessing a child with suspected pulmonary TB in the HIV-endemic setting. There are epidemiological aspects to consider, added clinical and diagnostic challenges, and problems of poorer response to anti-TB treatment in the child with TB/HIV, especially in the absence of ART.
EPIDEMIOLOGICAL ASPECTS The incidence of TB is low in HIV-infected children living in areas where the incidence of pulmonary TB is low in adults, such as the United States or Western Europe. In the early stages of the HIV epidemic in Africa, it was uncertain as to how common TB was in HIVinfected African children.36 Autopsy studies indicated that TB was uncommon in HIV-infected children while clinical studies using mainly clinical and radiological criteria documented that HIV prevalence was high in children diagnosed with TB. Recent clinical studies from the region with large numbers of confirmed TB cases show that the incidence of TB is much higher in HIV-infected than in HIV-uninfected children and that HIV prevalence is high in children with pulmonary TB.3,37,38 This depends on the prevalence of pulmonary TB and HIV in the community. Most studies have reported on hospitalized children, which is likely to show a higher prevalence than community-based studies. The higher TB incidence among HIV-infected children is explained by an increased risk of TB infection and an increased risk of progression to active disease following infection. Notwithstanding, the risk of TB is high for all children living in communities where TB/HIV is endemic so that, in contrast to adults, most children with TB are not HIV-infected.1,3,38
DIAGNOSTIC ASPECTS Problems of TB diagnosis are more pronounced in HIV-infected children for many reasons:
clinical features that suggest pulmonary TB lack specificity or sensitivity in HIV-infected children (Table 16.3);17 most HIV-infected children are infected by mother-to-child transmission, which means that the peak age prevalence for HIV in children is the youngest children, also the most difficult age group in which to identify cause of respiratory disease; HIV-infected children have a very high incidence of acute and chronic respiratory disease due to a wide range of causes other than pulmonary TB (Table 16.4);25 TST has a significantly lower sensitivity in HIV-infected children with TB than in HIV-uninfected children;3,38 there is substantial overlap of clinical and radiological findings between TB and other HIV-related lung disease;3,25 confirmation of aetiological diagnosis is difficult in the lowresource setting for many potential causes of chronic lung disease including pulmonary TB;39 and HIV-infected children not uncommonly have more than one cause of lung disease which can mask response to empiric therapy.
There are two common clinical scenarios that challenge the clinician working in TB/HIV-endemic countries. The first is the child, often an infant, with acute severe pneumonia who is not responding to firstline antibiotics such as penicillin and gentamicin. HIV infection status for this age may be difficult to confirm in the resource-poor setting but
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Table 16.4 Possible causes of lung disease in HIV-infected children in TB endemic countries Age group
Common causes
Less common causes
Infants
Bacterial pneumonia PCP Viral pneumonia, e.g. RSV TB CMV pneumonitis Mixed infection Bacterial pneumonia TB LIP Bronchiectasis Mixed infection
Measlesa LIP
Children
Viral pneumonia Measlesa Malignancy Pulmonary KS Lymphoma Nocardiosis PCP Fungal pneumonia Candidiasis Cryptococcosis Aspergillosis Penicilliosisb Melioidosisb Paracoccidioidomycosisc Histoplasmosisc
PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus; LIP, lymphoid interstitial pneumonitis; KS, Kaposi’s sarcoma. a In regions with poor measles immunization coverage. b In older children in endemic regions of South-East Asia. c In older children in endemic regions of Latin America. Adapted from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
an antibody test is still useful. If HIV-seropositive with severe pneumonia and not improving, it is better to treat presumptively as HIVinfected and this will often be the case.40 Bacterial pneumonia is the commonest cause of severe pneumonia in HIV-infected children due to a wider range of bacterial pathogens than for HIV-uninfected children. Therefore, if first-line antibiotic treatment is failing, the choice of second-line treatment should cover for Gram-negative bacteria such as Klebsiella pneumoniae and for Staphylococcus aureus.11,37Pneumocystis jiroveci is also a common cause of severe pneumonia and death in HIV-infected infants.11,25Pneumocystis jiroveci pneumonia (PCP) is characterized by absence of fever and marked hypoxia and the recommended treatment is high-dose cotrimoxazole although treatment response is often poor. Infants with PCP are commonly coinfected with cytomegalovirus, influencing treatment response and management. Despite appropriate broad-spectrum antibiotics and treatment for PCP, the infant remains febrile with respiratory distress. This is when the possibility of pulmonary TB is often considered. Pulmonary TB can present as acute pneumonia especially in immune immature infants especially if HIV-infected. TST and CXR should be done but are likely to lack sensitivity and specificity, respectively. The typical CXR features of PCP are diffuse whereas pulmonary TB presents with more focal abnormalities (Figs 16.5 and 16.6). Sputum (or gastric aspirate) should be investigated by smear and culture. An important investigation is to identify a contact with a TB source case; this is frequently the mother or primary caregiver. Pulmonary TB is a much less likely cause of pneumonia in an infant if there is no source case identifiable.
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Fig. 16.5 Chest radiograph of an HIV-infected infant with confirmed
Pneumocystis jiroveci pneumonia showing bilateral diffuse infiltration. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
Fig. 16.6 Chest radiograph of an HIV-infected infant with confirmed
Pneumocystis jiroveci pneumonia showing hyperinflation. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
The other more common scenario is the older child with persistent respiratory symptoms either as an inpatient or as an outpatient not responding to broad-spectrum antibiotics. Pulmonary TB will be suspected and any child with suspected TB should be tested for HIV following consent. A negative HIV test will shorten considerably the list of possible diagnoses, increasing the likelihood of pulmonary TB as a cause. If HIV-infected, examination may reveal clinical features more consistent with other HIV-related lung disease.25 Digital clubbing is rare with uncomplicated pulmonary TB but common with LIP or bronchiectasis. Other features of LIP are persistent generalized lymphadenopathy and bilateral non-tender parotid swelling. Examine carefully for Kaposi’s sarcoma lesions including on the palate. Investigations again should include TST, CXR, and sputum for smear and culture if available. There are typical radiological features for LIP (Figs 16.2 and 16.3), bronchiectasis (Fig. 16.7), and pulmonary Kaposi’s sarcoma (Fig. 16.8). LIP typically causes diffuse bilateral abnormalities while
16
Fig. 16.7 Chest radiograph of a 6-year-old child with chronic cough and finger clubbing showing bronchiectatic changes in the right lower lobe. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
Fig. 16.8 Chest radiograph of an 8-year-old HIV-infected child with typical Kaposi’s sarcoma lesion on the palate showing bilateral adenopathy and infiltration with right pleural effusion. Reproduced with permission from Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis 2005;9:592–602.
pulmonary TB and bacterial pneumonia tend to cause more focal abnormalities, but there is the problem of possible coinfection especially with bacterial pneumonia but also with pulmonary TB. A lack of positive contact history becomes less useful for excluding pulmonary TB as the child gets older, especially in TB endemic areas where unrecognized TB exposure is common.
MANAGEMENT APPROACH Treatment for TB in children should not be undertaken lightly as it takes at least 6 months to complete and, although relatively rare in children, may cause serious side effects. It is important to resist the temptation to commence anti-TB therapy in children with suspected pulmonary TB on the basis that the diagnosis is difficult to exclude and that treatment response is a way of confirming or
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excluding the diagnosis. HIV-uninfected children with drugsusceptible disease usually have an excellent response to standard anti-TB therapy, with symptom resolution and weight gain within 2 months of therapy. However, it is well established that children with definite pulmonary TB do not always respond well to antiTB therapy, especially if they are severely immunosuppressed.3,38 Therefore a poor treatment response does not necessarily exclude TB. On the other hand, it is often quoted that children without pulmonary TB, but with recurrent bacterial infection, may improve on anti-TB therapy because of the broad-spectrum antibiotic action of rifampicin. Most children with suspected pulmonary TB are not acutely ill and so can be safely observed and reassessed over time. Careful clinical follow-up can provide very useful additional information, as symptom resolution occurs within 2–4 weeks in the vast majority of children without TB.17 The importance of HIV testing has already been emphasized, as the result affects the list of diagnostic possibilities. It also may be the first opportunity for the HIVinfected child and family to access HIV-related care such as cotrimoxazole chemoprophylaxis and antiretroviral therapy.
Box 16.4 Standard case definitions of pulmonary tuberculosis in children Pulmonary TB, sputum smear-positive two or more initial sputum smear examinations positive for AFB; or one sputum smear examination positive for AFB plus CXR abnormalities consistent with active pulmonary TB, as determined by a clinician; or one sputum smear examination positive for AFB plus sputum culture-positive for M. tuberculosis. Pulmonary TB, sputum smear-negative at least three sputum specimens negative for AFB; and radiological abnormalities consistent with active pulmonary TB; and no response to a course of broad-spectrum antibiotics; and decision by a clinician to treat with a full course of anti-TB chemotherapy. AFB, acid-fast bacilli, CXR, chest radiograph.
STANDARD CASE DEFINITIONS OF PULMONARY TUBERCULOSIS IN CHILDREN Once a child has been diagnosed as having pulmonary TB, he/she should be registered with the National TB Control Programme for treatment according to standard regimens (Chapter 61). The registration for pulmonary TB will be either as ‘sputum smear-positive’ or as ‘sputum smear-negative’. The latter is the commonest registered
REFERENCES 12. 1. Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of disease in children treated for tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006;10:732–738. 2. Harries AD, Hargreaves NJ, Graham SM, et al. Childhood tuberculosis in Malawi: nationwide casefinding and treatment outcomes. Int J Tuberc Lung Dis 2002;6:24–431. 3. Palme IB, Gudetta B, Bruchfeld J, et al. Impact of human immunodeficiency virus 1 infection on clinical presentation, treatment outcome and survival in a cohort of Ethiopian children with tuberculosis. Pediatr Infect Dis J 2002;21:1053–1061. 4. Mandalakas AM, Starke JR. Current concepts of childhood tuberculosis. Semin Pediatr Infect Dis 2005;16:93–104. 5. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:278–285. 6. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004;363:212–214. 7. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the prechemotherapy era. Int J Tuberc Lung Dis 2004;8: 392–402. 8. Rieder HL. Interventions for Tuberculosis Control and Elimination. Paris: International Union against Tuberculosis and Lung Disease, 2002. 9. Schaaf HS, Gie RP, Beyers N, et al. Tuberculosis in infants less than 3 months of age. Arch Dis Child 1993;69:371–374. 10. Maltezou HC, Spyridis P, Kafetzis DA. Tuberculosis during infancy. Int J Tuberc Lung Dis 2000;4:414–419. 11. Zar HJ, Hanslo D, Tannenbaum E, et al. Aetiology and outcome of pneumonia in human
162
13.
14.
15.
16.
17.
18.
19.
20.
21.
form of TB in children but in most cases would be more accurately referred to as ‘sputum not examined’ rather than ‘sputum smearnegative’. There are recommended criteria for standard case definitions and those for pulmonary TB are listed in Box 16.4.13
immunodeficiency virus-infected children hospitalized in South Africa. Acta Paediatr 2001;90:119–125. Chintu C, Mudenda V, Lucas S, et al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002;360:985–990. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. Geneva: World Health Organization, 2006. WHO/HTM/TB/2006.371. Schaaf HS, Donald PR, Scott F. Maternal chest radiography as supporting evidence for the diagnosis of tuberculosis in childhood. J Trop Pediatr 1991;37:223–225. Marais BJ, Gie RP, Obihara CC, et al. Well defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis. Arch Dis Child 2005;90: 1162–1165. Marais BJ, Obihara CC, Gie RP, et al. The prevalence of symptoms associated with pulmonary tuberculosis in randomly selected children from a high burden community. Arch Dis Child 2005;90:1166–1170. Marais BJ, Gie RP, Hesseling AC, et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics 2006;118: e1350–e1359. Farhat M, Greenaway C, Pai M, et al. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10:1192–1204. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761–776. Theart AC, Marais BJ, Gie RP, et al. Criteria used for the diagnosis of childhood tuberculosis at primary health care level in a high-burden, urban setting. Int J Tuberc Lung Dis 2005;9:1210–1214. Weismuller MM, Graham SM, Claessens NJ, et al. Diagnosis of childhood tuberculosis in Malawi: an audit of hospital practice. Int J Tuberc Lung Dis 2002;6:432–438.
22. Marais BJ, Gie RP, Hesseling AC, et al. Radiographic signs and symptoms in children treated for tuberculosis: possible implications for symptom-based screening in resource-limited settings. Pediatr Infect Dis J 2006;25:237–240. 23. Swingler GH, du TG, Andronikou S, et al. Diagnostic accuracy of chest radiography in detecting mediastinal lymphadenopathy in suspected pulmonary tuberculosis. Arch Dis Child 2005;90:1153–1156. 24. Gie R. Diagnostic Atlas of Intrathoracic Tuberculosis in Children: A Guide for Low Income Countries. Paris: International Union against Tuberculosis and Lung Disease, 2003. 25. Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int.J Tuberc Lung Dis 2005;9:592–602. 26. Zar HJ, Tannenbaum E, Apolles P, et al. Sputum induction for the diagnosis of pulmonary tuberculosis in infants and young children in an urban setting in South Africa. Arch Dis Child 2000;82:305–308. 27. Abadco DL, Steiner P. Gastric lavage is better than bronchoalveolar lavage for isolation of Mycobacterium tuberculosis in childhood pulmonary tuberculosis. Pediatr Infect Dis J 1992;11:735–738. 28. Marais BJ, Hesseling AC, Gie RP, et al. The bacteriologic yield in children with intrathoracic tuberculosis. Clin Infect Dis 2006;42:e69–e71. 29. Thakur A, Coulter JB, Zutshi K, et al. Laryngeal swabs for diagnosing tuberculosis. Ann Trop Paediatr 1999;19:333–336. 30. Franchi LM, Cama RI, Gilman RH, et al. Detection of Mycobacterium tuberculosis in nasopharyngeal aspirate samples in children. Lancet 1998;352:1681–1682. 31. Vargas D, Garcia L, Gilman RH, et al. Diagnosis of sputum-scarce HIV-associated pulmonary tuberculosis in Lima, Peru. Lancet 2005;365:150–152. 32. Montenegro SH, Gilman RH, Sheen P, et al. Improved detection of Mycobacterium tuberculosis in Peruvian children by use of a heminested IS6110 polymerase chain reaction assay. Clin Infect Dis 2003;36:16–23.
CHAPTER
Clinical features and index of suspicion of tuberculosis in children 33. Oberhelman RA, Soto-Castellares G, Caviedes L, et al. Improved recovery of Mycobacterium tuberculosis from children using the microscopic observation drug susceptibility method. Pediatrics 2006;118:e100–e106. 34. Hesseling AC, Schaaf HS, Gie RP, et al. A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. Int J Tuberc Lung Dis 2002;6:1038–1045. 35. Van Rheenen P. The use of the paediatric tuberculosis score chart in an HIV-endemic area. Trop Med Int Health 2002;7:435–441. 36. Coovadia HM, Jeena P, Wilkinson D. Childhood human immunodeficiency virus and tuberculosis co-
infections: reconciling conflicting data. Int J Tuberc Lung Dis 1998;2:844–851. 37. Madhi SA, Petersen K, Madhi A, et al. Increased disease burden and antibiotic resistance of bacteria causing severe community-acquired lower respiratory tract infections in human immunodeficiency virus type 1-infected children. Clin Infect Dis 2000;31:170–176. 38. Madhi SA, Huebner RE, Doedens L, et al. HIV-1 co-infection in children hospitalised with tuberculosis in South Africa. Int J Tuberc Lung Dis 2000;4:448– 454. 39. Kiwanuka J, Graham SM, Coulter JB, et al. Diagnosis of pulmonary tuberculosis in children in an
16
HIV-endemic area, Malawi. Ann Trop Paediatr 2001;21:5–14. 40. Thirsk ER, Kapongo MC, Jeena PM, et al. HIVexposed infants with acute respiratory failure secondary to acute lower respiratory infections managed with and without mechanical ventilation. S Afr Med J 2003;93:617–620. 41. Graham SM, Coulter JBS, Gilks CF. Pulmonary disease in HIV-infected African children. Int J Tuberc Lung Dis 2001;5:12–23.
FURTHER READING Donald PR, Fourie PB, Grange JM. Tuberculosis in Childhood. Pretoria, IL: JL van Schaik, 1999. Miller FJW. Tuberculosis in Children. Edinburgh: Churchill Livingstone, 1982.
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Clinical features and index of suspicion in adults (HIV-negative and HIV-positive) Dermot Maher
INTRODUCTION The role that clinicians play in good clinical care of TB patients through prompt diagnosis and effective treatment is also key to the public health approach to TB control. This chapter reviews the importance of clinical features and index of suspicion for both individual patient care and public health, paving the way for a detailed description of clinical presentations in Section 5.
THE CLINICIAN’S ROLE IN GOOD PATIENT CARE AND GOOD PUBLIC HEALTH The focus of the primary stratagem of TB control is on people with TB and the aim is to reduce the average number of people infected by each infectious case so that the case reproduction number is less than 1.1 With proper treatment, a person with infectious TB very quickly becomes non-infectious and so can no longer spread disease to others. With the correct application of anti-TB drugs, it is possible to cure over 90% of new smear-positive TB patients who neither have bacillary resistance to first-line drugs nor are infected with human immunodeficiency virus (HIV). Before the spread of HIV, countries that met the two international targets of at least 70% case detection and at least 85% treatment success could expect to see a decline in TB incidence rates of 5–10% per year or more.1,2 This expected epidemiological impact has been demonstrated in, for example, Peru.3 It has been supported by observed reductions in prevalence, for example in the areas of China that have implemented the directly observed treatment, short course (DOTS), strategy.4 Prompt, accurate diagnosis and effective, standardized treatment of TB are thus not only essential for good patient care but they are the key elements in the public health response to TB and the cornerstone of TB control.5,6 The clinician diagnosing and treating TB patients works at the interface of clinical medicine and public health, since the identification and cure of infectious cases has been recognized as the most cost-effective measure currently available to control TB.7,8 Case-finding and treatment success lie at the heart of World Health Organization’s (WHO) Stop TB Strategy,9 which incorporates and goes beyond the DOTS strategy.10 Good clinical management of TB patients, with rapid diagnosis and successful treatment outcomes for individuals with TB, contributes to global TB control. Conversely, inadequate clinical management (delayed diagnosis and failure to ensure adherence to a recommended standardized treatment regimen) results in a poor
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outcome for the individual patient and exacerbation of the TB epidemic. Patients with infectious TB who receive inadequate treatment are at high risk of remaining infectious, often with drug-resistant TB. The pool of infectious cases therefore increases. The generation of drug resistance is converting a treatable epidemic into an untreatable epidemic. The clinician therefore has both an individual patient responsibility and a public health responsibility in ensuring proper case management.11,12
APPROACH TO DIAGNOSIS OF TUBERCULOSIS The first step in diagnosing TB is recognizing the clinical features of the disease. For the clinician, the index of suspicion consists of detecting clinical features consistent with TB in a patient following the question, ‘Could TB be the cause of this patient’s illness?’ Once this question is asked, the answer is pursued by diagnostic evaluation which in all cases involves seeking microbiological, or sometimes histopathological, confirmation of TB.11 However, in some cases TB is presumed as the most likely diagnosis without such gold standard confirmation, e.g. sputum smear-negative pulmonary TB.13
THE CLINICAL FEATURES OF TUBERCULOSIS Tuberculosis presents with clinical features due to systemic disturbance and related to pathology at the local site or sites of disease. Systemic symptoms include fever, night sweats, tiredness, loss of appetite, weight loss, and secondary amenorrhoea. Systemic signs include fever, wasting, and tachycardia. Since extrapulmonary and pulmonary TB can occur concurrently, the diagnostic evaluation of a patient with extrapulmonary TB should always include evaluation for pulmonary TB with a chest radiograph and sputum microbiology. The clinical features of TB are generally the same irrespective of whether the patient presents in a setting with low or high TB incidence. However, patients in settings with high TB incidence tend to present at a more advanced stage of illness and therefore with more pronounced clinical features, on account of barriers to access within often weak health systems in developing countries, where 95% of TB patients live. The following account of the clinical features of TB draws substantially on the WHO publication TB/HIV: A Clinical Manual.14
CHAPTER
Clinical features and index of suspicion in adults (HIV-negative and HIV-positive)
Pulmonary tuberculosis Since the predominant site of TB is the lungs, the commonest presenting symptoms are those of pulmonary TB – cough, sputum, chest pain, haemoptysis, and breathlessness. Haemoptysis is often the result of cavitating lung disease causing erosion of pulmonary blood vessels – one large cavity or several smaller cavities may be associated with haemoptysis. Chest wall pain may be due to extensive lung inflammation, particularly if the pleural surface is involved. Breathlessness is an uncommon symptom in pulmonary TB, and usually indicates extensive lung disease or disease complications/ forms, such as pneumothorax, pleural effusion, or endobronchitis. Weight loss and fever are more common in HIV-positive pulmonary TB patients than in those who are HIV-negative. Conversely, cough and haemoptysis are less common in HIV-positive pulmonary TB patients than in those who are HIV-negative. This is probably because there is less cavitation, inflammation, and endobronchial irritation in HIV-positive patients. Since the sensitivity of cough as a symptom of TB is very high, all persons with otherwise unexplained productive cough lasting 2–3 weeks or more should be evaluated for TB.15 The specificity of cough as a symptom of TB is low, since cough occurs in a wide range of respiratory conditions, including acute respiratory tract infections (upper and lower), asthma, chronic obstructive pulmonary disease, bronchiectasis, and lung cancer. In patients presenting with chronic cough, the proportion of cases attributable to TB will depend on the prevalence of TB in the community.15 An overall focus on adults and children presenting with chronic cough maximizes the chances of identifying patients with pulmonary TB. Inadequate evaluation of patients with respiratory symptoms for TB results in missed opportunities for earlier detection of TB and leads to increased disease severity at diagnosis for patients and a greater likelihood of transmission of Mycobacterium tuberculosis to family members and others in the community. Failure to perform a proper diagnostic evaluation before initiating treatment also potentially exposes the patient to the risks of unnecessary or wrong treatment with no benefit or even harm. Moreover, such an approach may delay accurate diagnosis and proper treatment of the non-TB condition. The physical signs in patients with pulmonary TB are non-specific. They do not help to distinguish pulmonary TB from other chest diseases. Finger clubbing may be present as a general sign and chest signs on auscultation may include crackles, wheezes, bronchial breathing, and amphoric breathing. There are often no abnormal signs in the chest. If there is concurrent extrapulmonary TB there may be consistent clinical findings, e.g. lymphadenopathy, especially in patients with HIV infection. Extrapulmonary tuberculosis In addition to systemic features, patients with extrapulmonary TB present with features related to the pathology at the local site of disease. Tuberculosis lymphadenopathy Cervical lymph node enlargement (regardless of HIV serostatus) is the commonest presentation. Lymphadenopathy can also be found in the axilla and the groin. Initially, lymph nodes are firm and discrete, but later they become matted together and fluctuant. The overlying skin may break down with the formation of abscesses and chronic discharging sinuses, which heal with scarring. In the patient with HIV infection, lymphadenitis can be acute and resemble acute pyogenic infection. A number of other conditions present with lymphadenopathy. In areas with high HIV prevalence the commonest differential diagnosis is persistent generalized lymphadenopathy (PGL), which
17
Box 17.1 Features of lymph nodes which indicate increased likelihood of tuberculosis
Size greater than 4 cm in diameter. Asymmetrical enlargement. Rapid increase in size. Pain or tenderness not associated with local inflammation. Matted or fluctuant. Marked systemic disturbance such as fever and weight loss. Associated hilar and mediastinal lymphadenopathy.
presents as symmetrical non-painful lymph node enlargement, often involving the posterior cervical chain or axilla. As it is impossible to investigate all patients with enlarged lymph nodes it is important to distinguish features which indicate the possibility of TB (see Box 17.1). The differential diagnosis includes lymphoma, carcinoma, Kaposi’s sarcoma in HIV-positive patients, and sarcoidosis.
Serous effusions Serous (i.e. inflammatory) effusions may occur in the pleural cavity, in the pericardial cavity, and in the peritoneal cavity. They are more common in HIV-positive patients than in HIV-negative patients, although the clinical presentation in both groups of patients is similar. Pleural effusions are often accompanied by chest pain and breathlessness. Physical signs reveal the presence of fluid within the pleural space, giving rise to reduction of air entry on auscultation and dullness on percussion. HIV-positive patients with a pleural effusion usually have a primary infection newly acquired. There is a large number of differential diagnoses including malignancy, pneumonia, and pulmonary embolism. Pericardial effusions are potentially serious because of fluid developing in a tightly enclosed sac causing external pressure on the heart with a fall in cardiac output and death unless the pressure is relieved. Presentation is usually with precordial chest pain, shortness of breath, orthopnoea, and oedema of the legs. Physical signs reveal a low cardiac output, elevated jugular venous pressure, peripheral oedema, an impalpable apex beat, and quiet heart sounds. Many conditions cause pericardial effusion, and a careful clinical assessment needs to be done to particularly rule out malignancies and chronic renal failure. Pericardial effusion may be the result of rupture of a mediastinal lymph node into the pericardial space or haematogenous dissemination, and in HIV-positive patients it is probably the result of a primary TB infection. Peritoneal effusions (or ascites) present with a distended abdomen and the physical signs of fluid within the abdominal cavity. Peritoneal TB often arises as a result of spread from mesenteric lymph nodes, and the clinical presence of palpable abdominal masses is a pointer to the diagnosis. There is a very wide range of differential diagnoses from transudates caused by liver cirrhosis, congestive cardiac failure, and nephrotic syndrome to exudates caused by malignancy and other infections within the abdominal cavity. Tuberculosis meningitis Tubercle bacilli usually gain access to the cerebrospinal fluid via small subependymal cerebral tuberculomas, but direct spread can occur as part of miliary TB. There is usually evidence of a chronic meningitis with gradual onset of fever, headache, and altered consciousness. Involvement of the base of the brain can cause cranial
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GENERAL CLINICAL FEATURES AND DIAGNOSIS
nerve palsies. Tuberculomas, vascular occlusions, and hydrocephalus can all give rise to focal neurological defects and seizures. There is again a wide differential diagnosis, especially in patients with HIV infection. The two main differential diagnoses are partially treated bacterial meningitis and in HIV-positive patients cryptococcal meningitis.
Miliary tuberculosis Miliary TB occurs when tubercle bacilli are spread through the blood stream. This disease occurs either from a recent primary infection or from reactivation of a tuberculous lesion with erosion of a blood vessel. The disease presents with gradual fever, malaise, and weight loss. Physical examination may reveal enlargement of the liver and spleen, and occasionally characteristic choroidal tubercles can be found on fundoscopy. A high index of suspicion is required. The main differential diagnoses are bacteraemia, especially typhoid fever, and the acquired immunodeficiency virus (AIDS) wasting syndrome. Tuberculosis of the spine Starting as an inflammation of the intervertebral disc (most commonly in the thoracic spine), TB then spreads along the anterior and longitudinal ligaments to involve adjacent vertebral bodies. The disease is important because the consequences of missing the diagnosis can lead to irreversible paraplegia. The disease presents as a painful spine, sometimes with a gibbus (a visible protrusion of the spine) and in the case of neurological involvement a spinal cord compression syndrome with paraplegia. Other forms of extrapulmonary tuberculosis Box 17.2 shows the key clinical features of other forms of extrapulmonary TB. IMPACT OF HIV ON CLINICAL PRESENTATION OF TUBERCULOSIS Tuberculosis can appear at any stage of HIV infection, and its presentation varies with the stage. When cell-mediated immunity is only partially compromised, pulmonary TB presents in a typical manner with upper lobe infiltrates and cavitation, without significant lymphadenopathy or pleural effusion. In late stages of HIV infection, a primary TB-like pattern, with diffuse interstitial or miliary infiltrates, little or no cavitation, and intrathoracic lymphadenopathy, is more common. Overall, sputum smears may be positive less frequently among TB patients with HIV infection than among those without; thus the diagnosis of TB may be unusually difficult, especially in view of the variety of HIV-related pulmonary conditions mimicking TB.
Box 17.2 Clinical features of other forms of extrapulmonary tuberculosis Site of disease
Clinical features
Bone Peripheral joints Ileocaecal disease Renal and urinary tract Adrenal gland Female genital tract Male genital tract
Chronic osteomyelitis Usually monoarthritis Diarrhoea and palpable mass right iliac fossa Micturition frequency, dysuria, haematuria, loin pain/swelling Features of hypoadrenalism Infertility, pelvic inflammatory disease
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Epididymitis
Extrapulmonary TB is common among HIV-positive patients. In various series, extrapulmonary TB – alone or in association with pulmonary disease – has been documented in 40–60% of all cases in HIV coinfected individuals. The most common forms are lymphatic, disseminated, pleural, and pericardial. Mycobacteraemia and meningitis are also frequent, particularly in advanced HIV disease. The diagnosis of TB in HIV-positive patients may be difficult not only because of the increased frequency of sputum-smear negativity (up to 40% in culture-proven pulmonary cases) but also because of atypical radiographic findings, a lack of classic granuloma formation in the late stages, and a negative tuberculin skin test. Delays in treatment may prove fatal.
INDEX OF SUSPICION An awareness of the main groups at risk of TB serves to alert clinical suspicion of TB. This section highlights some common TB risk factors – those interested in a full account of TB risk factors should see Rieder’s Epidemiologic Basis of Tuberculosis Control.16 Environmental risk factors include substance abuse (smoking, alcohol abuse, and injecting drug use) and nutrition, and medical conditions identified as risk factors include silicosis, diabetes, malignancy, renal failure, measles, gastrectomy, and corticosteroid treatment. In this section some common risk factors in suspecting TB are discussed separately for developing and developed countries since their usefulness generally depends on the setting. However, because HIV is such a strong risk factor for TB, anywhere in the world the presence of HIV infection in a patient with consistent clinical features should always alert the clinician to the possibility of TB.
DEVELOPING COUNTRIES Poverty Although poverty is a risk factor for TB it is not sufficiently specific, where poverty is common, to be of much use in alerting the clinician as to the likelihood of TB. Hence the recommendation is that all persons with otherwise unexplained productive cough lasting 2–3 weeks or more should be evaluated for TB.15 HIV infection With 11% of the world’s population, 70% of the world’s HIV-positive people, and 85% of the world’s HIV-positive new TB cases, sub-Saharan Africa bears a disproportionate burden of HIV infection and of HIV-related TB.17,18 In sub-Saharan Africa, TB is often the first manifestation of HIV infection, the leading cause of respiratory illness among HIV-positive patients in hospitals and primary health clinics, and the leading cause of death among HIV-positive patients.17,18 DEVELOPED COUNTRIES In developed countries, TB is uncommon among young adults of European descent, who have only rarely been exposed to M. tuberculosis infection during recent decades. In contrast, because of a high risk in the past, the prevalence of M. tuberculosis infection is relatively high among elderly Caucasians, who remain at increased
CHAPTER
Native-born
14000 Number of reported cases
60 50 40 30 20
Norway
Sweden
Denmark
Netherlands
UK
Belgium
Luxembourg
France
Italy
Germany
Austria
Iceland
0
Greece
10
Fig. 17.2 Contribution of the foreign-born to TB in countries in Europe in 2002.
HIV infection The impact of HIV on TB in Western Europe has been largely limited to certain countries (e.g. Portugal, Spain) and cities (e.g. Amsterdam, Paris).24 In most countries in Western Europe, the proportion of AIDS cases diagnosed with TB is low. The two notable exceptions are Portugal and Spain,25 where the overlap between the population infected with HIV and the population infected with M. tuberculosis is greater than in the other countries of Western Europe. Poverty Poverty, with its attendant social disadvantage, has been strongly associated with the incidence of TB.26,27 It can be difficult to disentangle the relative effect of low socioeconomic indicators on the risk of TB incidence, but overcrowded living conditions are conducive to increased transmission of TB bacilli, and poor nutrition tends to increase the risk of progression of M. tuberculosis infection to disease. Poverty may also result in reduced access to healthcare services, leading to delayed diagnosis and treatment, with prolongation of the period of infectiousness of TB patients and increased likelihood of an unsatisfactory clinical outcome.28
CONCLUSION
16000 Foreign-born
12000 10000 8000 6000 4000 2000 0
70
Portugal
Immigration Effectively applied chemotherapy in the latter half of the twentieth century further accelerated the already declining TB case notifications in industrialized countries. From the mid-1980s onwards, however, several countries saw a slowdown in the decline, while others saw the trend reversed, with case notifications increasing for the first time in many years. For example, in the USA, after 30 years of steady decline, TB incidence increased regularly between 1985 and 1992.19 Factors responsible for this reversal included increased poverty among marginalized groups in inner city areas, immigration from countries with high TB prevalence, the impact of HIV, and most importantly the failure to maintain the necessary public health infrastructure (as in the case of New York City), under the mistaken belief that TB was a problem of the past.20 Many countries in Europe, including Denmark, The Netherlands, Sweden, and the UK, reported this slowdown in the decline, or even a steady rise, in TB cases.21 The high proportion of cases in the foreign-born (e.g. 24% in France, 51% in The Netherlands, 54% in Sweden, 68% in Switzerland) suggested immigration as the main cause of this change in trend.22 Annual case rates among the foreign-born often exceed 50 per 100,000 and may even exceed 100 per 100,000 (e.g. in The Netherlands), in contrast to rates in native-born populations of usually less than 15 per 100,000. In many countries, TB has declined steadily among the native-born, while rising among the foreign-born (see Fig. 17.1). The foreign-born now account for a large proportion of TB cases in developed countries, as shown, for example, by many countries in Europe (see Fig. 17.2).23
17
80
Finland
risk of developing TB. In many developed countries TB has re-emerged as an important public health problem mainly as a result of cases among immigrants from countries with high TB incidence. However, risk of TB is also increased in people who are HIV-positive or disadvantaged, e.g. the homeless. The commitment to ensuring universal access to quality TB diagnosis and treatment implies particular efforts to reach those groups at increased risk of TB, including the poor, the homeless, and immigrants (whether legal or illegal).
TB cases among foreigners in 2002 (%)
Clinical features and index of suspicion in adults (HIV-negative and HIV-positive)
1998
1999
2000
2001
2002
Fig. 17.1 The number of TB cases in 16 European countries among native-born and foreign-born. The 16 countries include Austria, Belgium, Czech Republic, Denmark, Finland, Greece, Hungary, Ireland, Netherlands, Slovakia, Slovenia, UK, Iceland, Norway, and Switzerland. EuroTB. Surveillance of tuberculosis in Europe. Report on tuberculosis cases notified in 2002, Saint-Maurice, France. December 2004.
Although new and improved drugs, methods of diagnosis, and vaccines will be developed eventually, which could greatly decrease the global burden of TB, until then control of the disease is mainly based on interruption of its transmission through the rapid identification and cure of infectious cases. The rapid identification of TB that is essential to ensure good outcomes for TB patients and good public health control depends on clinicians’ knowledge of the clinical features of TB, linked to an index of suspicion. In developing countries it is difficult to ascertain the extent to which people die from unrecognized TB because most of these cases never become known. Even in developed countries a small but significant proportion of TB cases are diagnosed at death. For example, in a 4year period from 1985 to 1988, 5% of all TB cases notified in the USA never received anti-TB treatment.29 In each country closing the gap between diagnosed and true incident TB cases depends on improved clinical diagnostic performance, for which the starting point is knowledge of the clinical features of the disease, linked to a judicious index of suspicion.
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19.
Health Organization, 1999. WHO/CDS/CPC/TB/ 99.270. International Standards for Tuberculosis Care. The Hague: Tuberculosis Coalition for Technical Assistance, 2006. Hopewell P, Pai M, Maher D, et al. International standards for tuberculosis care. Lancet Infect Dis 2006;6:710–725. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. Geneva: WHO, 2003. WHO/CDS/TB/2003.313. Harries AD, Maher D. TB/HIV: A Clinical Manual, 2nd edn. Geneva: World Health Organization, 2004. WHO/HTM/TB/2004.329. Luelmo F. What is the role of sputum microscopy in patients attending health facilities? In: Frieden TR (ed.). Toman’s Tuberculosis: Case Detection, Treatment and Monitoring, 2nd edn. Geneva: World Health Organization, 2004: 7–10. Rieder HL. Epidemiologic Basis of Tuberculosis Control. Paris: International Union against Tuberculosis and Lung Disease, 1999. World Health Organization. Global Tuberculosis Control: Surveillance, Planning and Financing. Geneva: World Health Organization, 2006. WHO/HTM/ TB/2006.362. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1009–1021. Cantwell MF, Snider DE Jr, Cauthen GM, et al. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994;272:535–539.
20. Frieden TR, Fujiwara PL, Washko RM, et al. Tuberculosis in New York City: turning the tide. N Engl J Med 1995;333:229–233. 21. Raviglione MC, Sudre P, Rieder HL, et al. Secular trends of tuberculosis in Western Europe. Bull World Health Organ 1993;71:297–306. 22. Rieder HL, Zellweger JP, Raviglione MC, et al. Tuberculosis control in Europe and international migration. Report of European Task Force. Eur Respir J 1994;7:1545–1553. 23. EuroTB. Surveillance of tuberculosis in Europe. Report on tuberculosis cases notified in 2002. SaintMaurice, France. December 2004. 24. Centers for Disease Control and Prevention. Tuberculosis—Western Europe, 1974-1991. MMWR Morbid Mortal Wkly Rep 1993;42:628–631. 25. European Centre for the Epidemiological Monitoring of AIDS. HIV/AIDS Surveillance in Europe: Quarterly Report, No. 46, 30 June 1995. 26. Enarson DA, Wang JS, Dirks JM. The incidence of active tuberculosis in a large urban area. Am J Epidemiol 1989;129:1268–1276. 27. Cantwell MF, Snider DE, Cauthen GM, et al. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994;272:535–539. 28. Bergner L, Yerby AS. Low income and barriers to use of health services. N Engl J Med 1968:278:541–546. 29. Rieder HL, Kelly GD, Bloch AB, et al. Tuberculosis diagnosed at death in the United States. Chest 1991;100;678–811.
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18
Microbiological testing for Mycobacterium tuberculosis Andrew C Whitelaw and Willem A Sturm
INTRODUCTION Approximately one-third of the world’s population is infected with Mycobacterium tuberculosis, making this microbe one of the most successful human pathogens. This is, amongst others, attributable to its ability to survive in the host for prolonged periods of time without inducing any symptoms and its capability to switch between this asymptomatic non-infectious phase and a clinically apparent infectious phase. Its close association with poverty and human immunodeficiency virus (HIV)-induced immunodeficiency makes it into one of the most important public health problems in underdeveloped parts of the world. Addressing these issues is crucial to control TB. However, interventions that convert an infectious individual into a non-infectious one as early as possible in the course of the disease are also important. It would be even better to prevent those who are developing clinical disease from becoming infectious. From a therapeutic point of view, the tools to achieve this are available. Despite that, the global TB burden remains extremely high, as well as the infectious disease with the highest mortality worldwide. This indicates that TB control programmes are still far from successful. The main reason for that is an inability to detect sufficient numbers of cases before transmission to uninfected individuals has occurred. The effectiveness of early case finding depends on a number of factors, of which access to healthcare facilities, contact tracing, and laboratory diagnosis are the most important. Efficient and rapid laboratory diagnostic tests are essential to make improvements in other interventions work. This is becoming even more important with the growing prevalence of effectively transmissible drug-resistant strains of M. tuberculosis. These strains, such as W-Beijing and F15/LAM4/KZN, pose a serious threat to the efficacy of TB control programmes.1,2 Their presence in significant numbers results in initiation of treatment of increasing numbers of patients on inadequate treatment regimens if rapid susceptibility tests are not available. In general, laboratory tests for the diagnosis of infections can be grouped in two main categories, as shown in Box 18.1. Whole microbes can be detected by means of microscopy or by culture. The sensitivity of these depends on the quality of the specimen, the concentration of microorganisms, and the volume of specimen received. Microbial macromolecules can be either secreted or released from dying organisms. As macromolecules are antigenic, antibodies can be produced against them, and then used to detect the macromolecules in test systems such as enzyme-linked immunosorbent assay (ELISA) or immuno-chromatography. Such tests are rapid and can be designed
with a high specificity for the microbe in question. The sensitivity is dependent on the concentration of the microbial components in the specimen. For generalized infections or infections with microbes that secrete vast amounts of such molecules, blood can be used. However, for many infections a specimen from the site of infection is needed. Detection of nucleic acids is becoming more popular. Nucleic acid detection tests can be performed without or with an amplification step. The commonest nucleic acid amplification test (NAAT) is the polymerase chain reaction (PCR), although other NAATs have also been described.3 The second category of tests measures the activity of the immune system against microbe-specific antigens in the possibly infected host. The problem with these tests is that immune activity is downregulated after the antigenic stimulus has disappeared. The time that it takes for the immune parameters measured in the test to decrease significantly varies per antigen and depends on whether there is repeat exposure. Such repeat exposure is present in endemic environments. Tests measuring immune activity may not reliably differentiate between current infection and past infection, and this problem is most prominent in populations in which the microbe to be detected is endemic. In this chapter, microscopy, culture, and antigen detection tests for TB will be discussed, while tests that measure immune activity and nucleic acid detection tests will be discussed in Chapters 19 and 20, respectively. This chapter is not a comprehensive laboratory manual, and serves mainly to highlight some of the important issues regarding current methods of laboratory-based detection, identification, and susceptibility testing of mycobacteria.
SPECIMEN COLLECTION, STORAGE, AND TRANSPORT One of the most important parameters affecting the performance of a microbiological diagnostic test is the quality of the specimen. Specimens need to be representative of the site of infection, preferably collected aseptically, and stored and transported to the laboratory to minimize multiplication of contaminating organisms. Tuberculosis is a disease that can affect all parts of the body and therefore all different specimens that can be collected for microbiological investigations need to be considered. Specimens for microbiological investigations are grouped according to the level of contamination, assuming applying optimal collection methods have been used.4,5 Examples of specimens with contamination levels are shown in Table 18.1.
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Box 18.1 Laboratory tests to diagnose infection 1. Detection of microbes or components of microbes: a. microscopy; b. culture; c. antigen detection; d. nucleic acid detection. 2. Detection of components of the immune response to the microbe: a. antibody detection; b. activated T cells.
Table 18.1 Common specimens for mycobacterial investigation showing likely degree of contamination Disease manifestation
Specimen
Contamination level
Generalized TB
Blood Percutaneous liver biopsy Expectorated sputum Induced sputum Bronchoalveolar lavage Bronchoscopic protected brush Gastric aspirate Percutaneous lung biopsy Open lung biopsy Pleural fluid aspirate Pleural fistula fluid Cerebrospinal fluid
None None
Pulmonary TB
Tuberculous pleuritis Tuberculous meningitis Ocular TB Bone and joint TB
Abdominal TB Cutaneous TB
Mucosal TB Tuberculous lymphadenitis ‘Cold’ abscesses TB in any other tissue
Corneal ulcer scrape Vitreous fluid aspirate Joint aspirate Bone marrow aspirate Bone chip Peritoneal fluid Stool Nodule biopsy Ulcer scrape Blood Ulcer scrape Fine needle biopsy Sinus aspirate Transcutaneous aspirate Percutaneous/surgical biopsy Transmucosal biopsy/ aspirate
Moderate Moderate Low Low Low to moderate Low Low None Moderate None Low None None None None None Heavy None Heavy None Heavy None Moderate to heavy None None Moderate
Specimens collected aseptically from a site without commensal organisms should not be contaminated. These specimens can be obtained by aspiration, biopsy, or surgical excision and include cerebrospinal fluid, lymph node aspirates, aspirates from deepseated abscesses, bone marrow and joint aspirates, and tissue biopsies such as liver biopsies. These specimens do not require a decontamination procedure. The second group of specimens are secretions from parts of the body with no or minimal commensal organisms, but that are
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connected to the body’s surface by means of an open connection which harbours commensal organisms. These commensal organisms will be mixed with the secretions from the infected site as they pass through the opening to the surface. Such specimens are therefore always contaminated. This group of specimens includes those from the respiratory tract, gastric aspirates, urine as well as menstrual fluid aspirates and uterine specimens. These specimens can usually be effectively decontaminated before culture is performed. The third group of specimens are specimens from parts of the body colonized with commensal and/or environmental organisms. This not only includes normally colonized areas such as the skin, oropharyngeal cavity, colon, and vagina but also secondarily colonized areas such as ulcers, open wounds, and fistulating lymph nodes. Specimens such as stool, scrapings from ulcers in mucosa and skin, and draining lymph nodes or abscesses belong to this group. These specimens are more heavily contaminated, which can affect the accuracy of microscopy and increases the chances of an unsuccessful mycobacterial culture. Many pathogenic organisms die during prolonged specimen storage or transport, due to:
exposure to lower temperatures; increased oxygen concentration; or decreased pH due to metabolic products of contaminants.
Mycobacteria are hardy organisms not easily killed in such adverse circumstances. However, the circumstances in which specimens are stored and/or transported may allow multiplication of contaminants. The generation time of M. tuberculosis is approximately 12 hours at 37 C versus 20–45 minutes for most contaminants. At moderate temperatures M. tuberculosis stops multiplying while many contaminating species only slow down their replication rate. As the level of contamination affects the sensitivity (not the specificity) of culture and to a lesser extent that of microscopy, the duration of storage should be minimized while transport lines should be as short as possible. Ideally, storage and transport should take place in temperature-controlled circumstances between 4 and 10 C,5,6 and specimens should arrive in the laboratory on the day of collection. In specimens from the respiratory tract a significant decrease in culture sensitivity due to contamination occurs if specimens arrive in the laboratory more than 48 hours after collection.6 Unfortunately TB is commonest in developing countries where patient care facilities are far away from laboratories with culture facilities. The difficulties in obtaining a reliable culture also render susceptibility testing impossible. If prolonged storage or transport is unavoidable, preservatives can be added to the samples to inhibit growth of contaminants and thus improve the yield from culture. Examples of these preservatives include sodium carbonate, cetylpyridinium chloride, and sodium borate. There are concerns that some of these compounds may not be compatible with some of the newer liquid-based culture systems such as the Bactec 460 or Mycobacterial Growth Indicator Tube (MGIT) system, and they may also reduce the sensitivity of microscopy.7–9
MICROSCOPY Microscopic detection of microbes in clinical specimens is the oldest approach to the laboratory diagnosis of infectious diseases, including TB. Based on its cell wall structure, M. tuberculosis is a
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Gram-positive bacterium. Indeed, on Gram-stained smears of clinical specimens of patients with TB, mycobacteria can be detected. However, it needs an alert microscopist to recognize the thin-beaded Gram-positive bacilli as mycobacteria. Therefore, microscopic detection of mycobacteria relies on the acid-fast nature of the organisms, resulting from the high lipid content of the mycobacterial cell wall. Two staining methods make use of this characteristic:
In the Ziehl-Neelsen (ZN) stain, carbol fuchsin enters the bacteria when heated but does not leave the cells when exposed to an alcohol/hydrochloric acid mixture. Mycobacteria are therefore seen as red-stained rods in a methylene blue-stained background. A modification of the ZN stain, the Kinyoun or cold stain, uses a higher concentration of phenol with the carbol fuchsin, and the slide does not need to be heated. In the Auramine-O stain, carbol fuchsin is replaced by auramine. Auramine fluoresces when bound to DNA and viewed under a fluorescence microscope. After decolourization of non-acid-fast bacteria and other material, only the acid-fast bacilli fluoresce.
While ZN-stained smears need to be viewed under high-power magnification (800–1000), auramine-stained smears can be viewed at a lower magnification (450–500) because of the easier visual detection of the fluorescence. The advantages of the auramine stain are an improved sensitivity (by about 10%) over the ZN stain, with less time required to read the smears since they are examined at lower magnification. There is also limited evidence that fluorescent stains are more sensitive than conventional microscopy in HIV-infected adults.10 There are concerns that the fluorescent stains may be less specific than the ZN stain, especially in low-prevalence areas. Therefore, it was recommended that auramine-stained smears with scanty acidfast bacilli (< 1þ) should be re-examined with the ZN stain. However, in areas with a high prevalence of TB the specificity of the auramine stain is much higher, and the need to restain low positives is probably unnecessary.10,11 The sensitivity of microscopic detection of TB depends on the duration of viewing, the viewing technique, the expertise of the microscopist, and the concentration of bacteria in the specimen. The advised maximum duration of viewing for ZN-stained smears is 20 minutes. About half this time is needed to view auraminestained smears, owing to the lower magnification used. The sensitivity of microscopy on sputum samples can vary considerably, but, in HIV-uninfected adults, it is probably of the order of 60–70%. Sensitivity can be increased by various techniques such as use of fluorescent stains as just discussed, specific processing methods, and examination of multiple samples.11–13 Liquefaction of sputum specimens is part of the preparation of specimens for culture and/or PCR. However, this is also recommended in settings where only microscopy is performed. If culture is to follow, the treatment should not kill the mycobacteria (see later). However, if only microscopy is performed, killing the mycobacteria in the process renders the specimen safe to handle. This can be achieved by the use of diluted household bleach. The use of bleach as a liquefying agent along with concentration of the specimen by centrifugation has been shown to improve the sensitivity of microscopy by about 18%.12 With respect to multiple samples, examination of a second sample significantly increases sensitivity of microscopy, but a third sample probably adds little to this. The World Health Organization (WHO) has recently recommended that only two sputum samples
18
Table 18.2 Grading of tuberculosis microscopy results for Ziehl–Neelsen- or auramine-stained smears Number of acid-fast bacilli per number of fields
Report
Ziehl–Neelsen (x1,000)
Auramine-O (x450)
0
0
1–9/100 fields 10–99/100 fields 1–10/field > 10/field
1–18/50 fields 4–36/10 fields
Negative (no acid-fast bacilli observed) Scanty positive (record exact count) Positive–1þ
4–36/field > 36/field
Positive–2þ Positive–3þ
Note: The grading of auramine-stained smears depends on the magnification used. This table shows the numbers of bacilli needed for grading if an auramine-stained smear is examined at a 450 magnification.
be used for microscopy-based diagnosis of TB.14 In extrapulmonary TB, in HIV-infected patients and in children, the sensitivity of microscopy is significantly reduced, and alternative approaches including culture-based methods are often required.15,16 Microscopy results are usually reported as shown in Table 18.2, corresponding semi-quantitatively with the concentration of acidfast bacilli per volume of specimen.17
NEW DEVELOPMENTS Apart from improvements in specimen preparation and staining, automated systems for reading ZN-stained smears have been described.18 This is still in the very early stages, but if available at an affordable cost may significantly reduce technologist time. Microscopes that use light-emitting diodes (LEDs) rather than traditional mercury vapour lamps for reading fluorescent stained smears have also been developed. They are cheaper and the LEDs last considerably longer than mercury vapour lamps. This may allow for the introduction of fluorescent microscopy in resource-limited settings. The performance of LED microscopes has been shown to be virtually identical to traditional fluorescent microscopes.18a
CULTURE SPECIMEN PREPARATION Specimens likely to be contaminated with commensal flora are first processed to remove viable organisms other than mycobacteria. This is essential as the contaminating bacteria or fungi invariably grow faster than M. tuberculosis. This not only depletes the culture media of nutrients but it makes it difficult to recover the mycobacteria in pure culture, which is essential to speciate the organism and to perform susceptibility tests. However, decontamination can also affect the mycobacterial cells and decrease their numbers. Therefore, uncontaminated specimens are inoculated directly onto the culture media (after centrifugation if necessary). Decontamination of specimens for mycobacterial culture involves striking a balance between effective killing of contaminants and
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survival of the mycobacteria. The more effective the decontamination, the less sensitive the culture, as more mycobacteria are lost. Whether this balance is reached is shown in the contamination rate which needs to be consistently monitored. A contamination rate of 0% indicates too harsh decontamination and loss of culture sensitivity. However, contamination also results in decreased sensitivity owing to the faster growth of the contaminants. A contamination rate of 3–5% is thought to be acceptable,5 although this varies with the culture system used (discussed later). Specimens from the respiratory tract are usually mucoid, and mycobacteria are embedded in this mucus. Recovery of these mycobacteria by culture improves if the mucus is digested to liquefy it. This also makes it possible to concentrate the bacteria present by means of centrifugation. Decontamination and digestion is performed in the same process. Of the various different digestion/decontamination methods, the most frequently used are the NaOH method and the NALC-NaOH method. In the NaOH method, the sodium hydroxide is both mucolytic and decontaminant. To achieve both effectively in a heavily contaminated mucoid specimen, a 2% NaOH concentration is needed in the specimen. This kills mycobacteria as well, but at a slower pace than the contaminants. Therefore, different concentrations of NaOH (from 2% to 4%) are used, depending on consistency of the specimen and the expected level of contamination. With this method, culture contamination rates need careful monitoring as these are influenced by the choice of the NaOH concentration, the shaking method, and the accuracy of the timing. The NALC-NaOH method uses N-acetyl-L-cysteine (NALC) to digest the mucus and other organic debris. Its lytic effect at a concentration of 1–2% is highly effective and provides full exposure of all microbes in the specimen to the NaOH. The NaOH concentration in the specimen need thus not exceed 1%. As a result fewer mycobacteria will be killed, providing increased sensitivity of the culture compared with the NaOH method. Although the NALC-NaOH method has more steps than the NaOH method, the process is better controlled and not significantly more time-consuming.
CULTURE METHODS After decontamination, specimens are inoculated into one or more culture media to allow for growth of mycobacteria. A variety of different culture media and culture systems (commercial and inhouse) have been used for this purpose. The most convenient way of dividing culture media is into solid and liquid, each with its own advantages and limitations.
Solid media These can be either egg- or agar-based. Egg-based media, of which Lo¨wenstein–Jensen (LJ) is the most well known, have a long shelf life and support growth of many mycobacterial species. However, quality may vary from batch to batch, depending on the quality of the eggs, and it can be difficult to detect the presence of mycobacterial colonies early on in the culture process. Agar-based media (such as Middlebrook 7H10 or 7H11) are transparent, and the presence of colonies can be detected earlier than with egg-based media. Standardization from batch to batch is more easily achieved, which makes agar-based media potentially more reliable for susceptibility testing. However, the shelf life of some of the agar-based media is shorter than that of egg-based, and they are more expensive.4 In some circumstances, antimicrobial agents (such as penicillin, nalidixic acid, lincomycin and cycloheximide) can be added to solid media
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to help prevent contamination by other flora. Growth supplements such as hemin or ferric ammonium citrate can also be added to support the growth of Mycobacterium haemophilum. Supplemented media should only be used when clinically indicated, and should always be used in conjunction with non-selective solid or liquid media.4
Liquid media Commonly used liquid media preparations are Middlebrook 7H9 and Dubos Tween albumin broths.4,19 Although solid media formed the mainstay of laboratory-based culture for many years, and are still used in many centres, the use of liquid media offers a number of advantages. Chief amongst these is that mycobacterial growth in liquid media is significantly more rapid than on solid media, reducing the delay associated with mycobacterial culture. Additionally, isolation rates using liquid media are generally higher than with solid media, especially with commercially available liquid-based culture systems. A number of commercial liquid-based mycobacterial culture systems, including the Bactec 460TB system, the Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system, VersaTREK (ESP II) culture system and MB/BacT system, are available. While a full description of the merits of each commercial system is beyond the scope of this chapter, a few short and pertinent points follow. The Bactec 460 (Becton Dickinson) is a semi-automated system and was the first commercial liquid-based mycobacterial culture system. It is often still regarded as the gold standard with which other systems are compared. The culture medium contains radiolabelled palmitic acid as a carbon source in the medium. This is metabolized by growing organisms, and radiolabelled CO2 is given off. The amount and rate of the CO2 emitted is monitored by repeated aspiration of the atmosphere in each vial to detect growth. The need for needles to sample the atmosphere in each vial and the need for disposal of radioactive waste are disadvantages to this system. The Bactec MGIT system (Becton Dickinson) uses modified 7H11 broth, with an indicator at the base of the tube that fluoresces under UV light. Oxygen quenches the fluorescence, but, if the oxygen in the medium is consumed, the indicator will fluoresce. The fluorescence can be read manually (using a Woods lamp), or, if a Bactec MGIT 960 instrument is used, the fluorescence is read automatically and continuously. The MB/BacT system (bioMerieux) consists of a bottle with a colorimetric sensor. As increasing amounts of CO2 are produced by growing organisms, the sensor changes colour, which is detected by the instrument. In the VersaTREK system (TREK diagnostics), previously marketed as the ESP II culture system, growth is detected by monitoring gas-related pressure changes brought about by multiplication of organisms in the bottle. A limitation of the MGIT 960 system is that blood cannot be directly inoculated into the tubes. The Bactec 460 system supports the culture of blood or bone marrow samples directly inoculated into vials, as do other mycobacterial culture systems such as the BacT/Alert MB and VersaTREK systems. The use of Myco/F Lytic (Becton Dickinson) blood culture bottles for mycobacterial culture of blood or marrow has been shown to be at least as good as other systems.20 A summary of the performance of the above four systems compared with solid media is shown in Table 18.3. As can be seen, time to detection in all the non-radiometric automated systems is faster than on solid media, although slightly slower than the Bactec 460. Mycobacterial recovery rates for all systems are similar, although the MGIT 960 and Bacetec 460 may be slightly better.
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Table 18.3 Comparison of the performance of various mycobacterial culture methods System
Time to positivity (days)
Recovery a rate (%)
Contamination rate (%)
Bactec MGIT 960 Bactec 460 MB/BacT ESP II / VersaTREK Solid media (LJ slopes)
10–22
88–100
5.0–13
8–14 14–18 3–34
86–98 90–93 79–87
3.7–11.7 4.6–7.7 7.0–8.6
23–30
55–87
3.0–14
a
Recovery rate reflects recovery of all mycobacteria, not specifically M. tuberculosis. Data from Drobniewski et al.,19 Somoskovi et al.,22 Chew et al.,23 Pfyffer et al.,24 Piersimoni et al.,25 Woodes et al.,26 Tortolli et al.27
The lack of needles and radioactive waste, as well as full automation, provide some advantages over the Bactec 460. However, contamination rates in the MGIT system tend to be higher than for Bactec 460, and specimen-processing procedures may need to be modified to counteract this.21 A major disadvantage of many of the commercial liquid-based systems is cost – in terms of both instrumentation and reagents. In laboratories that process relatively small numbers of specimens this is always going to be one of the deciding factors in choosing which culture system to use.
IDENTIFICATION FROM CULTURE Once there is growth on either solid or liquid media, the organism must be identified. The first step is to perform a ZN stain (and possibly also a Gram stain) to confirm that the organisms growing are mycobacteria and not contaminants. If a culture is contaminated, it can either be re-decontaminated or discarded. There are a number of ways of identifying acid-fast bacilli growing in the culture. A full description of all available identification methods is beyond the scope of this chapter, and only some of the relevant issues will be mentioned.
Phenotypic methods Phenotypic tests, which determine growth rates, pigmentation and growth at different temperatures, as well as a range of biochemical tests allow a laboratory in most cases to differentiate M. tuberculosis complex organisms from other mycobacteria (the non-tuberculous mycobacteria, NTM). However, phenotypic tests can also be used to identify specific non-tuberculous mycobacteria. One of the commoner tests used to identify M. tuberculosis is the niacin test. Niacin is excreted by M. tuberculosis due to a block in the NADscavenging pathway, and the detection of niacin can be used to presumptively identify an isolate as M. tuberculosis.28 However, other NTM (such as M. simiae) can also occasionally produce niacin, and rare niacin-negative strains of M. tuberculosis may occur.29,30 An alternative is to determine whether p-nitro-benzoic acid inhibits the growth of the organism – M. tuberculosis will show inhibition of growth.31 Biochemical tests can be time-consuming and often require the organism to be re-grown on specific media. In the case of identification for NTM, a wide range of biochemical tests need to be
18
performed, which is labour-intensive and expensive, and results can be difficult to interpret.
Mycolic acid analysis Analysis of mycolic acids (a component of mycobacterial cell walls) can be used to identify mycobacteria, and is one of the recommended tests when a new mycobacterial species is described. The analysis is usually performed by high-performance liquid chromatography (HPLC), and is generally used only in a research setting.32 Genotypic analysis Given the complexities associated with phenotypic identification, as well as the delays associated with these methods, an increasing number of identification methods based on DNA analysis have been described – both commercial and in-house. The major advantages of the nucleic-acid-based assays are speed and (usually) ease of interpretation. The drawbacks are often expense (especially commercial assays) and a real (or imagined) lack of expertise among laboratories in performing ‘high tech’ tests. The MicroSeq 500 system (Applied Biosystems, California, USA) is based on amplification of a portion of the 16S rDNA gene, DNA sequencing and comparison of the resultant sequence with the library of sequence data in the MicroSeq 500 bacterial database. The system allows for identification of a large number of mycobacteria (as well as other bacteria – an added advantage). However, certain of the nontuberculous mycobacteria are difficult to identify using this system (for example, the system cannot distinguish between Mycobacterium avium and Mycobacterium paratuberculosis, Mycobacterium abscessus and Mycobacterium chelonae) and it similarly cannot differentiate between different members of the M. tuberculosis complex.33,34 The Accuprobe (Gen-Probe, San Diego, CA, USA) test targets ribosomal RNA, and can be used to identify M. tuberculosis complex, M. avium, Mycobacterium intracellulare, Mycobacterium gordonae and Mycobacterium kansasii. A separate probe must be used for each species, and a limited number of species can be identified. However, for identification of M. tuberculosis complex, this test is rapid and reliable, showing excellent agreement with traditional phenotypic methods as well as other genotypic methods.35–37 There have been reports of misidentification of Mycobacterium celatum as M. tuberculosis using the Accuprobe. The Inno-LiPA Mycobacteria assay (Innogenetics, Ghent, Belgium) involves hybridization of PCR amplification products of a portion of the 16–23S rDNA spacer region to oligonucleotide probes on a membrane strip, which allows for identification of M. tuberculosis as well as a range of the commoner NTM. This assay can be used on cultures from both the MGIT and Bactec 460 system, and has shown a high degree of correlation (> 95%) with reference methods.35,36,38 The GenoType assays (Hain Lifesciences, Nehren, Germany) are more recent identification systems, and different versions of the kit can be used either for detection of M. tuberculosis directly from clinical samples or for identification of mycobacteria from culture. The underlying principle involves multiplex amplification of extracted mycobacterial DNA by PCR, with subsequent hybridization of the biotin-labelled amplicons to oligonucleotide probes bound to a membrane strip. Identification is done by evaluation of the resultant banding pattern. Kits are available either to differentiate different members of the M. tuberculosis complex (GenoType MTBC)39–41 or to identify a variety of NTM (GenoType Mycobacterium CM/ AS).42,43 Again, the kits have been shown to have excellent correlation with reference methods, usually over 95%.
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Table 18.4 Examples of in-house assays that have been used to identify Mycobacterium tuberculosis (and other mycobacteria) from culture Methodology
Target
Species identified
Ref
PCR Multiplex PCR PCR with RE digestion of product PCR with DNA sequencing
IS6110, pncA, Ag85 (among others) RD1, RD9 65-kDa hsp gene 16S rDNA gene
M. tuberculosis M. bovis BCG (differentiated from other MTBC) Wide range of mycobacteria (> 30 species including MTBC) Wide range of mycobacteria (> 50 species including MTBC)
44–46 44,47 48 49
MTBC: M. tuberculosis complex; BCG, Bacillus Calmette–Gue´rin; PCR, polymerase chain reaction.
A large number of in-house assays have also been described, with the purpose of identifying both M. tuberculosis complex and a variety of NTM. Examples of some of these assays are summarized in Table 18.4. This is by no means a comprehensive listing, and serves only to illustrate some of the different in-house methods that have been described.
NEW DEVELOPMENTS Two exciting developments deserve mention. The microscopic observation of drug susceptibility (MODS) assay combines culture and susceptibility testing in one step, reducing turnaround times for susceptibility testing, and is also a relatively low-cost process. It will be discussed in more detail later in the chapter under Susceptibility Testing. A new solid medium has also been described. TK medium (Salubris Inc, Cambridge, MA, USA) is a solid medium that contains various dyes that enable early detection of mycobacterial growth as well as detection of contamination. It can be read by the naked eye, making it a relatively low-cost culture option. Preliminary studies have shown that the time to positivity is faster than on LJ slopes (15 vs 26 days), but still slower than Bactec 460.50 The medium is unfortunately not yet available commercially, and further studies are planned to evaluate its performance in a routine setting.
NON-CULTURE-BASED METHODS OF DETECTING M. TUBERCULOSIS ANTIGEN DETECTION METHODS Lipoarabinomannan (LAM) is a mycobacterial cell wall component excreted in the urine. Detection of LAM has been evaluated as a diagnostic tool,51 and recently a commercial kit to detect urinary LAM in an ELISA plate format has been marketed (Chemogen, Portland, ME, USA). Quoted sensitivity ranges from 57% to 81% in HIV-infected and uninfected patients, respectively. While the concept sounds attractive, more research is needed to evaluate the product in different settings.
PHAGE ASSAYS The use of mycobacteriophages to diagnose TB is also a relatively recent development. This is discussed more fully in Chapter 23. Phages can also be used to perform susceptibility testing as discussed later.
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SUSCEPTIBILITY TESTING Resistance to anti-mycobacterial drugs occurs spontaneously at a rate of about 107 to 1010/cell division,52,53 varying with the drug. In cavities where one may typically find 107 organisms, there will almost certainly be a small proportion naturally resistant to at least one of the antimycobacterial agents. Use of a single drug as therapy may select for this resistance, and this is one of the reasons why combination therapy is now the standard of care. If combination therapy is not well managed, as may happen with poor adherence to therapy, poor supply of drugs and poorly managed treatment programmes, resistance is likely to emerge. Drug resistance in M. tuberculosis is a growing concern. Multidrug-resistant TB (MDR-TB), defined as resistance to at least isoniazid and rifampicin, occurs world-wide and is associated with longer, more expensive and more toxic treatment courses as well as with worse outcomes. In addition, emergence of extensively drug-resistant TB (XDR-TB) has focused attention on the need for more regular susceptibility testing as well as more rapid availability of susceptibility test results.1,54 There are a number of old and new methods available to the clinical laboratory to test susceptibility to antimycobacterial drugs, as shown in Boxes 18.2 and 18.3. Many current phenotypic methods require weeks for a result, and new methods are being developed to reduce this delay. This section will provide an overview of the commonly used methods, and describe some of the newer research in the field of drug susceptibility testing.
CONVENTIONAL (PHENOTYPIC) SUSCEPTIBILITY TESTING Conventional susceptibility testing essentially determines whether an isolate is resistant to an agent by evaluating growth (or metabolic Box 18.2 Commercial/established tests Phenotypic Absolute concentration method Resistant ratio method Proportion method Agar or broth. Direct or indirect. Genotypic Commercial line probe assays Phage-based assays Phage amplification assays
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Microbiological testing for Mycobacterium tuberculosis
Box 18.3 Non-commercial/in-house tests Phenotypic Microscopic observation of drug susceptibility (MODS) assay Colorimetric Genotypic Various in-house assays Phage based Luciferase reporter phages
activity) in the presence of the drug. The three standard methods using solid media are:
absolute concentration method; resistant ratio method; and proportion method.
The details of these methods have been described in numerous books and reviews,52,53,55,56 and only a brief summary of the principles of the first two methods is laid out here.
Absolute concentration method This is essentially a method of determining a minimal inhibitory concentration (MIC). The drug is incorporated into medium (usually solid medium) in twofold dilutions, and the organism inoculated onto each concentration. After incubation, the lowest concentration of drug that inhibits growth is read and used to determine whether the organism is resistant or susceptible. It is important to ensure that drug concentrations and inoculum size are carefully standardized; otherwise, erroneous results will be obtained. Resistant ratio method This is similar to the absolute concentration method; however, the MIC of the test isolate is compared with the MIC for a reference strain tested simultaneously. If the ratio of the MICs for the test strain to the reference strain is 2, the isolate is susceptible. If the ratio is 8, the isolate is resistant. Since this method compares to a reference strain, it is less prone to errors related to preparation of media. Inoculum preparation is, however, still important. Proportion method This test relies on the premise that, if more than 1% of a given population of organisms are resistant to a drug, the strain is regarded as resistant to that drug. When the proportion method is performed on solid media, agar plates containing the drug in question at a set concentration are prepared. This concentration is known as the critical concentration of the drug. The organism is inoculated onto both drug-free and drug-containing medium, and incubated for up to 3 weeks. The number of colonies on the drug-free medium is compared with the number on the drug-containing medium, and the proportion of resistant colonies calculated. The proportion method has been modified to be performed in broth culture, and the proportion method performed on the Bactec 460 radiometric culture system is now one of the most commonly used susceptibility testing methods. In essence, a vial containing a critical concentration of the drug and a drug-free vial are both inoculated with the test organism; however, the inoculum in the drug-free vial is a 1:100 dilution of the inoculum in the drugcontaining vial. If the drug-free vial registers growth before the drug-containing vial, the isolate is regarded as susceptible. If the drug-containing vial registers growth at the same time as, or before, the drug-free vial, the isolate is resistant. The Bactec 460
18
proportion method is quicker than the agar proportion method, but has the drawback of using radioisotopes. It is important to remember that the critical concentration of the drug varies, depending on the type of medium used, and use of the incorrect critical concentration can lead to incorrect results. When testing isoniazid, ethambutol, and streptomycin, two concentrations may be tested – low and high critical concentrations. There is some debate about the value of doing this, particularly for ethambutol, given the fact that presence of resistance mutations is more associated with resistance at the high concentration. For the other drugs, if only the low concentration is tested and the isolate is resistant, the high concentration should also be tested. Resistance at the high concentration indicates resistance, while an isolate resistant to the low concentration but susceptible to the high concentration suggests low-level resistance. Dosage adjustment may be necessary and careful follow-up to monitor for the emergence of resistance may be warranted.56,57
Direct and indirect testing Direct testing refers to testing directly from a clinical sample. It is possible to inoculate a smear-positive specimen directly onto the drug-containing and drug-free agar after decontamination, and compare the amount of growth. Direct testing in the liquid-based Bactec 460 system is thought to be less reliable, and there is little evidence to support its use. Indirect testing refers to testing performed on a culture of M. tuberculosis that has been grown from a clinical sample. Pyrazinamide testing Susceptibility testing of pyrazinamide (PZA) is difficult, since the drug is active at a low pH, which can inhibit mycobacterial growth.52 However, both agar and broth proportion methods for performing PZA testing have been described. Of concern are reports showing that some phenotypic PZA resistance tests do not always correlate with the presence of resistance mutations in the pncA gene.58 The pyrazinamidase assay (for detecting PZA-resistant strains) has been advocated as an alternative; however, later studies have shown that there is little correlation between presence of the enzyme and susceptibility or resistance.52 Non-radiometric broth-based methods Given the problems associated with disposal of radioactive materials in the Bactec 460 system, it is not surprising that non-radioactive liquid-based culture systems have also been adapted to perform susceptibility testing. The principle is the same as for the Bactec 460 system, although the details of inoculation, growth monitoring, and critical concentration obviously differ from system to system. The Bactec MGIT 960 system, the MB/BacT system and the VersaTREK have all been used as non-radiometric susceptibility testing systems. While the MGIT 960 system has been most extensively described, all the systems appear to perform very well in comparison with the Bactec 460 or agar proportion methods, although the ideal critical concentrations for some of the systems still need to be clarified.59 It is also worth considering that a thorough correlation of the results from these methods and clinical outcomes has not yet been performed (and is probably unlikely to happen).55 MOLECULAR METHODS As with the molecular identification systems, a number of in-house and commercial assays for detecting resistance mutations in M. tuberculosis have been described. Most work has been done on detecting resistance to isoniazid and rifampicin – partly because the resistance mutations (especially for rifampicin) are well described, and partly because these two drugs form the cornerstone of therapy for TB.
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Rifampicin in particular lends itself to molecular testing as the vast majority of resistance (> 95%) has been associated with mutations in a fairly limited area of the rpoB gene. Resistance to isoniazid (INH) is slightly more difficult, as at least four different genes may be involved, and in about 10–15% of cases the molecular basis of resistance is still unclear.
Commercial assays Two commercial reverse-hybridization assays have been released for the detection of rifampicin and INH resistance – the Inno-LiPA Rif TB assay (Innogenetics, Ghent, Belgium) and the GenoType MTBDR assay (Hain Lifesciences, Nehren, Germany). The principles underlying the tests have been described earlier in this chapter, although the probes bound to the membrane strip now correspond to sequences in the rpoB and katG/inhA genes. The Inno-LiPA Rif assay only detects resistance to rifampicin, while the MTBDR detects resistance to both rifampicin and INH. The performance of both systems in detecting rifampicin resistance appears to be excellent, ranging from 95% to 100% sensitivity, compared with phenotypic tests. The ability of the MTBDR system to detect INH resistance is slightly poorer (unsurprisingly given the wider range of resistance mutations), but still of the order of 73–90% sensitivity. The specificity of both assays approaches 100%.55,60,61 Both systems have also been used to detect resistance directly from smear-positive clinical samples (usually sputum), and the performance in this setting, while not quite as good as when performed on cultured isolates, is still excellent.62 The main drawback to the routine implementation of these methods for susceptibility testing (whether it be from culture or specimen) is expense. In-house assays A wide range of in-house assays designed to detect resistance mutations have been described. It is again impractical to discuss them all in detail, but Table 18.5 serves to illustrate some examples of the different approaches that have been taken. PHAGE-BASED ASSAYS Mycobacteriophages have been used both to detect viable organisms in specimens (as a rapid diagnostic method) and to perform rapid susceptibility testing to rifampicin, using either clinical samples or cultured organisms. Phage-based assays have a turnaround time of 48–72 hours, compared with 3–6 weeks for current phenotypic tests. When performing susceptibility testing, the sample is first incubated in the presence of rifampicin. If the isolate is rifampicin resistant, viable bacilli will still be present after this step. The sample or Table 18.5 Examples of in-house assays for detecting resistance in Mycobacterium tuberculosis Methodology
Target
Antibiotic
Ref
Line probe assay
pncA gyrA rpoB katG,inhA-mabA rpoB katG embB
PZA Quinolones Rifampicin INH Rifampicin INH Ethambutol
63,64
Macroarrays Pyrosequencing
PZA, pyrazinamide; INH, isoniazid.
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65 66
culture is then inoculated with a mycobacteriophage, which will infect any viable bacilli in the sample, and this can be detected in two ways: 1. A virucide is added to kill off any phages outside the mycobacteria. The phages inside infected bacilli replicate, lyse the bacilli and, release more phage. This is inoculated onto a lawn of a rapidly growing mycobacterium (Mycobacterium smegmatis), and, if phage is present, it will infect the M. smegmatis and cause the formation of plaques. The absence of plaques indicates no phage; thus there were no viable bacilli after the initial exposure to rifampicin. 2. Luciferase reporter phages (LRPs) are phages containing a luciferase gene, which can be detected by light emission without the need to infect M. smegmatis. Although no commercial assays have yet been developed using LRPs, commercial assays using phage amplification are available (FASTPlaque-TB Rif, Biotec Laboratories, London, UK). The performance of these assays was reviewed in a meta-analysis in 2005,67 and both LRPs and phage amplification assays were shown to have very good sensitivity and specificity for detection of rifampicin resistance – although the majority (19/21) of studies reviewed had performed the test on cultured isolates rather than clinical samples. Sensitivity ranged from 81% to 100%, and specificity from 73% to 100%. The obvious concern is the lower than expected performance in some studies, and more research identifying the underlying reasons for the poor performance need to be identified. More recently, LRPs have also been used to test INH resistance, with promising results (96.9% agreement with Bactec 460).68
COLORIMETRIC METHODS A relatively new method of rapid susceptibility testing uses colorimetric methods to indicate growth and these were recently reviewed.69 A coloured indicator is added to the medium after exposure of M. tuberculosis to the anti-mycobacterial drug (thus far, usually only INH and rifampicin). The presence of viable mycobacteria is detected by a change in colour of the indicator. The assays are usually performed in microtitre plates with a range of concentrations of the drugs, and in this way an MIC can be derived. The indicators that have been used to date include tetrazolium salts (XTT and MTT), Alamar blue and resazurin. The turnaround time of these tests is usually 7–14 days, which again compares very favourably with current methods. The pooled sensitivities for detection of rifampicin and INH resistance were both 98%, while the pooled specificities were 99% and 98%, respectively. There does not appear to be a difference in performance amongst the different dyes.
MICROSCOPIC OBSERVATION DRUG SUSCEPTIBILITY (MODS) The assay was first described in Peru in 2000 and entails inoculating a sputum sample into the wells of a tissue culture plate containing Middlebrook 7H9 broth.70 Some wells contain antibiotics at set concentrations. The wells are examined with an inverted microscope on a daily basis, and assessed for the presence of the typical corded appearance of M. tuberculosis. The presence of growth in the control well but not in the drug-containing wells indicates susceptibility to that drug. Although initially only INH and rifampicin were tested, more recent studies have included ethambutol and streptomycin.71
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The assay has proven extremely reliable in terms of diagnosing TB and compares favourably with both the MB/BacT and MGIT 960 systems. Time to detection of growth is at least as good as automated systems, with some reports of better time to detection.71,72 The accuracy of the susceptibility tests has been equally impressive, with most studies showing excellent correlation between the MODS result and that of a reference method (agar proportion or Bactec 460). Two reservations about the assay are that, while it is relatively cost-effective in terms of reagents and equipment, it is labour-intensive. There have also been concerns about the potential for crosscontamination. This is alleviated in part by ensuring that each tray is in its own plastic bag, and cross-contamination can be avoided.73
SUMMARY The mainstay of TB diagnosis, especially in resource-poor settings, is still microscopy. Although this has limited sensitivity there are a
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number of ways of optimizing the sensitivity of microscopy, including proper specimen preparation and use of fluorescent stains if possible. Although there are some promising new tests for rapid diagnosis of TB available or on the horizon (see also Chapters 19 and 20), the implementation of these in resource-limited settings where TB is endemic is going to be challenging. If culture is to be carried out, commercial broth-based systems are probably still regarded as the first prize, although affordability is the main obstacle. Newer developments such as the MODS assay should be considered as alternatives. Although it may not be practical to perform susceptibility tests on every isolate, especially in areas with a high TB prevalence, every effort should be made to provide susceptibility test results as soon as possible if they are indicated. One of the new challenges facing TB control programmes may be deciding in what circumstances susceptibility testing should be performed, and which method to use, to facilitate early detection of patients with drugresistant strains, while not over-burdening already stretched healthcare budgets.
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Immune-based tests for tuberculosis Dick Menzies, Kevin Schwartzman, and Madhukar Pai
INTRODUCTION Immune-based tests have great appeal for the diagnosis of TB, because the disease is notoriously difficult to diagnose. Active disease is a diagnostic challenge; because of the protean clinical manifestations, radiographic tests are insensitive and/or non-specific, while microbiological tests tend to be slow and labour intensive, and have suboptimal sensitivity, especially for extrapulmonary disease. The diagnosis of latent TB infection (LTBI) has assumed ever greater importance in many high-income countries. As rates of disease have fallen, emphasis has shifted to identification of latent infection and treatment to prevent later reactivation. Immune-based tests include some of the oldest and some of the newest tests for TB. In this chapter we will review two tests for detecting latent TB infection – the tuberculin skin test (TST) and interferong release assays (IGRA) – and one designed to diagnose active TB disease – serological assays. Both tests of latent infection measure cellmediated response to TB antigens, but otherwise differ markedly. The TST measures a complex in vivo response to intradermal injection of a fairly crude mixture of protein antigens derived from cultures of Mycobacterium tuberculosis – reflecting its origins of almost 100 years ago. IGRA have been introduced as commercial tests in many countries within the past 5 years. They are elegant in vitro tests that measure interferon-g (IFN-g) production by sensitized lymphocytes after in vitro exposure to antigens found in M. tuberculosis but not in several other organisms including Mycobacterium avium and Mycobacterium bovis Bacillus Calmette–Gue´rin (BCG). These new tests are promising because of their operational advantages and better specificity compared with the TST. Although many questions remain, this is a very active area of research in many settings, and the role of these tests is being constantly redefined. On the other hand serological tests measure humoral, or antibody, response to antigens from M. tuberculosis. Amazingly, the first serological assay was described in 1896! Despite having the longest history of use, and despite the efforts of many investigators in that time, serological assays remain the least utilized because of suboptimal test performance for diagnosis of latent or active TB in many populations and settings.
TUBERCULIN SKIN TESTING INTRODUCTION The tuberculin skin test was first introduced almost 100 years ago, giving it the distinction of being one of the oldest tests in current
clinical use. It is still the primary method of diagnosis of latent TB infection; an estimated 40 million TSTs are applied worldwide. Despite this long history, and common use, certain aspects of its use and interpretation remain controversial. And, with the advent of new in vitro immune-based tests for diagnosis of LTBI, the utility and limitations of the TST are important to review. The first tuberculin test material was prepared by Robert Koch, who filtered heat-sterilized cultures of M. tuberculosis grown on veal broth and then evaporated the filtrate to 10% of the original volume.1 This became known as old tuberculin (OT). In 1907 von Pirquet recognized its potential value for detection of persons infected with TB.2 The next year, Mantoux introduced the intradermal technique, which still bears his name.3 After considerable standardization work to create a purified protein derivative (PPD), a large quantity was carefully prepared by Dr Seibert in 1939 – termed PPD-standard, or PPD-S.4 With this, and other technical improvements, highly reproducible tuberculin test results could be obtained.5,6 In Europe, the Staten Serum Institute of Copenhagen, Denmark, developed a tuberculin test material termed RT-23. After considerable standardization work, this product was accepted as a standard tuberculin by the World Health Organization (WHO).7,8 Results from studies indicate that 2 TU of RT-23 provides equivalent results to testing with 5 TU of PPD-S.9 The available tuberculin tests and materials are summarized in the glossary of terms (Box 19.1). Injection of tuberculin material intradermally into a person previously infected with M. tuberculosis will result in infiltration of previously sensitized lymphocytes circulating in peripheral blood. At the site of injection, CD4 and CD8 T-lymphocytes, as well as monocytes and macrophages, will accumulate. These release inflammatory mediators, which produce oedema and erythema. Although there is increased blood flow, the locally increased metabolic activity of these inflammatory cells results in relative hypoxia and acidosis, which may be severe enough to result in ulceration and necrosis.10 Tuberculin reactions have often been equated with immune status. Even though both result from exposure and acquisition of infection, TST reactions and protective immunity are independent phenomena.
TECHNICAL ASPECTS OF TUBERCULIN SKIN TESTING Administration of the test Tuberculin test materials are commercially available in strengths ranging from 1 to 250 TU per test dose. Administration of 1 TU is not recommended because this preparation has reduced
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Box 19.1 Glossary of Terms Heaf
Multipuncture method of tuberculin testing introduced by Heaf in 1951. The prongs are dipped in tuberculin solution and then pressed into the skin. No longer in use.
IGRA (interferon-g release assays)
New in vitro tests for diagnosis of LTBI. Employ M. tuberculosis-specific antigens to stimulate lymphocytes from whole blood overnight, then measure interferon-g produced by sensitized circulating lymphocytes.
Mantoux
Intradermal method of tuberculin skin testing, first described by Mantoux in 1912. Tuberculin material is injected intradermally, and the resultant induration is measured 48–72 hours later.
NTM (nontuberculous mycobacteria)
Also know as MOTT (mycobacteria other than TB) and environmental mycobacteria. Includes diverse organisms such as M. avium, M. intracellulare, M. scrofulaceum, and M. kansasii. Not contagious although may be pathogenic. Important as may cause positive TST through cross-reactivity to very similar mycobacterial antigens.
PPD (purified protein derivative)
Material for tuberculin testing, prepared from culture of mycobacterial species, filtered, and purified by precipitation with ammonium sulphate or trichloroacetic acid. This is standardized against one large batch of standard PPD (PPD-S) produced from M. tuberculosis by Dr Florence Seibert in 1941. Stored by the Food and Drug Administration (FDA) (in the USA) and used worldwide as standard lot. One tuberculin unit (1 TU) is defined as 0.02 mg of PPD-S. Standard dose is 5 TU ¼ 0.1 mg. All commercial lots of PPD must be tested for bio-equivalence against PPD-S. This PPD is used mainly in North America.
QuantiFERONTB Gold
Commercial IGRA test, in which whole blood is incubated overnight with TB-specific antigens, then interferon-g produced by sensitized lymphocytes is measured using an enzyme-linked immunosorbent assay (ELISA) technique.
RT-23
Commercial PPD produced from M. tuberculosis, validated against PPD-S, and standardized by the WHO. This tuberculin test material is the most commonly used outside North America. Manufactured by Statens Serum Institute (Copenhagen). Standard dose is 2 TU, which is equivalent to 5 TU of PPD.
TINE
Multipuncture method of tuberculin testing. Four prongs (tines) coated with dried tuberculin material are pressed into the skin for about 2 seconds.
T-SPOT-TB
Commercial IGRA test, in which lymphocytes are separated, incubated with TB-specific antigens overnight, then lymphocytes expressing interferon-g are counted (Elispot technique).
sensitivity in children and adults, and it is not as safe.11–13 Higher strength formulations such as 100 or 250 TU are not recommended because positive reactions are very non-specific, have no correlation with risk of infection, and are more likely to revert later.14–16 Despite clear recommendations, published studies continue to use substandard tuberculin doses, reducing sensitivity, while others have used
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excessive doses such as 10 TU PPD-S, worsening specificity.17–23 The tuberculin skin test can be administered using the Mantoux method of intradermal injection, or using multipuncture techniques such as the Tine test. The multipuncture tests have lower sensitivity, and are less reproducible.24–28 It is recommended that for all tuberculin testing a dose bioequivalent to 5 TU of PPD-S, or 2 TU of RT23, be administered using the Mantoux technique of intradermal injection with a 26-G needle.8 The size of the wheal produced following intradermal injection is affected by age and gender – so is not reliable for verifying the amount injected.8 If injections are given subcutaneously, larger, more diffuse reactions will result, which are more difficult to read.15,29 The site of injection is not important, although the inner or volar aspect of the forearm is generally used for convenience.15
Reading the test Reactions that appear after 6 hours are non-specific, and readings at 24 hours are less sensitive and specific than readings at 48 hours.30,31 Readings made at 7 days following tuberculin administration will be 19–21% less sensitive.12,32 When two-step testing is performed, reading the first tuberculin test after 7 days has been suggested because the second test can be administered immediately for those with negative reactions. This approach is more practical, but is not recommended, because of the 20% lower sensitivity, plus 5% lower specificity.32 As well, all information regarding risk of TB (reviewed below) is based on TST measured 48–72 hours after testing. Hence, readings made later will be harder to interpret. Induration can be defined by palpation, or the ballpoint method, introduced by Sokal – the methods are equivalent.33–35 Selfreading by patients is not recommended as it is inaccurate. In two studies, 63–94% of patients with positive reactions believed they were negative.31,36 The variability of results with the Mantoux technique from two simultaneous tuberculin tests is remarkably small given the inherent variability resulting from administration and reading. Differences in readings, leading to misclassification errors, are less frequent when the same readers repeat their measurements (i.e. intrareader variability) than when different persons are asked to measure the same reaction (inter-reader variability).8 In two studies systematic differences between one reader and the others contributed the majority of variance and misclassification errors – a potentially correctable problem.37,38 Other potential causes of reader error are terminal digit preference or rounding, and conscious or unconscious reader bias. These problems can be minimized by using simple measuring calipers, such as those used by mechanics or tailors. Adverse reactions Adverse reactions to TSTs are rare. Vasovagal reactions can occur as with any injection. Immediate wheal and flare with a local rash was seen in 2% of allergy clinic patients.39 These reactions were associated with atopic history but not with positive tuberculin reactions at 48–72 hours. Well-documented anaphylaxis has been reported once following Mantoux testing.13 There have been two well-documented cases of anaphylaxis, one of them fatal, associated with Tine testing.40,41 In patients with severe blistering and ulceration, hydrocortisone cream is often given but was of no benefit in the only randomized controlled trial to assess its use.42 There is no evidence whatsoever that tuberculin testing poses any risk in pregnancy nor that tuberculin reactions are influenced by pregnancy, although in past years the manufacturers’ product monograph mentioned this as a potential precaution.43–45
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Immune-based tests for tuberculosis
INTERPRETING THE TST: FALSE-NEGATIVE AND FALSE-POSITIVE REACTIONS False-negative tests The TST may be false negative because of technical problems in the preparation or storage of material, or in the administration or reading of the test. Most of these problems can be avoided by meticulous technique in test administration and reading. Proper storage is important because test material will deteriorate if exposed to light or heat, or if frozen. Biological causes of false-negative results are more difficult to avoid. False-negative tests may occur in patients with active TB disease: estimates range from 5–8% in cross-sectional studies of patients already on treatment to 17% at the time of diagnosis, 30% among elderly patients, and 50% in patients with advanced disease in Nigeria.46–49 False-negative tests in TB patients are associated with more advanced forms of TB, malnutrition, and elevated serum creatinine levels.50–52 False-negative tests increase with older age.53 In most highincome countries, the proportion with a positive tuberculin reaction increases up to the age of 65, after which it declines.32,54,55 The proportion of false-negative reactions in dually infected (human immunodeficiency virus (HIV) and TB) patients ranges from 15–28% in those with CD4 counts greater than 400–500 up to 100% in patients with CD4 counts less than 200.56–58 Anergy testing, reviewed extensively elsewhere, has been suggested for the assessment of individuals with possibly false-negative TSTs.59,60 Among HIV-infected patients with negative tuberculin tests, the incidence of TB was significantly higher in those who were anergic than in those who were not.61–63 However, in individual patients results of anergy testing can be very misleading.64,65 Perhaps the most important finding is that in five placebo-controlled randomized trials, isoniazid (INH) was of no benefit in TST-negative, HIV-infected individuals.66 Accordingly anergy testing is not recommended for patient management.67
19
Table 19.1 Summary of effect of BCG vaccination on TST Parameter
Value
10 years > 10 years 10–14 mm 15þ mm 10–14 mm 15þ mm
Interval TST size TST size if interval 10 years
Age when BCG vaccination given Infancy (% 10þ mm)
Older (% 10þ mm)
8.7 1.0 4.6 1.9 1.4 0
43 21 20 19 11 8
From meta-analysis of 24 studies with 240,203 subjects BCGvaccinated in infancy, and 12 studies of 12,728 subjects BCG-vaccinated after the age of 1 year. Adapted from Farhat M, Greenaway C, Pai M, et al. False positive tuberculin skin tests - What is the absolute effect of BCG and nontuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10(11):1–13.
NTM may result in disease in humans.82,83 Testing with NTM antigens is not recommended for clinical use to diagnose nontuberculous mycobacterial disease.84,85 Antigens from NTM and M. tuberculosis are similar, which results in cross-reactivity when tuberculin testing. In experimental studies, animals infected with different mycobacteria developed the largest reactions to antigens prepared from that specific mycobacteria, and smaller reactions to antigens from other mycobacteria.86,87 In experimental animals infected with NTM, the proportion
25%
Fig. 19.1 Effect on TST reactions of BCG vaccination in infancy. Dashed
False-positive tests: non-tuberculous mycobacteria Non-tuberculous mycobacteria (NTM) exist in soil and water in the environment, particularly where the climate is warm and moist.80,81 In many parts of the world, a high proportion of individuals will have sensitivity to at least one NTM antigen by the age of 20. Although much less pathogenic than M. tuberculosis, these
line: weighted average effect in studies where the interval from BCG until TST was < 10 years. Dotted line: weighted average effect in studies where the interval from BCG until TST was > 10 years. Circles: point estimates (and SE bars) from individual studies with interval < 10 years. Squares: point estimates from individual studies with interval 10 years. Reprinted from Farhat M, Greenaway C, Pai M, et al. False positive tuberculin skin tests - What is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10(11):1–13.
Percent FP TST BCG (prevalence of TST positive attributable to BCG vaccination)
False-positive tests: BCG vaccination Of the 1.2 million infants born each year worldwide, approximately 88% receive BCG vaccination.68 BCG vaccination will almost invariably result in tuberculin conversion within 4–8 weeks.69 Although the size of TST reactions may vary somewhat with different vaccine manufacturers, dose, or methods of administration, the pattern of TST reactions is similar to that in TB-infected persons.69–73 Post-vaccinal TST reactions have no relationship to protective efficacy.74–77 Post-vaccinal tuberculin reactions will wane over time, particularly in those vaccinated in infancy. In a meta-analysis of 24 studies of 240,203 subjects who had received BCG vaccination in infancy, 7% of subjects aged less than 10 years and only 1% of subjects older than 10 years had positive reactions attributable to BCG (see Table 19.1).78 By contrast in 12 studies involving 12,728 subjects vaccinated after the age of 1 year, a positive TST was seen in 40% overall, and in 20% of those tested after an interval of 10 years or more (see Figs 19.1 and 19.2).78 This may reflect the relative immaturity of the immune systems in infancy.79
20% 15% 10% 5% 0% 5% 10%
0
2
4 6 8 10 12 14 16 18 20 Study number BCG given in infancy (age: 01)
22
24
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found among intravenous drug users (IVDUs), persons receiving social assistance, and homeless persons.92–95 The elderly also have high rates of positive tests attributable to the much higher risk of tuberculous infection during their youth. Among the foreign-born, prevalence of infection is correlated with incidence of TB in their country of origin and age of immigration. Contacts of active cases also have high prevalence of TB infection, particularly close contacts, or if the index case is smear positive.
Percent FP TST BCG (prevalence of TST positive attributable to BCG vaccination)
90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
1
5
8
13
14
25
26
27
28
29
30
31
Study number BCG given after the age of 1
Fig. 19.2 Effect on TST reactions of BCG vaccination given after the age of 1. Dashed line: weighted average effect in studies where the interval from BCG until TST was < 10 years. Dotted line: weighted average effect in studies where the interval from BCG until TST was > 10 years. Circles: point estimates (and SE bars) from individual studies with interval < 10 years. Squares: point estimates from individual studies with interval 10 years. Reprinted from Farhat M, Greenaway C, Pai M, et al. False positive tuberculin skin tests - What is the absolute effect of BCG and nontuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10(11):1–13.
What is the likelihood of a false-positive test? In any population, the importance of NTM as a cause of falsepositive TST depends upon the relative prevalence of infection with M. tuberculosis, and sensitization to NTM. If the prevalence of true TB infection is low, the relative importance of NTM will increase. Reactions to PPD or RT-23 caused by cross-reactivity by NTM are generally smaller than reactions caused by infection with M. tuberculosis. Hence increasing the cut-point will improve the specificity, but will reduce the sensitivity of the TST.46,96 BCG vaccination given in infancy has no effect on TST in all settings in persons older than 10 years. However, if BCG is given after infancy, the effect on TST will persist for many years, so this will be important when the likelihood of true TB infection is low. On the other hand, when the expected prevalence of tuberculous infection is high, such as in close contacts of smear-positive cases or persons from high-TB-incidence countries, the effects of BCG vaccination and sensitivity to NTM can be ignored.
demonstrating cross-reactivity to tuberculin antigens was reasonably constant.87 This appears to be true in human populations although the populations studied and the non-tuberculous mycobacterial antigens used varied considerably.88 As summarized in Table 19.2, in 12 studies involving a total of more than 1 million subjects, skin test sensitivity to NTM antigens accounted for less than 3% of all reactions to PPD-S or RT-23 of 10 mm or greater.78
The third dimension: risk of tuberculosis for a given TST The third dimension is the risk of development of disease. As shown in Table 19.4, the risk of developing TB disease relative to a person with no risk factors varies by several orders of magnitude. When risk, positive predictive value (PPV), and size of reaction are all considered together, the risk of developing active disease is affected most by BCG vaccination if given after infancy, and by the presence of risk factors. These factors are also considered in a TST interpretation algorithm available on-line from the authors (http://meakins.mcgill.ca/respepi/homeE.htm).
INTERPRETING THE TST – THINKING IN 3D
SERIAL TUBERCULIN TESTING
The first dimension: size This dimension is the easiest to understand, but least important. A criterion of > 5 mm for a diagnosis of latent TB has sensitivity of > 98%, but lower specificity. This criterion is used when maximum sensitivity is desirable because the risk of development of active disease is high. A criterion of > 10 mm will have sensitivity of 90%, and specificity of > 95% in countries with low prevalence of NTM and/or high prevalence of true TB infection. A criterion of > 15 mm or more has sensitivity of only 60–70%, but will have high specificity (> 95%) in all countries. The 15-mm criterion is not appropriate in countries with low prevalence of NTM, or high prevalence of true TB infection, nor for patients at increased risk for reactivation.
Repeated tuberculin testing can result in larger reaction sizes because of non-specific variation, due to differences in administration, reading, and minor variation in response. These factors result in standard deviation of results of 2–3 mm, meaning that, in 95% of all tested, random variation should result in increased reactions of less than 6 mm. Logically, increases of 6 mm or more should represent a true biological phenomenon – either conversion or boosting.
The second dimension: predictive value of a positive initial tuberculin test What is the likelihood of a true positive test (i.e. LTBI)? As shown in Table 19.3, the prevalence of positive TST varies widely in different populations. In high-income countries, prevalence is very low in schoolchildren and young adults, although higher in certain ethnic minorities.89–91 Particularly high rates are
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Boosting – from two-step tuberculin testing Boosting is defined as a newly positive test resulting from recall of immunity in the absence of new infection. As seen in Table 19.5, the boosting phenomenon is seen when there has been mycobacterial sensitization many years earlier – from BCG vaccination at any age, NTM sensitization, or remote TB infection.97–99 An initial TST results in a rapid increase in the number of circulating sensitized lymphocytes; this causes a much larger reaction to a second TST 1–5 weeks later.100 Boosting is less if the interval is only 48 hours or more than 60 days, although it can be seen up to 2 years after a first test.101–103 The boosting phenomenon is generally lower but roughly proportional to the prevalence of initial tuberculin reactions in the same populations, as shown in Table 19.6.
CHAPTER
Immune-based tests for tuberculosis
19
Table 19.2 Estimating the rate of false-positive tuberculin skin tests (TSTs) per 100 persons who are non-tuberculous mycobacteria (NTM)-sensitized Author(s) (year)
Setting
Participants
Prevalence of NTM infection
False-positive TST/100 with NTM dominant (FP TSTNTM) (%)
Age (years)
n
Antigen
Standardized and corrected (%)
10–11 mm
10–14 mm
6–15 6–15 4–6 6–17 11.6 16.1 8–9
3,108 2,038 1,594 34 2,408 983 2,819
A A A/B/G A/G B B A/G
6.4 3.0 3 24 3 8 34.1
1.5 4.8 12 0 0 7.9 0.7
4.0 11.3 12 5 1.4 7.9 1.1
1.6
2.7
— 1.0 0.7 0.9 2.4 0 0 1.6 —
3.1 1.5 1.3 1.3 5.7 0 0 3.6 8.2
1.1
2.0
Studies providing complete dataa Bleiker (1968)182 Brickman et al. (1974)183 Paul et al. (1975)184 Menzies (1989)185
Netherlands France Montreal Kenya Montreal
Lind et al. (1991)186
Sweden
Cumulative false-positive TST/100 NTM from five studies Studies with categorical dataa Jeanes et al. (1969)187 Edwards et al. (1973)188
Baily (1980)179 Wells et al. (1982)189 Frappier-Davignon et al. (1989)190 Von Reyn et al. (2001)191 Bierrenbach et al. (2003)172
Canada USA—northb USA—centralc USA—southd India Barbados Quebec USA Brazil
14–22 17–21 17–21 17–21 1–14 3–8 15–19 29 10.9
33,741 573,141 268,554 185,475 101,106 908 1,047 784 315
B/G B/G B/G B/G B B B A A/G
6.2 16 28 44 85 23 3 38 35
Cumulative false-positive TST/100 NTM from all 12 studies
Results in 11 studies with dual NTM and purified protein derivative (PPD) testing: The first five studies provided mm by mm data for all skin test reactions. The remaining six provided categorical data (i.e. reactions of 5–9 mm, 10–14 mm, etc.). b Northern US states includes the following: CA, CO, CT, ID,IL, ID, IA, KY, ME, MA, MI, MN, MT, NH, NJ, NY, OH, OR, PA, RI, SD, UT, VT, WA, WI, WY, and Washington DC. c Central US states: DE, KS, MD, MO, NE, NV, NM, NC, ND, OK, TN, VA, WV. d Southern US states: AL, AZ, AR, FL, GA, LA, MS, SC, TX. Adapted from Farhat M, Greenaway C, Pai M, et al. False positive tuberculin skin tests - What is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis 2006;10(11):1–13. a
Table 19.3 Prevalence of positive tuberculin tests (initial or single tests): results of Mantoux testing with purified protein derivative (PPD) 5 TU or RT-23 2 TU Population
General population Whites Blacks Hispanics Nursing home residents Urban poor (homeless, IVDUs) Close contactsa Smear-positive cases Smear-negative cases Casual contactsa Smear-positive cases Smear-negative cases Foreign-born Refugees (adults) Immigrants (adults) Children
Countries
No. of subjects
Positive TST (10þ mm) Number
%
1,167,482 82,535 3,368 1,542 6,044
45,922 11,213 744 423 1,606
3.9 13.6 22.1 27.4 26.5
7,180 3,333
2,288 463
31.9 13.9
8,649 3,592
1,050 0
12.1 0
11,445 4,840 2,309
4,179 2,039 379
36.5 42.1 16.4
References
USA, Canada
USA, Canada, Holland USA, Canada England, USA, Canada, Holland, New Zealand England, USA, Canada, Holland, New Zealand UK, USA, Canada, Netherlands
89–91, 165, 185, 192 89–91, 192 90, 91, 192 32, 99, 193 92–95, 194 195–199
197–199
200–204 205 206–208
a
Prevalence in contacts corrected for prevalence of positive tuberculin skin test (TST) in the general population in the same year. IVDUs, intravenous drug users.
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Table 19.4 Among persons with latent tuberculosis infection, risk for active tuberculosis relative to a healthy person with normal chest radiograph and no risk factors
Table 19.5 Summary of effect of BCG vaccination and non-tuberculous mycobacteria on two-step tuberculin testing
Risk factor
Population
Estimated relative risk
References
110–170
61, 62
50–110
221, 222
20–74
223–226
30 10–25
227, 228 229–232
16.0 15.0 6.0–19
233 106, 234 105, 235, 236
High risk Acquired immunodeficiency syndrome (AIDS) Human immunodeficiency virus infection (HIV)a Transplantation (on immunesuppressant therapy) Pulmonary silicosis Chronic renal failure requiring haemodialysis Carcinoma of head and neck Recent TB infection (< 2 years) Abnormal chest radiograph with fibronodular disease
Initial TST 10þ mm (%)
Two-step TST 10þ mm (%)
References
3,699
5.9
4.0
98, 219
1,469
6.3
9.9
98, 220
3,159
43
18
165
BCG vaccination Never vaccinateda BCG in infancy BCG after age 5
Non-tuberculous mycobacterial (NTM) sensitivity
Moderate risk Diabetes mellitus (all types) Underweight (< 90% ideal body weight) Age of 0–5 years, when infected Abnormal chest Radiograph – granulomas Tumour necrosis factor-a inhibitors
No. of subjects
2.0–3.6 2.0
237–240 241
2.2–5.0 2.0 2.0–3.0 4.0
242 236, 243 244 245
Data from cohort, and placebo-containing randomized trials in which latent TB infection is defined on the basis of a positive tuberculin skin test. Adapted from Long,17 with permission. a Patients with early asymptomatic or early HIV infection, but without clinical AIDS.
A simple and practical definition of boosting is that the second TST should be considered positive if induration is 10 mm or greater. Subjects with such reactions should not undergo further tuberculin testing (ever), and should be referred promptly for
Not sensitive to NTM Reacts to NTM antigens
362
1.6
1.4
98, 211
128
2.2
12.7
101
a
Data for never vaccinated from two studies in Canadian-born populations in Montreal, Canada; (i) school-children and young adults;219 and (ii) healthcare professional students.98 BCG, Bacille Calmette–Gue´rin; TST, tuberculin skin test. Adapted from Menzies RI, Vissandjee B, Rocher I, et al. The booster effect in two-step tuberculin testing among young adults in Montreal. Ann Intern Med 1994;120:190–198 and Sepulveda RL, Burr C, Ferrer X, et al. Booster effect of tuberculin testing in healthy 6-year-old school children vaccinated with Bacillus Calmette-Guerin at birth in Santiago, Chile. Pediatr Infect Dis J 1988;7(578):581.
medical evaluation including a chest radiograph. If the chest radiograph is normal and there are no associated factors that increase the risk of TB reactivation, then preventive therapy is probably not warranted. This is because boosting is less likely to represent true infection,98,102 future risk of developing active TB is low, as little as 0.05% annually,100,104 and it is well established that the risk of TB is very low among those with initially negative TST.89,105
Table 19.6 Comparison of prevalence of positive initial and two-step tuberculin skin tests (TSTs) Population
Countries
Subjects (n)
Initial TST a positive (%)
Two-step TST b positive (%)
References
Healthcare workers Hospitalized patients Nursing home residents Intravenous drug users
USA, Canada USA USA, Holland USA USA, Canada, Holland USA Uganda
5.5 12 29 13 13 37 13 71
2.0 6 13 8 12 30 8 29
98, 101, 111, 209–211 212 32, 55, 99, 213, 214 215
Foreign-born HIV-infected
4,942 162 3,193 HIV 900 HIVþ 95 3,748 95 345
97, 102, 201, 202, 216 217 218
Initial test – % calculated using denominator of number undergoing TST1, considered positive if 10 mm. Second test – % calculated using denominator of number undergoing TST2, considered positive using different definitions in different studies. Long R. Canadian tuberculosis standards. 5th edition. Toronto: Canadian Lung Association and the Public Health Agency of Canada (2000). Reprinted with the permission of the Minister of Public Works and Government Services Canada. a b
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Reversion is less common with larger initial TST, or manifestations of primary TB.120,122 The phenomenon of reversion emphasizes that, once a tuberculin reaction reaches 10 mm or greater, results of further testing becomes uninterpretable. If the tuberculin reaction reverts to negative and then becomes positive again, no clinical or epidemiological information is available to allow interpretation of such a phenomenon.
Number with conversion
80 60 40 20 0
19
CONCLUSIONS 0
1
2
3
4 5 6 Interval in weeks
7
8
9
Fig. 19.3 Interval from infection to tuberculin conversion in 172 cases with documented time of exposure. Reprinted from Menzies D. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir Crit Care Med 1999;159(1):15–21. Official Journal of the American Thoracic Society. # American Thoracic Society.
Conversion – from new tuberculosis infection Conversion is defined as development of new hypersensitivity to mycobacteria following new TB or non-tuberculous mycobacterial infection, including BCG vaccination. Conversion from new TB infection has been associated with a 4–6% incidence of TB within 2 years in adolescents or in contacts of smear-positive active TB.106,107 The size of the TST can be used to distinguish conversion from boosting, but many conflicting criteria, including increases of 10, 12, 15, and 18 mm, have been recommended.96,108–111 The last three criteria were based on cross-sectional studies in elderly subjects and in populations with high prevalence of BCG vaccination and/or NTM;110,112,113 none accounted fully for boosting. As with initial tuberculin testing, tuberculin conversions should be interpreted in light of the risk of infection, and the risk of disease, if infected. Hence the size to define conversion should be less for young children or adolescents, close contacts, and immunocompromised hosts, because of their increased risk of disease. The cut-point should also be less if there have been two or more negative tuberculin tests in the past – particularly if prior two-step testing was negative.111 All available evidence suggests the time between acquisition of infection and tuberculin conversion is not more than 8 weeks, as shown in Fig. 19.3.114–117 If the interval from infection to conversion is never more than 8 weeks, then the interval between first and second TST for contact investigation could be shortened to 8 weeks. This would mean that new conversions among high-risk contacts would be detected 1 month sooner. A more important advantage is that this could simplify the contact investigation of casual contacts and reduce the occurrence of false-positive conversions. When two sequential tuberculin tests are done, boosting is much more likely to account for apparent conversion in casual contacts in populations where BCG or NTM sensitivity is common.118 A single tuberculin test at 8 weeks would be sufficient to detect all low-risk casual contacts with infection. Performing only one test would avoid the difficulties of distinguishing boosting from conversion in this group. Waiting for 8 weeks to perform a single test would not be appropriate for contacts who are young children and/or are immunocompromised, such as HIV-infected contacts. Reversion Serial tuberculin testing has also revealed that tuberculin reversion may occur.16,119 Reversion is most common for those who react only to 250 TU dose, have initial reactions in the ranges 5–9 or 10–14 mm, or demonstrate the booster phenomenon.16,120,121
The TST is a test – not a condition. As with all tests in clinical medicine, the tuberculin test is most useful when it is clearly indicated, and the clinical situation is well characterized. It is a test for diagnosis of LTBI, and is not recommended for the diagnosis of active disease – sensitivity is only 70–85%. More importantly the TST cannot distinguish active disease from latent infection. Hence the specificity for active TB is low. Individuals with tuberculin reactions > 10 mm (or > 5 mm, or > 15 mm depending upon the clinically appropriate cut-point) should be referred for medical and radiological evaluation to identify those with active disease. Although the dictum ‘once TST positive, always positive’ may not be true, the corollary ‘once TST positive, no further utility’ is correct. Persons with a positive TST should not have further tuberculin testing, although proper documentation should remain available. When interpreting the TST, greater emphasis should be placed on thinking in three dimensions. This means considering the PPV and risk of development of active TB, in addition to the size of the reaction. There is no association between tuberculin reactions and immunity subsequent to BCG vaccination. Therefore, the ideal future TB vaccine would stimulate immunity, but have no effect on tuberculin reactions. TST conversion occurs within 8 weeks of mycobacterial infection. The best definition of tuberculin conversion is unclear, although available data suggest that 10 mm is a useful criterion. Larger increases will be more specific but less sensitive. Healthy, casual contacts can have a single tuberculin test performed 8 weeks after the end of exposure. A major advantage of the TST is that results have been validated through follow-up of large cohorts to determine subsequent incidence of active TB. This allows risk of disease to be predicted with some accuracy, depending on the TST size and clinical factors.
INTERFERON-g RELEASE ASSAYS A major breakthrough in the diagnosis of LTBI in recent years has been the development of T-cell-based ex vivo assays to detect cellular immune response to TB antigens.
DEVELOPMENT OF IGRAs Because of advances in molecular biology and comparative genomics, for the first time, an alternative to the TST has emerged in the form of a new class of ex vivo assays that measure interferon-g (IFN-g) released by sensitized T cells after stimulation by M. tuberculosis antigens. Early versions of IFN-g release assays (IGRAs) used PPD as the stimulating antigen, but these tests have been replaced by newer versions that use antigens that are more specific to M. tuberculosis than the PPD. These antigens include early secreted antigenic target 6 (ESAT6), culture filtrate protein 10 (CFP-10), and TB7.7 (Rv2654). ESAT-
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6 and CFP-10 are encoded by genes located within the region of difference 1 (RD1) segment of the M. tuberculosis genome; they are more specific than PPD because they are not shared with any of the BCG vaccine strains nor by several species of non-tuberculous (environmental) mycobacteria, including M. avium.123 IGRAs have a number of important advantages over the TST. Testing requires only one patient visit. They are ex vivo tests – eliminating risk of adverse effects from in vivo administration of antigens, and potential for boosting when testing is repeated. However, IGRA tests have higher material cost, and require a blood draw plus an equipped laboratory capable of performing ELISA or enzymelinked immunospot (Elispot). Although boosting will not occur, the variability of these tests, such as in serial testing of healthcare workers, has not been well studied. Their greatest disadvantage is the lack of prospective data regarding the risk of active TB for a positive IGRA test, as has been established for TST reactions of different sizes in many large-scale cohort and experimental studies. This extensive evidence base allows estimation of risk of disease, hence benefit of therapy, from size of TST reaction and the clinical context.
FORMATS OF COMMERCIALLY AVAILABLE IGRAs Two IGRAs are now available as commercial kits: the QuantiFERON-TB Gold (Cellestis Ltd, Carnegie, Australia) assay, and the T-SPOT.TB test (Oxford Immunotec, Oxford, UK). The QuantiFERON-TB Gold (QFT-G) is an ELISA-based assay that uses whole blood. It is available in two formats, a 24-well culture plate format (second-generation test, approved by the US Food and Drug Administration (FDA)), and a newer, simplified In-Tube format (also FDA approved). Figure 19.4 is a schematic of the In-Tube version of QFT-G assay. The T-SPOT.TB test (Fig. 19.5) is an assay based on Elispot technology. It is currently CE marked for use in Europe, and
FDA approved in 2008. In Canada, the T-SPOT.TB was licensed in 2005, and the QFT-G was licensed in 2006. Table 19.7 compares the characteristics of the two commercial IGRAs with the conventional tuberculin skin test. It is worth noting that the TST response is a complex one, involving multiple antigens in the PPD and multiple cytokine responses; several cells are involved in the overall response, measured over a longer period of time (i.e. delayed-type hypersensitivity). In contrast, both IGRAs use few antigens, and measure only the IFN-g subset of the various cytokines involved in cellular immune response. The overall response is measured after only 16–24 hours of incubation. Thus, TST and IGRAs do not measure exactly the same immune response.
SUMMARY OF PUBLISHED RESEARCH EVIDENCE ON IGRA PERFORMANCE The available research evidence on IGRAs (Table 19.8) has been reviewed extensively in recent meta-analyses and systematic reviews.124–127 In patients with newly diagnosed active TB, sensitivity of QFT-G (on average about 76%) appears to be similar to that of the TST (about 77%) while Elispot is more sensitive (90%).124,127 However, none of the tests can distinguish between latent TB and active disease. Specificity of both commercial IGRAs is excellent; the QFT-G appears slightly more specific (98%) than Elispot (93%). In the absence of a gold standard for LTBI, active TB was used as a surrogate for LTBI in most published studies. Given the gold standard problem, the sensitivity and specificity for LTBI cannot be directly estimated, and there is some concern that sensitivity for LTBI might be less than that of the TST, especially in vulnerable populations. Thus, a negative IGRA alone should not be used to rule out TB infection in a high-risk population.
Stage One — Blood incubation and harvesting
After blood collection, mix QuantiFERON¤-TB Gold tubes thoroughly, by shaking vigorously for 5 seconds
As soon as possible, and within 16 hours of collection, incubate tubes upright at 37¡C for 16 — 24 hours
Centrifuge tubes at 2000 — 3000 g (RCF) for 15 minutes
Harvest at least 200 μL plasma from each tube. Store in racked microtubes or uncoated microplates
Stage Two — Human IFN-γ ELISA
Add 50 μL of conjugate solution to each well. Add 50 μL of plasma or standard
Shake covered plate for 1 min. Incubate for 120 minutes at Room Temperature
Wash plate ‡ 6 times. Add 100 μL of substrate. Incubate 30 min. at Room Temperature
Add 50 mL of stop solution. Read absorbance within 5 min. at 450 nm (620 — 650 nm ref.)
Calculate results using QuantiFERON¤-TB Gold In-Tube Analysis Software
Fig. 19.4 Test procedure for the QuantiFERON-TB Gold In-Tube Assay. Reproduced with permission from Cellestis Limited, Victoria, Australia.
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STAGE 1
Separated white blood cells are counted and added to microtiter plate wells that have been coated with monoclonal antibodies [ ] to interferon gamma (IFN-g) [ ]. TB-specific antigens [ ] are added, causing the release of IFN-g from sensitive T cells [ ] which is captured by the antibodies.
STAGE 2
Wells are washed and conjugated secondary antibodies [ ] are added to bind to any captured IFN-g. Substrate [ ] is added to visulise the IFN-g, producing highly visible spots.
The spots can then be counted. One spot is one T cell.
Fig. 19.5 Test procedure for the T-SPOT.TB Assay. Reproduced with permission from Oxford Immunotec, Oxford, UK
A key finding in most available IGRA studies is that discordant TST and IGRA results are frequent and largely unexplained, although some may be related to varied definitions of positive test results.128 These discordant results pose difficulties in clinical interpretation. Most studies used cross-sectional designs with the inherent limitation of no gold standard for latent TB
infection, and most involved small samples with a widely varying likelihood of true-positive and false-positive test results. Thus the biological basis and prognosis of discordance is largely unknown. Although several IGRA studies have been published, there is insufficient evidence on IGRA performance in children,
Table 19.7 Characteristics of the three tests for latent tuberculosis infection TST
QFT-Gold In-Tube
T-Spot.TB
Administration Antigens Standardized Units of measurement Definition of positive test
In vivo (intradermal) PPD-S or RT-23 Mostly Millimetres of induration 5, 10, 15 mm
Ex vivo ELISA-based ESAT-6 þ CFP-10 TB 7.7 Yes International units of IFN-g Patient’s IFN-g 0.35 IU/mL (after subtracting IFN-g response in nil control)
Indeterminate
If anergy (rarely tested)
Time to result Cost per testa Materials Labour/other Total cost
48–72 hours
Poor response to mitogen (< 0.5 IU/mL in positive control) or high background response (> 8.0 IU/mL in nil well) 16–24 hours (but longer if run in batches)
Ex vivo Elispot-based ESAT-6 þ CFP-10 Yes IFN-g spot-forming cells (SFC) 6 SFC in the antigen wells, with 250,000 cells/well, and, at least double negative well Poor response to mitogen (< 20 SFC in positive control well) or high background (> 10 SFC in negative well) 16–24 hours (but longer if run in batches)
$12.73
$19 $22 $41
$63 $22 $85
All costs in Canadian dollars (Can$1 ¼ US$0.91). For the IGRA tests, the materials cost is based on quotes from the manufacturers for shipment to a Canadian centre in September 2006. The cost for IGRA labour, shipping, and handling is taken from published field experience with QuantiFERON testing, as reported by the San Francisco TB programme. Costs may vary widely in different countries. Source: Table adapted from Menzies et al.124 and cost information from Oxlade et al.246
a
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Table 19.8 Comparison of tuberculin skin test (TST) and IFN-g release assays (IGRAs)
a
Performance and operational characteristics
TST
IGRA
Estimated sensitivity (in patients with newly diagnosed active TB) Estimated sensitivity in patients who have been treated for active TB Estimated specificity (in healthy individuals with no known TB disease/exposure)
70–80% (lower in immunocompromised populations) 93–95%
75–90% (inadequate data in immunocompromised populations) No studies with RD1-based assays
98% in BCG unvaccinated 90–98% in BCG vaccinated in infancy 60–80% in BCG-vaccinated if given after infancy Yes Yes, but modest effect
93–98% (not affected by BCG vaccination)
No Less likely, but limited evidence
Moderate to strong positive association
Insufficient evidence
Yes
Yes (correlated better with exposure than TST in some, but not all, head-to-head comparisons) No evidence
Cross-reactivity with BCG Cross-reactivity with non-tuberculous mycobacteria Association between test-positivity and subsequent risk of active TB during follow-up Correlation with M. tuberculosis exposure Benefits of treating test-positives (based on randomized controlled trials) Reliability (reproducibility) (other than boosting as below) Boosting phenomenon with repeated tests Potential for conversions and reversions
Yes Test–retest good (SD ¼ 2.5 mm) Good to excellent in population studies Yes Yes
Adverse reactions Material costs Patient visits Laboratory infrastructure required Time to obtain a result Trained personnel required
Rare Low Two No 2–3 days Yes
Limited evidence; limited evidence on within subject variability during serial testing No Yes (reversion rates are high when baseline results are discordant, and when baseline IFN-g levels are weakly positive) None Moderate to high One Yes 1–2 days, but longer if run as batches Yes
IGRA, interferon-g release assay; TST, tuberculin skin test. a Data from several sources.124, 127, 131, 246
immunocompromised persons, and the elderly. Data are also lacking on how IGRAs perform when used in serial testing (e.g. annual screening of healthcare workers). Available data, although limited, suggest that IGRAs are also prone to non-specific variations, conversions, and reversions.128,129 Reversion rates are particularly high when IGRA results are weakly positive, and when initial results are discordant (i.e. IGRAþ but TST-).128,129 The clinical significance of reversions are not clear, and it is unclear whether a simplistic negative to positive change is the best way to define an IGRA conversion. Because IGRAs appear to be more dynamic than TSTs, it is particularly important to evaluate their reproducibility in serial testing studies. Overall, IGRAs show considerable promise and have excellent specificity. Thus, they are likely to be particularly helpful in low-incidence settings where BCG vaccination may be given after infancy, or given multiple times. Additional studies are needed to better define their performance in high-risk populations and in serial testing. Longitudinal studies are needed to define the predictive value of IGRAs, and to better understand their performance in serial testing. If IGRAs are shown to be more predictive of active TB than the TST, then their use can be expected to expand exponentially, with the potential to revolutionize our approach to TB diagnosis and treatment.
RECOMMENDATIONS AND GUIDELINES ON IGRAs In December 2005, the US Centers for Disease Control and Prevention (CDC) published its updated guidelines on the QFT-G assay
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(the second-generation test).130 The CDC guidelines suggest that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of immigrants, and serial testing of healthcare workers.130 In recent guidelines for preventing the transmission of TB in healthcare settings, the CDC again suggested that QFT-G can be used in place of the TST for infection control surveillance, and that conversion is defined as change from a negative to a positive result.131 By contrast in the UK National Institute for Health and Clinical Excellence (NICE) TB guidelines from 2006, initial screening with TST is still recommended.132 IGRAs are recommended only for those who are TST positive (or in whom TST may be unreliable).132 These current recommendations should be viewed as interim guidelines that will need revision as new evidence rapidly accumulates.
UNRESOLVED ISSUES AND DIRECTIONS FOR FUTURE RESEARCH The body of literature supporting the use of IGRAs is rapidly growing, and several reviews and guidelines have been published in the past few years. However, several unresolved and unexplained issues remain, and ongoing and new studies should help to clarify the role of these assays in various settings. Unresolved issues include unexplained discordance between the TST and IGRA results, ill-defined correlation between bacterial burden and T-cell responses, unknown predictive value of IGRAs for the development of active TB, insufficient data
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on test performance in persons with HIV infection and children, inconsistent results of studies on effect of TB treatment on T-cell responses, inadequate information on IGRA performance in serial testing, and lack of evidence on the utility of IGRAs in epidemiological studies. Scientific knowledge gaps are matched by the paucity of data on feasibility, applicability, cost- effectiveness, and potential utility of these assays in high-incidence yet resource-limited settings. Recognizing the limitations of existing literature, several recent publications have outlined the key research questions,124,126 including a comprehensive agenda for research on T-cell-based assays.133 The engagement of agencies such as the Stop TB Partnership, the World Health Organization, and Foundation for Innovative New Diagnostics (FIND), development of new tools, and evaluation of existing tools figure prominently in The Global Plan to Stop TB, 2006–2015, and the new global strategy to Stop TB (2006).134,135 Thus, the emergence of novel tools such as IGRAs is a welcome development, because, for the first time, these assays have expanded the armamentarium of diagnostics available for LTBI. In addition to clinical utility, these tests may be promising as research tools to advance our knowledge of LTBI and its epidemiology. To fully exploit the potential of these new tests, investments must be made to stimulate focused, high-impact research, and to encourage investment of resources needed to tackle priority research questions especially in resource-limited settings. Ultimately, if adequately financed, the research findings will inform appropriate use of novel LTBI diagnostics in global TB control.
SEROLOGICAL TESTS INTRODUCTION Serological tests detect the antibody response to one or more mycobacterial antigens, most often in human serum. These are antigens common to M. tuberculosis organisms; ideally, they should be absent from non-tuberculous mycobacteria and other microorganisms, to maximize specificity. Serological tests therefore differ from assays which detect cell-mediated immunity. A simple serological test for the diagnosis of TB holds great appeal. However, effective serological tests have been elusive, for biological reasons and because of methodological challenges inherent to the evaluation and interpretation of such tests. To be most useful for the diagnosis of active TB disease, a serological test must reliably differentiate this from latent TB infection – particularly if it is to be useful in high-incidence settings. Ideally, the test should employ antigens relevant to the pathogenesis of acute, active disease, and not the antigens relevant to mycobacterial latency. However, the understanding of the contribution of the vast array of mycobacterial proteins to the pathophysiology of tuberculous infection and disease is still in its infancy. A different challenge relates to serological testing for the diagnosis of latent TB in low-incidence settings. There a highly useful test would be one that reliably differentiated persons with latent TB from persons with previous sensitization to non-tuberculous mycobacteria, or to M. bovis BCG because of vaccination.
ANTIGENS FOR SEROLOGICAL TESTING Researchers have reported a variety of ‘in-house’ serological assays, based on such antigens as ESAT-6 and CFP-10 as well as the 14and 38-kDa antigens.136–139 However, it is difficult to extrapolate such results to the field. These in-house test kits are neither standardized nor
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subject to commercial quality control standards. Hence, potential users cannot assume that preparation of apparently similar kits in their own practice settings will produce comparable results. Research laboratories also possess highly specialized equipment and personnel, which may not be available in most clinical settings. Several companies have developed and marketed commercial tests for the serological detection of antibodies to such antigens as antigen 60 and lipoarabinomannan – sometimes singly, sometimes in combination. As summarized in Table 19.9, most commercial tests detect antibodies of the IgG class, typically using the ELISA technique.140,141 Common to these is the use of prepared antigens (either by purification/filtration from mycobacteria, or by recombinant DNA technology) which coat a plastic surface or membrane; patient serum is then added, and the assay detects binding of patient antibodies to the antigens of interest. Antibody binding is not an ‘all-or-none’ phenomenon, so that criteria for a positive test vary with respect to threshold antibody levels. The lower the threshold, the higher the test sensitivity but the lower its specificity. The concurrent use of multiple antigens also predictably increases sensitivity and reduces specificity, if a ‘positive’ test denotes reaction to one or more antigens.
SEROLOGICAL DIAGNOSIS OF SMEAR-POSITIVE PULMONARY TUBERCULOSIS By definition, immunological testing cannot improve on the sensitivity of sputum smear microscopy for the diagnosis of smearpositive pulmonary disease. However, immune-based diagnostics could theoretically allow exclusion of smear-positive TB as a diagnostic consideration, given a sufficiently high negative predictive value (which reflects the sensitivity of the test as well as the prior probability of disease). The sensitivity of serological assays which target mycobacterial antigens putatively associated with active TB should be highest among persons with smear-positive pulmonary disease – because of the high bacillary load and ensuing stimulation of antibody production. However, the sensitivity of commercial assays in this context has been highly variable, with variation both between distinct assays and between reports of the same assays in apparently similar clinical settings. For example, al-Hajjaj and colleagues142 administered the Anda-TB test to 200 patients with newly diagnosed smear-positive pulmonary TB, as well as to 106 patients with non-mycobacterial pulmonary disease, and 75 healthy blood donors, all in Saudi Arabia. Using a cut-off value of 200 IgG units/mL, they estimated a sensitivity of 77% for the IgG assay, with an estimated specificity of 92% in the pulmonary disease patients and 99% in the blood donors. Hence there was some degree of overlap in the IgG values between the TB patients and those with other pulmonary diseases, which are the most relevant comparison group from a clinical and public health standpoint. The addition of a strong IgM test reaction (‘grades 4–5’) as an alternative criterion increased sensitivity to 87%, while estimated specificity was then 95%. It is noteworthy that the estimated sensitivity of a ‘high-grade’ IgM test alone was only 50% (although 100% specific), given the fact that the relevant IgM antibodies might be expected to rise and fall more acutely with the new onset of active disease. Using a different threshold for a positive reaction (261 IgG units/mL), Wu and colleagues143 estimated a sensitivity of 63% and a specificity of 88% for the Anda-TB test, among 92 patients with smear-positive pulmonary TB and a control group of 34 patients with other pulmonary diseases. Studies reporting the application of other serological assays in patients with smear-positive pulmonary TB have reported a similar
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Table 19.9 Commercial antibody detection tests for the diagnosis of pulmonary tuberculosis a
Name of test
Antigen(s)
Antigen source
Ig class
Laboratory technique
Name of manufacturer
Address/URL
Anda-TB
Antigen 60
Native
ELISA
Anda Biologicals S.A.
Detect TB
Five different proteins
ELISA
ADALTIS (formerly BioChem ImmunoSystems)
Strasbourg, France http://www. andabiologicals.com/ Montreal, Quebec, Canada http://www.adaltis. com
ICT TB test
38 kDa and four proprietary antigens
Three recombinant antigens and two synthetic peptides secreted by M. tuberculosis H37Rv Recombinant
IgG, IgA, IgM IgG
IgG
Immunochromatographic test
ICT diagnostics
Kaolin agglutination test MycoDot
Tuberculophosphatide
Native
IgG
Kaolin agglutination test
LAM
Native
IgG
Immunodot rapid (20 minute) test
Hitech Laboratories, Private Ltd Mossman Associates
Pathozyme Myco
LAM and 38 kDa
Native LAM and recombinant 38 kDa
IgG, IgM, IgA
ELISA
Omega Diagnostics Ltd
Pathozyme TB Complex Plus
38 and 16 kDa
Recombinant 38 and 16 kDa
IgG
ELISA
Omega Diagnostics Ltd
Tuberculosis enzyme immunoassay
KP90b contains LAM, 10, 16, 21, 30, 34, 65, and 95 kDa.
Native sonicated preparation
IgG and IgA
ELISA
Tuberculosis glycolipid assay
Contains: trehalose 6,60 dimycolate and trehalose Monomycolate, diacyltrehalose, phenolic glycolipid, 2,3,6,6tetraacyl-trehalose2-sulphate, and 2,3,6triacyl-trehalose
Native preparation from the cell walls of M. tuberculosis H37Rv
IgG
ELISA
Diagnostics, Hema Diagnostic Systems LLC (formerly Kreatech, Amsterdam) Kyowa Medex
Balgowlah, New South Wales, Australia Bombay, India
Blackstone, MA, USA http://www. mossmanassociates. com/ Alloa, UK http://www. omegadiagnostics. co.uk/ Alloa, UK http://www. omegadiagnostics. co.uk/ North Bay Village, FL, USA http://www.Rapid123. com
Tokyo, Japan http://www. kyowamx.co.jp/
Ig, immunoglobulin; LAM, lipoarabinomannan; ELISA, enzyme-linked immunosorbent assay; kDa, kilodalton. a Anda-TB tests include IgG (12); IgM (2); IgA (2); IgG and IgM (1); IgG, IgM, and IgA (2). Pathozyme Myco tests include Myco G (3); Myco M (3); Myco A (2); Myco G and M (1); Myco G and A (1); Myco M and A (1); Myco G, M, and A (1). Tuberculosis enzyme immunoassay includes IgA (4); IgG (1). Nine studies used various combinations of Pathozyme Myco and Pathozyme TB Complex Plus. b http://www.wipo.int/pctdb/en/wo.jsp?WO¼1999%2F30162&IA¼WO1999%2F30162&DISPLAY¼DESC Adapted from Steingart KR, Henry M, Laal S, et al. Commercial serological antibody detection tests for the diagnosis of pulmonary tuberculosis: a systematic review. PLoS Medicine Vol. 4, No. 6, e202 doi:10.1371/journal.pmed.0040202.
range of sensitivity estimates. A recent meta-analysis derived summary receiver operating characteristic (SROC) curves, summarizing the estimated test characteristics of commercially available serological assays for the diagnosis of smear-positive and smearnegative pulmonary TB across a variety of reports, antigens, and settings.140 The area under the curve is an index of combined sensitivity and specificity, with an area of 1 implying perfect sensitivity and specificity; an area of 0.5 implies test performance that is no
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better than chance. For smear-positive pulmonary disease (41 studies), the estimated area under the curve was 0.9, with 95% confidence interval (CI) 0.86–0.94. In summary, for the diagnosis of smear-positive pulmonary TB, the use of existing commercial serological tests cannot be recommended. In particular, their imperfect sensitivity means negative serological tests cannot exclude smear-positive TB with sufficient certainty to discharge ‘TB suspects’ from further testing and/or treatment.
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SEROLOGICAL DIAGNOSIS OF SMEAR-NEGATIVE PULMONARY TUBERCULOSIS Estimates for the sensitivity of serological assays for the diagnosis of smear-negative, culture-positive pulmonary TB have been consistently lower than for smear-positive disease. The lower bacillary load and milder illness in many patients may account for these findings. For example, Julia´n and colleagues141 found sensitivities of 0% for four different PATHOZYME assays, among 11 HIV-negative Spanish patients with smear-negative disease. Using the same assays, Imaz and colleagues144 estimated sensitivities ranging from 29% to 49% among 41 Argentinian patients with smear-negative pulmonary TB; sensitivity increased to 76% when all four tests were used in combination. The specificity of serological assays for the diagnosis of active pulmonary TB is also variable, and predictably reflects the spectrum of disease and the likelihood of latent TB among the control groups studied. In the meta-analysis just cited,140 the pooled specificity estimate for healthy controls, using eight studies, was 95% (95% CI 0.92–0.99); for 22 studies involving controls with non-TB respiratory disease, the pooled specificity estimate was 84% (95% CI 0.78–0.90). As a combined indicator of sensitivity and specificity for 27 studies involving smear-negative pulmonary TB, the estimated area under the summary ROC curve was 0.84 (95% CI 0.77–0.91) – a value somewhat lower than that for smear-positive disease. In resource-poor areas, a cheap serological assay might be valuable despite imperfect sensitivity, if it leads to additional true-positive diagnoses among persons with negative sputum smears but underlying TB. This will be particularly relevant where other tests (sputum cultures, chest radiography) are too cumbersome or expensive, so that persons with smear-negative pulmonary TB ordinarily remain undiagnosed. A high PPV is required, meaning that the specificity of the test as well as the pre-test probability of disease must be high. Kanaujia and colleagues145 found a PPV of 53% for an in-house ELISA assay (seven antigens) among 35 HIV-negative ‘TB suspects’ with negative sputum smears, in San Diego. The overall prevalence of culture-confirmed pulmonary TB was 31%. In other words, had clinicians initiated treatment on the basis of a positive ELISA among persons with negative sputum smears, about half would have been treated appropriately, with the remainder treated unnecessarily. HIV-positive persons with smear-negative pulmonary TB can pose particular diagnostic challenges. Few studies have specifically addressed the performance of serological assays in this context, probably because HIV-associated immune dysregulation would be anticipated to distort results of immune-based diagnostic tests. Indeed, the previously cited meta-analysis did not include any studies of HIV-positive persons, as none was of adequate methodological quality.140 An older Ghanaian study of the Anda-TB assay compared results between 46 HIV-negative patients with smear-positive pulmonary TB, seven HIV-positive patients with smear-positive TB, seven HIV-positive controls, and a mixed group of 29 HIV-negative controls, which included healthy hospital staff as well as patients with other conditions.146 While the quantitative level of antibody responses was significantly less intense among the HIV-positive TB patients than among the HIV-negative TB patients, sensitivity estimates based on the manufacturer-recommended cut-off were similar (71% and 78%, respectively). However, the antibody responses among the HIV-positive controls were virtually identical
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to those among the HIV-positive TB patients, yielding an estimated specificity of only 14%. In summary, available data suggest a limited role for serological assays in persons with negative sputum smears but a high index of suspicion for active pulmonary TB: a positive test will increase the accuracy of presumptive TB diagnoses, providing some additional justification for empiric treatment initiation where appropriate. Such a is relevant only if the test is cheap and easy to perform and interpret under field conditions. If so, a serological assay could be helpful in high-incidence locations, when an antibiotic trial has not improved persistent cough, and no other diagnosis is evident. Unfortunately, available data do not support the application of serological assays to HIV-positive persons or to children, who represent priority groups for the diagnosis of smear-negative disease.
SEROLOGICAL DIAGNOSIS OF EXTRAPULMONARY TUBERCULOSIS Extrapulmonary TB can present formidable diagnostic challenges. Hence serological assays hold substantial appeal in this context. Unfortunately, the sensitivity of these assays has been highly variable and often poor among persons ultimately established to have extrapulmonary TB. For example, Caminero and colleagues147,148 estimated a sensitivity of 53% for the IgG Anda-TB assay performed on serum of 30 patients with pleural TB, and a sensitivity of 32% among 56 patients with extrapulmonary TB involving other body sites. In contrast, with the same assay, Gevaudan and colleagues149 estimated a sensitivity of 94% among 91 patients with ‘primary’ extrapulmonary TB, and a sensitivity of 100% among 75 patients with ‘post-primary’ extrapulmonary TB. Specificity estimates have likewise been variable. Some studies were hampered by the use of healthy controls or persons with non-TB respiratory disease – as opposed to controls with nontuberculous extrapulmonary disease. In an Indian study of 30 patients with lymphatic TB and 32 healthy controls, the estimated specificity of the Anda-TB IgG assay was 59%.150 In the same series, the authors estimated a specificity of 88% for another assay, the SEVA TB test, an IgG-based ELISA which uses a different antigen (the 31-kDa glycoprotein). With two of the PATHOZYME IgG assays (Myco and TB Complex Plus), Nsanze and colleagues151 reported specificities of 100%, comparing 35 patients with extrapulmonary TB and a mixed group of 35 controls, although sensitivity was poor (51% and 11%, respectively). In a systematic review, Steingart and colleagues152 identified 21 studies that evaluated commercial serological antibody detection tests for extrapulmonary TB. These studies evaluated a total of seven distinct commercial tests, with Anda-TB IgG accounting for 48% of the studies. Results of the review demonstrated that: 1. overall, commercial tests provided highly inconsistent estimates of sensitivity (range 0–100%) and specificity (range 59–100%); 2. for all extrapulmonary sites combined, the Anda-TB IgG kit showed highly variable sensitivity (range 26–100%) and specificity (range 50–100%); 3. For all tests combined, sensitivity estimates for both lymph node TB (range 23–100%) and pleural TB (range 26–59%) were poor and inconsistent; and 4. there were no data for determining accuracy of the tests in children or patients with HIV infection, the two groups for which the test would be most useful.
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In summary, currently available serological tests cannot reliably diagnose or exclude extrapulmonary TB.
SEROLOGICAL DIAGNOSIS OF LATENT TUBERCULOSIS Any evaluation of serological tests for the diagnosis of latent TB involves the same methodological challenges as with other novel tests, notably the absence of a gold standard. One group of interest for the evaluation of new diagnostics is persons with inactive TB: the combination of significant radiographic scarring with a positive tuberculin test making latent TB highly likely. In one study involving 225 persons with inactive TB, 71% had positive reactions to the 14-kDa glycoprotein and 53% had positive reactions to ESAT-6, as judged by an in-house IgG ELISA.137 The corresponding proportions were 26% and 7% among 54 persons considered not to have latent infection, based on tuberculin testing and chest radiography. Another relevant group is close contacts of persons with active pulmonary TB. Among 100 household contacts of Gambian patients with smear-positive pulmonary disease, the prevalence of positive serological tests for four common mycobacterial antigens ranged from 32% to 82%, while that for three RD1 antigens ranged from 28% to 54%, using in-house assays.136 Virtually the same frequency of positive tests for each assay was observed among 100 Gambian community controls, while somewhat higher frequencies of positive reactions for ESAT-6 and CFP-10 were noted among patients with active TB. Serological tests are unlikely to prove more sensitive than the TST for the diagnosis of latent TB. Of course, any evaluation which relies on the tuberculin test to establish a diagnosis of latent infection will predictably demonstrate that a novel test is less sensitive. There is the most need for improved detection among HIVpositive individuals, but serological tests for TB are highly unlikely to perform better than the tuberculin test in this setting. A targeted serological test might one day circumvent the reduced specificity of the TST among persons with sensitization to non-tuberculous mycobacteria, or to M. bovis BCG – similar to the current rationale for IGRA use. Cross-reactions of this nature have been a major concern in low-incidence countries, as they focus increasingly on the treatment of latent TB.153 The most promising antigens for distinguishing sensitization to M. tuberculosis from that to non-tuberculous mycobacteria or M. bovis BCG would appear to be those encoded by the RD1 region, such as ESAT-6 and CFP-10. It is disappointing that a study comparing serological responses to ESAT-6 and a panel of other mycobacterial antigens (using in-house assays) found no differences between 32 tuberculin-positive and 50 tuberculin-negative immigrants.139 While the tuberculin-positive group undoubtedly included some individuals with ‘false-positive’ reactions because of BCG vaccination or sensitization to non-tuberculous mycobacteria, most probably did have latent TB.78
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In summary, existing serological tests do not reliably diagnose latent TB. It remains to be seen whether specific serological profiles can predict subsequent progression to active disease. Studies reporting prospective follow-up of sufficient subjects have not yet been reported. Moreover, cross-sectional data comparing groups with active TB, inactive TB, putative latent infection, and apparently uninfected controls will need to be more consistent and more promising with respect to any particular antigen(s), if such a largescale prospective follow-up study is to be justified.
SYNTHESIS For the diagnosis of active disease, the TST and IGRA have suboptimal sensitivity (70–87%), and very poor specificity, because neither test can distinguish latent from active disease. A theoretical advantage of both tests is that they measure cell-mediated immune response – considered the primary response to TB. Serological tests have the appeal of rapidity, simplicity, and low cost. However, these measure the humoral response to TB, rather than the primary host defence mechanism. The search for an accurate serological test has been the modern equivalent of the search for the Holy Grail – often sighted in preliminary studies, but never found in subsequent follow-up studies. Available serological tests do not reliably distinguish active from latent TB and other conditions, and do not reliably diagnose latent TB. Future improvements may yield serological tests that enhance the diagnosis of smear-negative pulmonary TB. However, for such tests to be useful where they are most urgently needed, they must be cheap and yield consistent results. Consistency has not been a feature of field evaluations to date, and the cost-effectiveness of these assays (e.g. conventional diagnostics) will also warrant careful consideration. For the diagnosis of latent infection, the TST has a long history of clinical use, but suffers from lack of specificity, particularly in populations where BCG vaccination is routinely given after infancy. Most importantly, the TST cannot accurately identify the subgroup of approximately 10% of persons with latent TB infection who will develop active TB. Risk factors are known, allowing some prediction; however, identification of persons with LTBI who will develop active disease remains an imperfect art. The new IGRAs are just being introduced into clinical practice, and are undergoing intense evaluation. They have certain operational advantages, but are more complex and expensive. They have excellent specificity, but their sensitivity for latent TB infection is difficult to define, and their value for predicting risk of active disease is unknown. However, they do hold the promise, together with other molecular biology advances, to improve our understanding of latent TB infection. This may improve our ability to predict development of active TB.
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193. Dorken E, Grzybowski S, Allen EA. Significance of the tuberculin skin test in the elderly. Chest 1992;2:237–240. 194. Grzybowski S, Allen EA, Black WA, et al. Innercity survey for tuberculosis: evaluation of diagnostic methods. Am Rev Respir Dis 1987;135(6): 1311–1315. 195. van Zwanenberg D. Tuberculous infection in the home. Tubercle 1955;36:238–244. 196. Zaki MH, Lyons HA, Robins AB, et al. Tuberculin sensitivity. N Y State J Med 1976;76:2138–2143. 197. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975;50:90–106. 198. Van Geuns HA, Meijer J, Styblo K. Results of contact examination in Rotterdam, 1967–1969. Bull Int Union Tuberc 1975;50:107–121. 199. Karalus NC. Contact screening procedures for tuberculosis in Auckland. NZ Med J 1988;101: 45–49. 200. Tamblyn RM, Battista R. Changing clinical practice: which interventions work? J Cont Educ Health Prof 1993;13. 201. Morse DL, Hansen RE, Swalbach G, et al. High rate of tuberculin conversion in Indochinese refugees. JAMA 1982;248(22):2983–2986. 202. Veen J. Aspects of temporary specific anergy to tuberculin in Vietnamese refugees. Amsterdam: KNCV, 1992: 1–119. 203. Fitzpatrick S, Johnson J, Shragg P, et al. Health care needs of Indochinese refugee teenagers. Pediatrics 1987;79(1):118–124. 204. Godue CB, Goggin P, Gyorkos TW. L’allergie tuberculinique chez les revendicateurs du statut de re´fugie´ nouvellement arrive´s au Canada. Can Med Assoc J 1988;139:41–44. 205. Blum RN, Polish LB, Tapy JM, et al. Results of screening for tuberculosis in foreign-born persons applying for adjustment of immigration status. Chest 1993;103:1670–1674. 206. Spinaci S, De Virgilio G, Bugiani M, et al. Tuberculin survey among Afghan refugee children. Tuberculosis control programme among Afghan refugees in North West frontier province (NWFP) Pakistan. Tubercle 1989;70:83–92. 207. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputumsmear-negative pulmonary tuberculosis. Am Rev Respir Dis 1989;139:871–876. 208. Ormerod LP. Tuberculosis screening and prevention in new immigrants 1983-88. Respir Med 1990; 84:269–271. 209. Valenti WM, Andrews BA, Presley BA, et al. Absence of the booster phenomenon in serial tuberculin skin testing. Am Rev Respir Dis 1982;125:323–325. 210. Gross TP, Israel E, Powers P, et al. Low prevalence of the booster phenomenon in nursing-home employees in Maryland. Maryland Med J 1984; 35:107–109. 211. Richards NM, Nelson KE, Batt MD, et al. Tuberculin test conversion during repeated skin testing, associated with sensitivity to nontuberculous mycobacteria. Am Rev Respir Dis 1979;120:59–65. 212. Burstin SJ, Muspratt JA, Rossing TH. The tuberculin test. Studies of the dynamics of reactivity to tuberculin and Candida antigen in institutionalized patients. Am Rev Respir Dis 1986; 134:1072–1074. 213. Alvarez S, Karprzyk DR, Freundl M. Two-stage skin testing for tuberculosis in a domiciliarly population. Am Rev Respir Dis 1987;136:1193–1196. 214. Barry MA, Regan AM, Kunches LM, et al. Twostage tuberculin testing with control antigens in patients residing in two chronic disease hospitals. J Am Geriatr Soc 1987;35:147–153. 215. Lifson AR, Grant SM, Lorvick J, et al. Two-step tuberculin skin testing of injection drug users recruited from community-based settings. Int J Tuberc Lung Dis 1997;1(2):128–134.
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216. Morse DL, Hansen RE, Grabau JC, et al. Tuberculin conversions in Indochinese refugees. Am Rev Respir Dis 1985;132:516–519. 217. Webster CT, Gordin FM, Matts JP, et al. Two-stage tuberculin skin testing in individuals with human immunodeficiency virus infection. Am J Respir Crit Care Med 1995;151:805–808. 218. Hecker MT, Johnson JL, Whalen CC, et al. Twostep tuberculin skin testing in HIV-infected persons in Uganda. Am J Respir Crit Care Med 1997;155: 81–86. 219. Sepulveda RL, Burr C, Ferrer X, et al. Booster effect of tuberculin testing in healthy 6-year-old school children vaccinated with Bacillus CalmetteGuerin at birth in Santiago, Chile. Pediatr Infect Dis J 1988;7(578):581. 220. Friedland IR. The booster effect with repeat tuberculin testing in children and its relationship to BCG vaccination. S Afr Med J 1990;77: 387–389. 221. Wood R, Maartens G, Lombard CJ. Risk factors for developing tuberculosis in HIV-1—infected adults from communities with low or very high incidence of tuberculosis. J Acquir Immune Defic Syndr 2000;23:75–80. 222. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320(9):545–550. 223. Sakhuja V, Jha V, Varma PP, et al. The high incidence of tuberculosis among renal transplant recipients in India. Transplantation 1996;61(2): 211–215. 224. Aguado JM, Herrero JA, Gavalda J, et al. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA. Transplantation 1997;63(9): 1278–1286.
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abnormalities, followed by the chest clinic service. Am Rev Respir Dis 1971;104:605–608. Kim SJ, Hong YP, Lew WJ, et al. Incidence of pulmonary tuberculosis among diabetics. Tuber Lung Dis 1995;76(6):529–533. Silwer H, Oscarsson PN. Incidence and coincidence of diabetes mellitus and pulmonary tuberculosis in a Swedish county. Acta Med Scand 1958;161(Suppl 335):1–48. Pablos-Mendez A, Blustein J, Knirsch CA. The role of diabetes mellitus in the higher prevalence of tuberculosis among Hispanics. Am J Public Health 1997;87(4):574–579. Boucot KR. Diabetes mellitus and pulmonary tuberculosis. J Chronic Dis 1957;6(3): 256–279. Comstock GW. Frost revisited: the modern epidemiology of tuberculosis. Am J Epidemiol 1975;101:363–382. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99(2):131–137. Horwitz O, Wilbek E, Erickson PA. Epidemiological basis of tuberculosis eradication. Longitudinal studies on the risk of tuberculosis in the general population of a low-prevalence area. Bull World Health Organ 1969;41:95–113. Maurya V, Vijayan VK, Shah A. Smoking and tuberculosis: an association overlooked. Int J Tuberc Lung Dis 2002;6(11):942–951. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor a neutralizing agent. N Engl J Med 2001;345 (15):1098–1104. Oxlade O, Schwartzman K, Menzies D. Interferongamma release assays and TB screening in high income countries: A cost effectiveness analysis. Int J Tuberc Lung Dis 2007;11:16–26.
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20
Nucleic acid amplification for detection of Mycobacterium tuberculosis Daniel Brodie and Neil W Schluger
The conventional approach to the laboratory diagnosis of active TB relies on acid-fast bacilli (AFB) smear and culture of relevant samples. In resource-poor areas of the world, AFB smears of respiratory samples may be the only means of laboratory confirmation of the disease, a problematic approach given that AFB smear – though rapid and inexpensive – has poor sensitivity (requires up to 10,000 bacilli per millilitre of specimen). The AFB smear does not distinguish between Mycobacterium tuberculosis complex (MTBC) organisms and non-tuberculous mycobacteria (NTM) impairing its specificity as well–although in TB-endemic areas the specificity is quite good. The resulting failure to accurately identify cases of active TB has profound implications for both the individual and the community. Culture methods are generally quite sensitive and specific; yet even where they are affordable, a delay ranging from 1 to 8 weeks for diagnosis significantly diminishes the ability to control the spread of TB. The need for a diagnostic tool whose results are both accurate and rapidly available to the clinician is self-evident. Beyond this, the prevalence of multidrug-resistant (MDR) TB (detected as reduced drug susceptibility in cultured strains – once again only after several weeks) creates an imperative for the development of diagnostic tools that also allow for more rapid detection of drug resistance (Box 20.1). Nucleic acid amplification (NAA), now widely available, is among the newest diagnostic methods to take up the challenge of accurate and rapid detection and identification of MTBC (as well as NTM). Nucleic acid amplification tests (NAATs) serve to complement – not to replace – the conventional laboratory approach to diagnosing active disease (Box 20.2). Their role in the rapid detection of drug resistance is promising although currently limited.
HOW THEY WORK NAATs amplify M. tuberculosis (MTB)-specific nucleic acid sequences using a nucleic acid probe. These sequences are located on regions of difference between mycobacterial DNA. The most commonly used target sequences are IS6110 and a 16s rRNA, which are specific to the MTBC. More recent targets have been developed specific for MTB itself.1 NAATs enable direct detection of MTBC organisms in clinical specimens. NAATs require as few as 10 bacilli from a given sample under research conditions,2 affording them a reasonable sensitivity for MTB. The sensitivity of the NAATs currently in commercial use is at least 80% in most studies, although the sensitivity of these assays in AFB smear-negative and non-respiratory samples is lower
than that for smear-positive and respiratory samples; newer assays perform considerably better in this regard than do earlier versions, increasing the sensitivity for smear-negative specimens as well as overall sensitivity.3,4 Sensitivity is potentially hampered both by a low burden of bacilli in a given sample and by the presence of inhibitors in the sample that may produce false-negatives (Box 20.3). The issue of overcoming inhibitors has been addressed recently.5–7 NAATs are also quite specific for MTB, with specificities generally reported to be 98% or higher.
THE ASSAYS COMMERCIAL ASSAYS: FDA-APPROVED There are currently two US Food and Drug Administration (FDA)-approved NAATs widely available for commercial use: the AMPLICOR MTB Test (Roche Molecular Diagnostics, CA, USA) and the Amplified MTD (Mycobacterium Tuberculosis Direct or MTD) Test (Gen-Probe, CA, USA). The AMPLICOR assay uses DNA polymerase chain reaction (PCR) to amplify nucleic acid targets. It was approved by the FDA for use in smear-positive respiratory specimens in December 1996. The COBAS AMPLICOR MTB Test (not available in the USA) uses the COBAS AMPLICOR Analyzer, an instrument which automates amplification and detection. The COBAS TaqMan MTB Test is a real-time PCR test made available in Japan in May 2006. This technology allows amplification and detection in a single step, cutting the measurement time in half. The MTD assay is an isothermal strategy for detection of MTB rRNA as described below. It was approved by the FDA in December 1995 for use with smear-positive respiratory specimens. The second-generation MTD, the Amplified MTD (AMTD or enhanced MTD or MTD-2), was FDA approved in May 1998 for smear-positive specimens and significantly, in September 1999, for detection of MTB in both smear-positive and smear-negative respiratory specimens. The AMTD uses an isothermal strategy known as transcriptionmediated amplification (TMA). As described by Shamputa and colleagues,8 mycobacterial rRNA is reverse transcribed to a cDNA–RNA intermediate, the RNA is degraded, and a second primer binds the cDNA, forming a double-stranded DNA. This is then transcribed by RNA polymerase, producing more copies of rRNA which themselves act as further targets for amplification. RNA amplicons are detected with labelled DNA probes via hybridization. A reaction with the label
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Box 20.1 Clinical uses of NAATs 1. Directly detect MTBC organisms in specimens. 2. Distinguish among MTBC organisms. 3. Identify specific NTM. 4. Rapidly detect drug resistance.
Box 20.2 Key point on NAATs 1 NAAT’s complement but do not replace conventional diagnostic techniques and clinical judgement.
Box 20.3 Factors that may lead to false-negative NAATs 1. Too few bacilli. 2. Inhibitors in the specimen. 3. Inadequate specimen handling. 4. Improper testing.
produces visible light measured by a luminometer. Results may be obtained in approximately 3.5 hours.8 In clinical and laboratory studies, the original MTD assay ranged in sensitivity from 83% to 98% for smear-positive respiratory samples and from 70% to 81% for smear-negative respiratory samples.9–17 The specificity in these studies was 98–99%. The AMPLICOR assay performed similarly. The sensitivity of the AMPLICOR for smearpositive respiratory samples was 74–92%,13,15,18–26 and for smearnegative samples 40–88%.15,18,19,23–27 Specificity ranged from 93% to 99%. Laifer and colleagues28 in Switzerland recently tested the AMPLICOR assay in 3,119 war refugees from Kosovo and found a sensitivity of only 64% for pulmonary TB. However, they noted that the negative predictive value (NPV) of three consecutive PCRs (in two sputa and one bronchoalveolar lavage) was 100%. The AMTD brings with it an improved sensitivity,3,4,9,29 especially in smear-negative specimens.3,4 Bergmann and colleagues3 investigated the AMTD in a 1999 study of Texas prison inmates. A total of 1,004 respiratory specimens from 489 inmates tested with AMTD were compared with culture, smear, and clinical course. Twenty-two inmates were diagnosed with pulmonary TB (10 smear-positive and 12 smear-negative). Overall, the AMTD had a sensitivity of 95.2% and a specificity of 99.1%. In smearpositive patients the sensitivity and specificity were both 100%. In smear-negative patients, the sensitivity was 90.2% and the specificity 99.1%.3 A 1999 study from the Central Public Health Laboratory in Etobicoke, Ontario, looked at 823 specimens (616 respiratory) over a 1-year period.4 Using clinical diagnosis as the gold standard, the specificity approximated 100% and the sensitivity for either smear-positive or smear-negative respiratory samples was 100%, an exceptionally high value especially for the smear-negative specimens. Of note, specimens that were smear-negative were preselected for testing with the AMTD based on a clinical determination that the patients were at high risk for TB. Pre-selection no doubt contributed to the high sensitivity and specificity in this study, but suggests there is great utility in selecting appropriate patients for testing.4
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COMMERCIAL ASSAYS: NOT FDA-APPROVED A multitude of other NAATs have been tested. Most of these are the so called ‘in-house’ assays that are not commercially available. Two other commercial tests that have been studied are the LCx test, a ligase chain reaction-based test (Abbott Diagnostics Division, Abbott Park, IL, USA), and the strand displacement amplification (SDA) test known as the BDProbeTec ET Mycobacterium tuberculosis Complex Direct Detection Assay (BDP) (Becton Dickinson Biosciences, Sparks, MD, USA). BDP is a 1-hour assay that couples SDA to a fluorescent energy transfer detection system. Investigators have increasingly tested the BDP in recent years. BDP performs similarly to the AMTD and to the COBAS Amplicor with a suggestion of a trade-off of lowered specificity for increased sensitivity.30–33 In one study, using the combined gold standard of culture and clinical diagnosis, the overall sensitivity of the BDP was 56.7%, which dropped to 40.5% in smear-negative samples, with a specificity of 95.3%.34 In another study by the same authors, the test characteristics were slightly better.35 This contrasts with a study by McHugh and colleagues36 where the sensitivity and specificity of the BDP in respiratory samples were noted to be 93% and 92% using final clinical diagnosis as the gold standard.36 Excellent performance was also observed by Rusch-Gerdes and colleagues.37 They evaluated the BDP in respiratory and non-respiratory specimens. In the 735 smear-positive respiratory specimens, the sensitivity and specificity were both 100%. In smear-negative respiratory specimens, the sensitivity was reported to be 87.1% and the specificity 96.5%. The BDP performed similarly in the 396 non-respiratory specimens.37 A separate NAA technology currently in development is the loopmediated isothermal amplification (LAMP) technology platform (Eiken Chemical Co., Tokyo, Japan). The LAMP platform has been used to detect other organisms; however, the first-generation LAMP-based assay for TB is now being developed by Eiken Chemical in conjunction with the Foundation for Innovative New Diagnostics (FIND) and may be available as soon as 2010 (FIND website: http://www.finddiagnostics.org/activities/tb/tb_pipeline. shtml). LAMP involves DNA amplification without the requirement for a thermocycler and with visual detection. It is rapid and yet it is also simpler and less expensive than available techonologies.38
PERFORMANCE OF COMMERCIAL ASSAYS A recent meta-analysis of the commercially available NAATs (Amplicor, COBAS Amplicor, AMTD, BDP, and LCx) in smearpositive and smear-negative respiratory specimens confirmed the exceptional sensitivity in smear-positive specimens (pooled sensitivity 96%) and the lower sensitivity in smear-negative specimens (pooled value 66%). However, while specificity remained 98% in smear-negative specimens, the analysis challenged the notion that the specificity is maintained in all samples with a pooled specificity of only 85% in smear-positive specimens.39 This would question the ability to rule in TB in smear-positive samples. Of note, the AMTD was alone in maintaining an overall excellent specificity (96% across studies) in the smear-positive specimens.39
IN-HOUSE ASSAYS The in-house assays mostly use PCR technology and vary significantly in their test characteristics. Flores and colleagues40 performed a meta-analysis of in-house NAATs for detecting MTB in sputum samples and demonstrated a vast range of sensitivities (9.4–100%)
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and specificities (5.6–100%). They noted that use of IS6110 and nested PCR methods were both associated with improved diagnostic accuracy. A meta-analysis of PCR techniques for the diagnosis just of smear-negative pulmonary TB was published by Sarmiento and colleagues.41 The sensitivity of PCR-based techniques is most suspect in smear-negative specimens as was seen in this analysis, which revealed a range of sensitivities from 9% to 100%. Specificities also varied significantly from 25% to 100%.41 A variety of less standardized techniques have been developed and tested.42–47 None of these tests has been approved for use in the USA.
THE ROLE OF CLINICAL SUSPICION OF MYCOBACTERIUM TUBERCULOSIS A clinically relevant investigation of the AMTD by Catanzaro and colleagues48 evaluated its performance in a multicentre, prospective trial. In this study, the AMTD was evaluated against the backdrop of a patient’s clinical suspicion for pulmonary TB, which was stratified into low, intermediate, or high risk as determined by physicians with expertise in evaluating patients for TB. The risk was determined by clinical investigators for 338 patients. The specificity of the AMTD was very high in all groups and the sensitivities were 83%, 75%, and 87%, respectively. However, the positive predictive value (PPV) was low in the low-risk group at 59%, as compared with 100% in the other two groups, whereas the NPV was especially high in the low-risk group, 99%, and remained high at 91% in the intermediate- and high-risk groups. These results compared very favourably with the AFB smear, which had PPVs of 36%, 30%, and 94%, and NPVs of 96%, 71%, and 37%. This study highlights the potential utility of the AMTD test and suggests that it may be particularly helpful for confirming disease in intermediate- and high-risk patients and for excluding cases in low-risk patients.48 The utility of incorporating the clinical judgement of specialists when reviewing the results of NAATs was also demonstrated by Piersimoni and colleagues.49 Applying clinical judgement to the results of the LCx test improved the sensitivity for the diagnosis of pulmonary TB from 68% to 93%.
GUIDELINES FOR USE In 2000, the Centers for Disease Control and Prevention (CDC) updated its recommendations for use of NAATs for the diagnosis of active tuberculosis.50 The CDC recommends that AFB smear and NAA be performed on the first of three sputum smears collected as well as the first positive sputum smear (if there is a positive sample). If smear and NAA are both positive, pulmonary TB is diagnosed with near certainty. Although they note that, unless there is clinical concern for NTM, the NAA test adds little additional information. If the smear is positive and the NAA is negative, the statement recommends testing the sputum for inhibitors by spiking the sputum sample with an aliquot of lysed MTB and repeating the assay. If inhibitors are not detected, the process is repeated on additional specimens (to a maximum of three in all scenarios) and, if still smear-positive, NAA-negative, and without inhibitors, the patient can be presumed to have NTM. If inhibitors are detected, the NAA test on that sample is unhelpful and additional samples may be tested with the NAA. If a sputum is smear-negative but AMTD-positive (only the AMTD is approved for smear-negative specimens), the CDC
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recommends sending additional samples. If further samples are AMTD-positive, the patient can be presumed to have pulmonary TB. If both the smear and AMTD are negative, an additional specimen should be tested by AMTD. If negative, the patient can be presumed not to be infectious. The recommendations conclude by noting that clinicians must always rely on clinical judgement and that, ultimately, definitive diagnosis rests on response to therapy and culture results.50 Although logically consistent, these recommendations are expensive and based on few published data. One study addressed the issue of always testing the first of three specimens for pulmonary TB with the AMTD, suggesting it may be worthwhile as it decreased turnaround time for diagnosis in 75% of cases from 21 days to 4 days.51 Nevertheless, this seems difficult to justify in smear-negative, low-risk patients given the low PPV. Overall, a reasonable use of NAATs (ideally the AMTD, again because it is approved for use with both smear-positive and negative specimens) for rapid diagnosis of pulmonary TB from respiratory samples is as follows (Fig. 20.1): NAATs should be used to confirm that a positive AFB smear does indeed represent MTB. If both smear and NAA are positive, pulmonary TB is diagnosed with near certainty. If the smear is positive and the NAA is negative, testing the sputum for inhibitors and repeating the assay is warranted.52 If inhibitors are not detected and the process is repeated on additional specimens and is negative, the patient can be presumed to have NTM. If smears are negative, but clinical suspicion is intermediate or high (based on the impression of experienced observers48,53,54), NAA should be performed on a sputum sample, and a presumptive diagnosis of TB made if the test is positive. NAA should not be performed on sputum samples from cases in which the AFB smear is negative and the clinical index of suspicion is low.48,54,55 This algorithm is less applicable in TB-endemic areas where a positive AFB smear is highly specific for MTB and further testing would add little to overall accuracy. However, the AMTD could still be used in smear-negative samples to confirm the diagnosis when the clinical suspicion is intermediate or high. Given the overall cost of underdiagnosis, such an approach might be prudent and effective. The optimal use of NAA testing for pulmonary TB requires further study. However, one issue that is clear is that NAATs, because they will detect nucleic acids from both living and dead organisms, cannot be used either to gauge response to therapy or as a test of cure. NAATs may be falsely positive for active disease in patients with a recent history of infection who have been adequately treated.12,56–58 Testing should be limited to those who have not been recently treated for active disease for more than 7 days.52 In contrast to NAATs that employ DNA or rRNA, the use of an assay to detect MTB mRNA with a half-life of only minutes offers an indicator of MTB viability. Assays that detect mRNA remain positive only so long as viable mycobacteria persist and are therefore useful as sensitive indicators of adequate treatment and for rapid determination of drug susceptibility.59 This technology is under study.
THE USE OF NAAT S FOR THE DIAGNOSIS OF EXTRAPULMONARY TUBERCULOSIS Diagnosing extrapulmonary TB is invariably more difficult than diagnosing pulmonary TB. In most cases the samples are paucibacillary, decreasing the sensitivity of diagnostic tests (Box 20.4). This applies to AFB smear and culture as well as to NAATs (which are
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GENERAL CLINICAL FEATURES AND DIAGNOSIS
TB suspect* Send sputum for culture AFB smear of sputum
+
Clinical suspicion of MTB
NAA assay
Intermediate or high
Low Unlikely MTB
NAA assay
+
Test for inhibitors
Unlikely MTB
NAA, no inhibitors
NAA+
Repeat sample
MTB NAA+
Presumed MTB
+
Test for inhibitors
Repeat sample If negative for inhibitors ¥2 NTM
*Not currently being treated for active disease for >7 days
Fig. 20.1 Use of NAATs in respiratory samples.
Box 20.4 Key point on NAATs 2 NAATs in extrapulmonary TB are less sensitive because of lower levels of bacilli and increased levels of inhibitors.
further hampered by an increased incidence of inhibitors present in non-respiratory specimens as compared with respiratory specimens7). Testing for extrapulmonary TB follows the same principles as those for pulmonary TB. However, as accuracy of diagnosis is attenuated in extrapulmonary TB, clinicians must rely more heavily on clinical judgement and response to treatment. NAATs are increasingly utilized in the diagnosis of extrapulmonary TB, although their role in this setting has yet to be fully defined. The performance characteristics of NAATs in non-respiratory specimens are reasonably good. The overall sensitivity for the MTD or AMTD ranged in several studies from 67% to 100%.4,9–11,17,29,30,60 In smear-negative samples, the sensitivity was 52% in one study and 100% in another.4,17 The AMPLICOR had a similar sensitivity in smear-positive samples,20,26,61 but the sensitivity in those that are smear-negative may be lower.26 The specificity of both remains very high in non-respiratory samples. The BDP may deliver similar sensitivity to the AMTD in nonrespiratory samples.30,62,63 NAA testing in extrapulmonary TB has been studied most closely in patients with tuberculous pleuritis and meningitis. However, reports from other anatomic sites are rapidly proliferating in the literature, including lymphadenitis;64–66 orchiepididymitis;66 urinary TB;27,67 peritoneal TB;68 gastric fluid, bone, pericardium, and abscess contents;27 and intestinal TB.69
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NAATs FOR TUBERCULOUS PLEURITIS AND MENINGITIS In tuberculous pleuritis, the low yields of microscopy and culture and the invasiveness of pleural biopsy have generated interest in alternative non-invasive diagnostics. While adenosine deaminase (ADA) and interferon-g levels in pleural fluid are promising,70 NAA testing has attracted considerable additional attention in recent years. So too, in the setting of tuberculous meningitis, the poor sensitivity of microscopy and culture and the time needed for cultures to become positive provide an opening for tests employing NAA from which results may be rapidly obtained. A recent meta-analysis by Pai and colleagues71 of NAA testing in tuberculous pleuritis looked at both commercially available tests and in-house tests. The commercial tests included the MTD, Amplicor, and LCx tests. These tests consistently yielded high specificities in the same range as those for sputum samples (overall 98%), but significantly lower sensitivities (overall 62%). Of note, five of the six studies employing the MTD test used the first-generation MTD, not the AMTD. Given the improved sensitivity of the enhanced MTD test in sputum samples (especially in smear-negative sputum samples), it is possible that these studies underestimate the sensitivity of this test in tuberculous pleuritis as well. In a more recent study, the COBAS Amplicor had an even lower sensitivity at 18.8%.72 Studies comparing the tests in this setting are lacking. By contrast, among the 26 studies involving in-house NAATs that were reviewed, there was such great heterogeneity in estimates of both sensitivity and specificity that no useful pattern emerged.71 Among the studies included in this meta-analysis, it is interesting to note that one of them also demonstrated that an in-house PCR technique which was compared with ADA was superior in both sensitivity
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(70% vs 55%) and specificity (100% vs 55%),73 and in another study a separate in-house PCR was similar in both sensitivity and specificity to ADA and interferon-g levels (88%, 85.7%, and 73.8% sensitive and 85.7%, 97.1%, and 90% specific, respectively).74 Pai and colleagues75 performed an earlier meta-analysis looking at both commercial and in-house NAATs in the setting of tuberculous meningitis. This analysis produced conclusions strikingly similar to that on tuberculous pleuritis. Summary estimates for the commercial assays revealed a sensitivity of 56% and a specificity of 98%. The in-house tests demonstrated significant variability in this population as well, ultimately precluding summary analysis. Notably, the authors point out that, among the 35 studies performed with in-house tests, ‘15 different methods were used for DNA extraction, and eight different target sequences were amplified.’75 In a recent study by Thwaites and colleagues76 of diagnosing tuberculous meningitis, acid-fast staining was superior to the AMTD in sensitivity (52% vs 38%). Combining the two tests yielded a higher overall sensitivity at 68%. And repeated sampling improved the sensitivities of smear (64%), AMTD (59%), and the combined tests (83%). The only advantage of using the AMTD alone in this study was in subjects who had begun anti-tuberculous therapy. After 5–15 days of treatment, AMTD maintained a sensitivity of 28%, while smear decreased to 2%.76 The BDP demonstrated similar test characteristics in a study that used it in the setting of tuberculous meningitis, although a modification to the assay increased the sensitivity from 61.5% to 76.9%.63 While the role of NAA testing in the diagnosis of tuberculous pleuritis and meningitis remains undefined, nevertheless the high specificities should render them rather useful for ruling in these diagnoses, as Pai and colleagues note.71,75 However, the lower sensitivities suggest that they are inadequate for excluding these diagnoses, if used alone. More study is needed to evaluate the relative benefits of NAA testing as compared with ADA or interferon-g levels in diagnosing tuberculous pleuritis. By contrast, in the case of tuberculous meningitis where the current diagnostic armamentarium is so limited, the potential immediate contribution of NAA testing, while currently difficult to quantify, appears to be significant. Assessing the utility of NAA testing of other anatomic sites awaits further data.
COST-EFFECTIVENESS Cost may be the main consideration limiting the use of the NAATs particularly in the developing world. A study in Nairobi in 1998 compared the cost-effectiveness of AMPLICOR with AFB smear.77 AFB smear was 1.8 times as cost-effective. However, the same group in Nairobi conducted a study from 2000 to 2001 which suggested that although the cost per correctly diagnosed case was higher with the PCR, when treatment costs were considered, overall the PCR was a more cost-effective tool.78 A cost-effectiveness analysis conducted in Finland in 2004 showed that the addition of COBAS AMPLICOR PCR to smear and culture was not cost-effective unless limited to smear-positive specimens.79 However, extending this to smear-negative specimens may be possible when employing the AMTD, given its superior sensitivity in smear-negative patients with PTB. Furthermore, centralized laboratories offer the ability to invest in technology and batch testing, develop expertise, and benefit from economies of scale. In such settings, regular NAA testing may be economically feasible.4,80
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USE OF NAA IN THE RAPID DETECTION OF DRUG RESISTANCE MDR TB poses a major public health problem in many parts of the world. Traditional methods of drug susceptibility testing rely on cultures of MTB inoculated with antibiotics and can take weeks for results to be known. The ability to rapidly detect drug resistance would be vitally important to TB control efforts, enabling appropriate treatment to be administered expeditiously and a decrease in transmission of the MDR strain. A major limitation of NAATs discussed so far is that they give no drug susceptibility information. Several NAATs cross over from simple detection of MTBC to the identification of specific mycobacteria and, more importantly, to the rapid detection of drug resistance. The detection of rifampin resistance may be used as a surrogate for uncovering multidrug resistance since most rifampin-resistant isolates are also isoniazid-resistant.81,82 Rifampin resistance signals the need for treatment with second-line drugs. It is currently feasible to rapidly detect rifampin resistance. One approach takes advantage of genotypic abnormalities by identifying mutations primarily in the region of the MTB rpoB gene. The rpoB gene encodes the beta subunit of the RNA polymerase to which rifampin binds under wild-type conditions. When a mutation occurs in this region, rifampin binding (and therefore efficacy) may be significantly reduced, leading to rifampin resistance. rpoB gene mutations are associated with the vast majority of rifampinresistant strains of MTB. Similarly, the detection of isoniazid resistance may also be accomplished by focusing on a mutation in the catalase peroxidase (katG) gene, which is reported to be found in 60–90% of isoniazid-resistant strains.83 Coupling a variety of NAA assays that identify genetic mutations (line probe assays and molecular beacons, for instance) to PCR, real-time PCR, or related technologies allows rapid detection of the drug-resistant mutations from specimens.81,84–90
LINE PROBE ASSAYS Line probe assays use PCR and reverse hybridization with specific oligonucleotide probes fixed to nitrocellulose strips in parallel lines and are therefore often referred to as ‘strip tests’. These assays may be used for both the detection and identification of a variety of mycobacterial species. They may also be used for the simultaneous and rapid identification of mutations in the katG gene (associated with isoniazid resistance) or the rpoB gene (associated with rifampin resistance) or both. The INNO-LiPA Mycobacteria v2 (Innogenetics, Ghent, Belgium), which targets the 16s-23s rRNA gene spacer region, and the GenoType MTBC and other GenoType Mycobacteria tests (Hain Lifesciences GmbH, Nehren, Germany), which focus on the 23s rRNA region, are line probe assays for the simultaneous detection and identification of most clinically relevant mycobacteria; both are very sensitive.91,92 The INNO-LiPA Rif.TB (Innogenetics) assay detects MTB and is very sensitive for simultaneously detecting rifampin resistance.86–88,93,94 The GenoType MTBDR (Hain Lifesciences GmbH) is used for the detection of resistance to both isoniazid and rifampin via the katG and rpoB genes. It operates under the same principles as the INNO-LiPA Rif.TB with the additional ability to directly detect isoniazid resistance. A recent meta-analysis of the INNO-LiPA Rif.TB by Morgan and colleagues.95 determined that the sensitivity for rifampin resistance
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Table 20.1 Summary of the NAATs and their primary functions NAA test
Test type
Detection of MTBC
Identification of mycobacteria species
Detection of resistance
AMPLICOR AMTD
DNA PCR rRNA transcription-mediated amplification DNA strand displacement amplification Ligase chain reaction Variable (mostly PCR) Line probe assay Line probe assay Line probe assay Line probe assay Real-time PCR with fluorescent labelled probes
Yes Yes
No No
No No
Yes Yes Yes Yes Yes Yes Yes Not primarily
No No No Yes No Yes No Not primarily
No No No No Yes (Rif) No Yes (Rif, INH) Yes (Rif and/or INH)
BDP LCx ‘In-house’ NAA tests INNO-LiPA Mycobacteria v2 INNO-LiPA Rif.TB GenoType mycobacteria tests GenoType MTBDR Molecular beacons
NAA, nucleic acid amplification; PCR, polymerase chain reaction; MTBC, M. tuberculosis complex; Rif, rifampin; INH, isoniazid.
when applied to clinical specimens was 80–100% with a specificity of 100%. When tested against TB isolates, the sensitivity was greater than 95%.95 A very recent study from the Institute of Tropical medicine in Antwerp, Belgium, involved 420 sputum samples from 11 countries (76% from Rwanda and Bangladesh) collected and stored between 1992 and 2005, the greatest number of clinical specimens tested to date.96 The INNO-LiPA Rif.TB demonstrated 99.6% concordance with culture for rifampin resistance. Of note, 92% of rifampin-resistant specimens were also isoniazid-resistant, consistent with the prior literature.96 The GenoType MTBDR when tested in MTBC isolates was 92–100% sensitive for rifampin-resistant isolates and 67–88% sensitive for isoniazid-resistant isolates with 100% specificity.97–100 When tested directly in smear-positive specimens, the sensitivities were 95–96% and 84%, respectively.101,102 In two comparisons of the GenoType MTBDR and the INNOLiPA Rif.TB in TB isolates, the GenoType MTBDR identified 90.4% of isoniazid-resistant isolates and 98.1% of rifampin-resistant isolates in the first study, and the INNO-LiPA Rif.TB also identified 98.1% of the rifampin-resistant isolates.83 In the second study, GenoType MTBDR identified 95.1% of 41 known rifampin-resistant isolates, whereas INNO-LiPA Rif.TB identified 98%. The GenoType MTBDR also identified 73% of 37 isoniazid-resistant isolates.103
MOLECULAR BEACONS Molecular beacons are nucleic acid hybridization probes. They are designed to bind to target DNA sequences in regions, such as the rpoB, where resistance mutations are known to occur. Molecular beacons will fluoresce only when bound to their targets so that a mutation – even a single nucleotide substitution – will prevent
REFERENCES 1. Soo PC, Horng YT, Hsueh PR, et al. Direct and simultaneous identification of Mycobacterium tuberculosis complex (MTBC) and Mycobacterium tuberculosis (MTB) by rapid multiplex nested PCRICT assay. J Microbiol Methods 2006;66(3): 440–448.
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fluorescence. A real-time PCR assay utilizing molecular beacons can identify drug resistance in sputum samples in less than 3 hours and is both sensitive and specific.104 Lin and colleagues84 designed a set of molecular beacons for the detection of isoniazid- and rifampin-resistant mutations in MTB organisms from both culture and smear-positive respiratory specimens. The sensitivity and specificity for detection of isoniazid resistance was 82.7% and 100%, and for rifampin resistance was 97.5% and 100%, respectively. Similar findings were previously reported by Piatek et al.105 Using real-time PCR and molecular beacons on isolates from Mexico and India, Varma-Basil and colleagues106 showed a sensitivity and specificity for rifampin resistance of 89% and 99%, respectively (Table 20.1).
CONCLUSIONS NAA offers a complementary approach to detecting MTBC and other mycobacterial species that combines rapid results with good diagnostic accuracy. NAA testing also offers an alternative means of rapidly detecting drug-resistant strains of MTB. These techniques do not supplant traditional AFB-smear, culture, and sensitivity testing but they add significantly to our ability to diagnose and therefore control the spread of TB. Cost and requirements for advanced technology and laboratory skills limit the applicability of some of these technologies. This is especially true in developing countries where standardization and quality assurance may also be significant barriers to reliable NAA testing. However, for those tests that are not yet cost-effective or easily performed, efforts to streamline the technologies may make the tests practical for widespread use in the near future in resource-rich and, in some cases, even in resource-poor countries.
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meta-analysis and meta-regression. BMC Microbiol 2005;5:55. Sarmiento OL, Weigle KA, Alexander J, et al. Assessment by meta-analysis of PCR for diagnosis of smear-negative pulmonary tuberculosis. J Clin Microbiol 2003;41(7):3233–3240. Sperhacke RD, Mello FC, Zaha A, et al. Detection of Mycobacterium tuberculosis by a polymerase chain reaction colorimetric dot-blot assay. Int J Tuberc Lung Dis 2004;8(3):312–317. Lemaitre N, Armand S, Vachee A, et al. Comparison of the real-time PCR method and the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for detection of Mycobacterium tuberculosis in pulmonary and nonpulmonary specimens. J Clin Microbiol 2004;42(9):4307–4309. Miller N, Cleary T, Kraus G, et al. Rapid and specific detection of Mycobacterium tuberculosis from acid-fast bacillus smear-positive respiratory specimens and BacT/ALERT MP culture bottles by using fluorogenic probes and real-time PCR. J Clin Microbiol 2002;40(11):4143–4147. Cleary TJ, Roudel G, Casillas O, et al. Rapid and specific detection of Mycobacterium tuberculosis by using the Smart Cycler instrument and a specific fluorogenic probe. J Clin Microbiol 2003;41(10): 4783–4786. Gill P, Ramezani R, Amiri MV, et al. Enzyme-linked immunosorbent assay of nucleic acid sequence-based amplification for molecular detection of M. tuberculosis. Biochem Biophys Res Commun 2006; 347(4):1151–1157. Suzuki T, Tanaka M, Otani S, et al. New rapid detection test with a combination of polymerase chain reaction and immunochromatographic assay for Mycobacterium tuberculosis complex. Diagn Microbiol Infect Dis 2006;56(3):275–280. Catanzaro A, Perry S, Clarridge JE, et al. The role of clinical suspicion in evaluating a new diagnostic test for active tuberculosis: results of a multicenter prospective trial. JAMA 2000;283(5):639–645. Piersimoni C, Nista D, Zallocco D, et al. Clinical suspicion as a primary guidance to use commercial amplification tests for rapid diagnosis of pulmonary tuberculosis. Diagn Microbiol Infect Dis 2005; 53(3):195–200. Centers for Disease Control and Prevention. Update: Nucleic acid amplification tests for tuberculosis. MMWR Morb Mortal Wkly Rep 2000;49(26):593–594. Moore DF, Guzman JA, Mikhail LT. Reduction in turnaround time for laboratory diagnosis of pulmonary tuberculosis by routine use of a nucleic acid amplification test. Diagn Microbiol Infect Dis 2005;52(3):247–254. Sloutsky A, Han LL, Werner BG. Practical strategies for performance optimization of the enhanced GenProbe Amplified Mycobacterium Tuberculosis Direct Test. J Clin Microbiol 2004;42(4):1547–1551. Divinagracia RM, Harkin TJ, Bonk S, et al. Screening by specialists to reduce unnecessary test ordering in patients evaluated for tuberculosis [see comments]. Chest 1998;114(3):681–684. Lim TK, Mukhopadhyay A, Gough A, et al. Role of clinical judgment in the application of a nucleic acid amplification test for the rapid diagnosis of pulmonary tuberculosis. Chest 2003;124(3):902–908. Van den Wijngaert S, Dediste A, VanLaethem Y, et al. Critical use of nucleic acid amplification techniques to test for Mycobacterium tuberculosis in respiratory tract samples. J Clin Microbiol 2004; 42(2):837–838. Yuen KY, Chan KS, Chan CM, et al. Use of PCR in routine diagnosis of treated and untreated pulmonary tuberculosis. J Clin Pathol 1993;46(4):318–322. Walker DA, Taylor IK, Mitchell DM, et al. Comparison of polymerase chain reaction amplification of two mycobacterial DNA sequences, IS6110 and the 65kDa antigen gene, in the diagnosis of tuberculosis. Thorax 1992;47(9):690–694. Schluger NW, Kinney D, Harkin TJ, et al. Clinical utility of the polymerase chain reaction in the diagnosis of infections due to Mycobacterium tuberculosis. Chest 1994;105(4):1116–1121.
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59. Hellyer TJ, DesJardin LE, Teixeira L, et al. Detection of viable Mycobacterium tuberculosis by reverse transcriptase-strand displacement amplification of mRNA. J Clin Microbiol 1999;37(3):518–523. 60. Lang AM, Feris-Iglesias J, Pena C, et al. Clinical evaluation of the Gen-Probe Amplified Direct Test for detection of Mycobacterium tuberculosis complex organisms in cerebrospinal fluid. J Clin Microbiol 1998;36(8):2191–2194. 61. Shah S, Miller A, Mastellone A, et al. Rapid diagnosis of tuberculosis in various biopsy and body fluid specimens by the AMPLICOR Mycobacterium tuberculosis polymerase chain reaction test. Chest 1998;113(5):1190–1194. 62. Mazzarelli G, Rindi L, Piccoli P, et al. Evaluation of the BDProbeTec ET system for direct detection of Mycobacterium tuberculosis in pulmonary and extrapulmonary samples: a multicenter study. J Clin Microbiol 2003;41(4):1779–1782. 63. Johansen IS, Lundgren B, Tabak F, et al. Improved sensitivity of nucleic acid amplification for rapid diagnosis of tuberculous meningitis. J Clin Microbiol 2004;42(7):3036–3040. 64. Bruijnesteijn van Coppenraet ES, Lindeboom JA, Prins JM, et al. Real-Time PCR assay using fineneedle aspirates and tissue biopsy specimens for rapid diagnosis of mycobacterial lymphadenitis in children. J Clin Microbiol 2004;42:2644–2650. 65. Kerleguer A, Fabre M, Bernatas JJ, et al. Clinical evaluation of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test for rapid diagnosis of tuberculosis lymphadenitis. J Clin Microbiol 2004;42(12):5921–5922. 66. Barisic Z, Vrsalovic-Carevic N, Milostic K, et al. Tuberculous orchiepididymitis diagnosed by nucleic acid amplification test: a case report. Int Urol Nephrol 2003;35(2):203–205. 67. Takahashi S, Hashimoto K, Miyamoto S, et al. Clinical relevance of nucleic acid amplification test for patients with urinary tuberculosis during antituberculosis treatment. J Infect Chemother 2005;11(6):300–302. 68. Dervisoglu E, Sayan M, Sengul E, et al. Rapid diagnosis of Mycobacterium tuberculous peritonitis with real-time PCR in a peritoneal dialysis patient. Apmis 2006;114(9):656–658. 69. Balamurugan R, Venkataraman S, John KR, et al. PCR amplification of the IS6110 insertion element of Mycobacterium tuberculosis in fecal samples from patients with intestinal tuberculosis. J Clin Microbiol 2006; 44(5):1884–1886. 70. Brodie D, Schluger NW. The diagnosis of tuberculosis. Clin Chest Med 2005;26(2):247–271, vi. 71. Pai M, Flores LL, Hubbard A, et al. Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis 2004;4:6. 72. Moon JW, Chang YS, Kim SK, et al. The clinical utility of polymerase chain reaction for the diagnosis of pleural tuberculosis. Clin Infect Dis 2005;41(5):660–666. 73. Nagesh BS, Sehgal S, Jindal SK, et al. Evaluation of polymerase chain reaction for detection of Mycobacterium tuberculosis in pleural fluid. Chest 2001;119(6):1737–1741. 74. Villegas MV, Labrada LA, Saravia NG. Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-gamma in pleural fluid for the differential diagnosis of pleural tuberculosis. Chest 2000;118(5): 1355–1364. 75. Pai M, Flores LL, Pai N, et al. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003;3(10):633–643. 76. Thwaites GE, Caws M, Chau TT, et al. Comparison of conventional bacteriology with nucleic acid amplification (amplified mycobacterium direct test) for diagnosis of tuberculous meningitis before and
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after inception of antituberculosis chemotherapy. J Clin Microbiol 2004;42:996–1002. Roos BR, van Cleeff MR, Githui WA, et al. Costeffectiveness of the polymerase chain reaction versus smear examination for the diagnosis of tuberculosis in Kenya: a theoretical model. Int J Tuberc Lung Dis 1998;2(3):235–241. van Cleeff M, Kivihya-Ndugga L, Githui W, et al. Costeffectiveness of polymerase chain reaction versus ZiehlNeelsen smear microscopy for diagnosis of tuberculosis in Kenya. Int J Tuberc Lung Dis 2005;9(8):877–883. Rajalahti I, Ruokonen EL, Kotomaki T, et al. Economic evaluation of the use of PCR assay in diagnosing pulmonary TB in a low-incidence area. Eur Respir J 2004;23(3):446–451. Dowdy DW, Maters A, Parrish N, et al. Costeffectiveness analysis of the Gen-Probe Amplified Mycobacterium Tuberculosis Direct Test as used routinely on smear-positive respiratory specimens. J Clin Microbiol 2003;41(3):948–953. Fan XY, Hu ZY, Xu FH, et al. Rapid detection of rpoB gene mutations in rifampin-resistant Mycobacterium tuberculosis isolates in Shanghai by using the amplification refractory mutation system. J Clin Microbiol 2003;41(3):993–997. Albert H, Trollip AP, Mole RJ, et al. Rapid indication of multidrug-resistant tuberculosis from liquid cultures using FASTPlaqueTB-RIF, a manual phage-based test. Int J Tuberc Lung Dis 2002;6(6):523–528. Makinen J, Marttila HJ, Marjamaki M, et al. Comparison of two commercially available DNA line probe assays for detection of multidrug-resistant Mycobacterium tuberculosis. J Clin Microbiol 2006;44 (2):350–352. Lin SY, Probert W, Lo M, et al. Rapid detection of isoniazid and rifampin resistance mutations in Mycobacterium tuberculosis complex from cultures or smear-positive sputa by use of molecular beacons. J Clin Microbiol 2004;42(9):4204–4208. Mokrousov I, Otten T, Vyshnevskiy B, et al. Allelespecific rpoB PCR assays for detection of rifampinresistant Mycobacterium tuberculosis in sputum smears. Antimicrob Agents Chemother 2003;47(7):2231–2235. Cooksey RC, Morlock GP, Glickman S, et al. Evaluation of a line probe assay kit for characterization of rpoB mutations in rifampinresistant Mycobacterium tuberculosis isolates from New York City. J Clin Microbiol 1997;35(5):1281–1283. Hirano K, Abe C, Takahashi M. Mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis strains isolated mostly in Asian countries and their rapid detection by line probe assay. J Clin Microbiol 1999;37(8):2663–2666. Marttila HJ, Soini H, Vyshnevskaya E, et al. Line probe assay in the rapid detection of rifampin-resistant Mycobacterium tuberculosis directly from clinical specimens. Scand J Infect Dis 1999;31(3):269–273. Yam WC, Tam CM, Leung CC, et al. Direct detection of rifampin-resistant mycobacterium tuberculosis in respiratory specimens by PCR-DNA sequencing. J Clin Microbiol 2004;42(10):4438–4443. Marin M, Garcia de Viedma D, Ruiz-Serrano MJ, et al. Rapid direct detection of multiple rifampin and isoniazid resistance mutations in Mycobacterium tuberculosis in respiratory samples by real-time PCR. Antimicrob Agents Chemother 2004;48(11):4293–4300. Padilla E, Gonzalez V, Manterola JM, et al. Comparative evaluation of the new version of the INNO-LiPA Mycobacteria and genotype Mycobacterium assays for identification of Mycobacterium species from MB/BacT liquid cultures artificially inoculated with Mycobacterial strains. J Clin Microbiol 2004;42(7):3083–3088. Franco-Alvarez de Luna F, Ruiz P, Gutierrez J, et al. Evaluation of the GenoType Mycobacteria Direct assay for detection of Mycobacterium tuberculosis complex and
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four atypical mycobacterial species in clinical samples. J Clin Microbiol 2006;44(8):3025–3027. Johansen IS, Lundgren B, Sosnovskaja A, et al. Direct detection of multidrug-resistant Mycobacterium tuberculosis in clinical specimens in low- and highincidence countries by line probe assay. J Clin Microbiol 2003;41(9):4454–4456. Watterson SA, Wilson SM, Yates MD, et al. Comparison of three molecular assays for rapid detection of rifampin resistance in Mycobacterium tuberculosis. J Clin Microbiol 1998;36(7):1969–1973. Morgan M, Kalantri S, Flores L, et al. A commercial line probe assay for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis. BMC Infect Dis 2005;5:62. Traore H, van Deun A, Shamputa IC, et al. Direct detection of Mycobacterium tuberculosis complex DNA and rifampin resistance in clinical specimens from tuberculosis patients by line probe assay. J Clin Microbiol 2006;44(12):4384–4388. Hillemann D, Weizenegger M, Kubica T, et al. Use of the genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis complex isolates. J Clin Microbiol 2005; 43(8):3699–3703. Brossier F, Veziris N, Truffot-Pernot C, et al. Performance of the genotype MTBDR line probe assay for detection of resistance to rifampin and isoniazid in strains of Mycobacterium tuberculosis with low- and high-level resistance. J Clin Microbiol 2006;44(10):3659–3664. Hillemann D, Rusch-Gerdes S, Richter E. Application of the Genotype MTBDR assay directly on sputum specimens. Int J Tuberc Lung Dis 2006;10(9):1057– 1059. Miotto P, Piana F, Penati V, et al. Use of genotype MTBDR assay for molecular detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis clinical strains isolated in Italy. J Clin Microbiol 2006;44(7):2485–2491. Somoskovi A, Dormandy J, Mitsani D, et al. Use of smear-positive samples to assess the PCR-based genotype MTBDR assay for rapid, direct detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin. J Clin Microbiol 2006;44(12):4459–4463. Bang D, Bengard Andersen A, Thomsen VO. Rapid genotypic detection of rifampin- and isoniazidresistant Mycobacterium tuberculosis directly in clinical specimens. J Clin Microbiol 2006;44(7): 2605–2608. Cavusoglu C, Turhan A, Akinci P, et al. Evaluation of the genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis isolates. J Clin Microbiol 2006;44(7): 2338–2342. El-Hajj HH, Marras SA, Tyagi S, et al. Detection of rifampin resistance in Mycobacterium tuberculosis in a single tube with molecular beacons. J Clin Microbiol 2001;39(11):4131–4137. Piatek AS, Telenti A, Murray MR, et al. Genotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular beacons: implications for rapid susceptibility testing. Antimicrob Agents Chemother 2000;44(1):103–110. Varma-Basil M, El-Hajj H, Colangeli R, et al. Rapid detection of rifampin resistance in Mycobacterium tuberculosis isolates from India and Mexico by a molecular beacon assay. J Clin Microbiol 2004;42(12):5512–5516.
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Histopathology and cytopathology Colleen A Wright and Juanita Bezuidenhout
HISTOPATHOLOGICAL DIAGNOSIS OF TUBERCULOSIS
The slides are stained with haematoxylin and eosin (HþE), the standard histopathological stain.1
SAMPLES
INTERPRETATION
The most common specimens received for histological examination of TB are lymph nodes and pleural biopsies, followed by lung biopsies. Skin and gastrointestinal (from the mouth to the rectum) biopsies are relatively frequent. Synovial, bladder, prostate, and endometrial biopsies may occasionally show granulomatous inflammation. To obtain optimal results, adequate sampling of the tissue and optimal fixation is of the utmost importance. It is advisable to always submit the largest possible specimen, with the least possible trauma artefact for histopathology examination. With small biopsies, the possibility of crush artefact is always present. This unfortunately results in destruction of the morphology, often leading to a preferred diagnosis of ‘tissue not suitable for histological examination’. When submitting a specimen for histological examination, adequate clinical information is always crucial, particularly in immunocompromised patients, where the histology may be atypical and classical granulomatous inflammation can often not be seen, as discussed in Chapter 12. A high index of suspicion in such cases is the only justification for performing a Ziehl–Neelsen (ZN) stain, which may often demonstrate acid-fast bacilli (AFB) in an unexpected morphological setting. If possible, it is important to ascertain whether a localized or a systemic process is present. The tissue sample should be immersed in a 10% formalin solution immediately after the procedure to guarantee optimal fixation, ensuring that the container is large enough to accommodate the specimen with ease and that the formalin covers the specimen. This affords the pathologist the best possible opportunity to effectively interpret the sections. A sample for culture (not in formalin) should always be submitted to microbiology if TB is clinically suspected. In complicated cases, where the clinical differential diagnosis often includes lymphoma, the specimen may be submitted fresh to the laboratory, but only if the laboratory is in close proximity. This will enable imprints of the lymph node to be made for cytology, a sample can be selected for microbiology, and the most suitable tissue can be selected for histopathology and other investigations, such as electron microscopy.
On the HþE-stained slides, the first step in the diagnosis is to decide whether granulomatous inflammation is present and to classify the granuloma. Is it a well-formed granuloma, as often seen in early TB or sarcoidosis, or a loosely packed granuloma dominated by giant cells, as seen in foreign body reactions or extrinsic allergic alveolitis? Is there surrounding fibrosis, suggestive of a chronic process as seen in sarcoidosis and long-standing or treated TB? Is central necrosis observed? What is the morphological appearance of the necrosis? Is the necrosis caseating (TB), suppurative (cat-scratch disease), or coagulative? The first indication of possible TB is the presence of granulomatous inflammation. Depending on the stage of disease, the immune status and age of the patient, empirical treatment for TB, and the type of specimen, this might be very easy, or extremely subtle to interpret. In classical TB, numerous granulomas in various stages of development can be seen, some with central caseous necrosis. A definitive diagnosis of mycobacterial infection can be made on a ZN stain (Fig. 21.1).1 Mycobacteria are characteristically beaded, rod-shaped AFB that stain red with the ZN stain. Organisms are usually found at the periphery of necrotic areas, amongst the epithelioid cells or sometimes in giant cells. In well-formed, non-necrotic granulomas, very few organisms may be seen. The number of organisms usually increases with the amount of necrosis, especially in immunosuppressed patients. The age of the lesion and previous treatment may also play a role in identifying the organisms. The advent of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) completely changed the classical picture of TB and three histological stages of cellular immune response correlating with depletion of the peripheral blood CD4þ lymphocyte count have been described.2 In immunocompetent individuals with HIV-1 infection, tuberculous granulomas are characterized by abundant epithelioid macrophages, Langhans giant cells, peripherally located CD4þ lymphocytes, and a paucity of bacteria. In individuals with moderate HIV-associated immunodeficiency, Langhans giant cells are not seen, epithelioid differentiation and activation of macrophages are absent, there is CD4þ lymphocytopenia, and AFB are more numerous. In individuals with advanced HIV-associated immunosuppression and AIDS, there is a striking paucity of granuloma formation with little cellular recruitment, very few CD4þ lymphocytes, and even larger numbers of AFB (for illustration please refer to Chapter 12).
PROCESSING Tissue samples are routinely processed according to a standard processing technique dependent on the laboratory equipment available.
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Fig. 21.1 (A) In classical TB very few acid-fast bacilli are visible. A single bacillus within a multinucleated giant cell is demonstrated (ZN, 1000 magnification immersion oil). (B) In immunocompromised patients, especially in HIV-related infections, numerous acid-fast bacilli are usually visible in the background of poor granuloma (400 magnification) formation.
Identification of AFB on histology must be confirmed by culture, as the organism cannot be subtyped on histology and drug susceptibility cannot be determined.
DIFFERENTIAL DIAGNOSIS To definitively diagnose mycobacterial infection, the organisms must be demonstrated microscopically, by culture or by any of the more recent techniques. In the absence of organisms, the following conditions will be amongst the histopathological differential diagnoses of granulomatous inflammation. Clinicopathological correlation is of the utmost importance.
Idiopathic diseases Sarcoidosis Sarcoidosis is a multisystem granulomatous disease of unknown aetiology, although several organisms have been investigated as possible causes, among these Mycobacterium tuberculosis.3–6 The disease is characterized by non-caseating granulomas, which either resolve or progress to fibrosis. The severity of disease varies and there are individuals whose disease is asymptomatic or subclinical.7 The radiological picture of pulmonary sarcoidosis may vary considerably, but the histological picture is always that of granulomatous disease, with or without accompanying fibrosis. Ninety per cent of patients present with hilar lymphadenopathy or pulmonary involvement on chest radiograph. Skin and eye lesions are also fairly common. Respiratory symptoms include shortness of breath, cough, chest pain, and haemoptysis, which may be massive. Although the chest radiograph findings may vary enormously, the classical finding is that of a reticulonodular infiltrate, implying delicate alveolar septum involvement (reticular) as well as aggregates of granulomas (nodular).8 The macroscopic size and distribution of the granulomas differ significantly and explain the variation in radiological findings. Since other diseases, including mycobacterial and fungal infections, can also produce non-caseating granulomas, the diagnosis of sarcoidosis is one of clinicopathological correlation. However, the granulomas in sarcoidosis do have a characteristic appearance suggestive of the diagnosis on histology.9 The granulomas are well formed, consisting of tightly clustered epithelioid macrophages, usually with Langhans or foreign body-type giant cells, and often
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lacking significant surrounding inflammation. Concentric fibrosis, surrounding the granuloma, is often a feature (Fig. 21.2). A variety of changes may be seen in the granulomas, but none are specific to this disease. These include small foci of fibrinoid necrosis and giant cells with inclusions such as Schaumann bodies, asteroid bodies, and calcium oxalate crystals. The granulomas are distributed along the pulmonary lymphatics in the pleura and septa, and along pulmonary arteries, veins, and bronchi, often involving these structures. An interstitial infiltrate of lymphocytes and plasma cells often occurs in the alveoli adjacent to granulomas. The lymphatic distribution is classical of sarcoidosis and assists in distinguishing sarcoidosis from other granulomatous diseases. More than 50% of cases show histological involvement of pulmonary arteries and/or veins. This can probably be explained by the lymphatic distribution of this disease. Both small and large airways are frequently involved by granulomas and are often visible as small submucosal nodules on bronchoscopy. An interstitial infiltrate of lymphocytes and plasma cells are frequently present in sarcoidosis, especially around the granulomas. Sarcoidosis can also be seen in
Fig. 21.2 The well-formed tight granulomas typical of sarcoidosis are evident. Well-established, concentric fibrosis is represented by the solid red rings around the granulomas.
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many other organs, resulting in a similar granulomatous response. These include the skin and salivary glands.
Crohn’s disease Crohn’s disease enters the differential diagnosis of especially intestinal TB. It is part of the group of inflammatory bowel disease, with numerous possible extraintestinal manifestations, including migratory polyarteritis, ankylosing spondylitis, erythema nodosum, and clubbing. Macroscopically it occurs predominantly in the distal part of the small bowel but the mucosa typically shows skip lesions, with areas of normal mucosa alternating with ulceration, arranged along the long axis of the bowel as opposed to the short crosswise ulcers of TB. Histologically transmural inflammation, ulceration, fissures, non-caseous granulomas, and fibrosis can be seen. On ZN, no organisms can be identified.10 Wegener’s granulomatosis Wegener’s granulomatosis is typically seen in the upper airways and kidneys. It consists of granulomatous inflammation, vasculitis, and necrosis (Fig. 21.3). Classically a leucocytoclastic vasculitis, with geographic necrosis, surrounded by palisading epithelioid histiocytes is seen.11 Rheumatoid disease In patients with rheumatoid disease, nodules may be found especially in the skin or in the lungs. They may be the only manifestation of disease and patients with pulmonary nodules may present with haemoptysis. These nodules may be quite large and can measure up to 3 cm in diameter. The nodules have a necrotic centre, surrounded by palisading macrophages, which is characteristic of this lesion. Some giant cells and plasma cells can also be seen.12 Fungal infections Most fungal infections elicit a granulomatous response. One of the fungi that mimics caseous necrosis is Histoplasma capsulatum. The granulomas are often isolated or small and scattered, thereby resembling miliary granulomas. The organism can be identified histologically. They are intracellular organisms, with 1–5 mm, round to oval yeast-like bodies, with a small, central round nucleus. Periodic acid–Schiff (PAS) and methenamine–silver (Meth-Ag) stains highlight these organisms.
21
Other fungi that may cause granulomas are Cryptococcus neoformans (Fig. 21.4A), Blastomyces dermatitides, Aspergillus (Fig. 21.4B), Mucorales, causing mucormycosis (Fig. 21.4C), and Coccidioides immitis.13 Some of these organisms are associated with definite geographical regions. Because of the ease of travel, however, diseases do not necessarily present in a geographic distribution. The granulomas in cryptococcal infection are usually poorly formed, but they may produce typical caseating granulomas. The organisms are 3–8 mm in diameter, and may be difficult to visualize on HþE stain. On staining with mucicarmine, the thick magentastaining capsule is easy to visualize. Aspergillosis often occurs in immunocompromised hosts, or as a complication of cavitary TB, especially in the lung. In healthy persons it may cause a granulomatous reaction, with caseous necrosis and cavity formation. Aspergillus has branching septate hyphae and is intermediate in size between Candida and Mucor. The hyphae are easily recognizable on HþE as well as on PAS and Meth-Ag stains. Culture is, however, required for confirmation of the diagnosis.
Parasites A number of parasites commonly elicit a granulomatous response. The most common of these would be Schistosoma, which may infect virtually any organ in the body, especially the urinary bladder and the urinary tract, appendix, and on occasion the lung, when passing through as part of the life cycle (Fig. 21.4D).13 Toxoplasmosis is caused by Toxoplasma gondii and typically involves the cervical lymph nodes in young women. In the lymph nodes prominent follicular hyperplasia, small granulomas within and on the edge of the reactive follicles, and distension of the sinuses by monocytoid B cells can be seen. Sometimes necrosis and isolated giant cells can be seen in the granulomas. Bacterial infections Environmental mycobacteria In infection by environmental mycobacteria (also called nontuberculous mycobacteria), the pathological changes are fairly similar to those in TB. In a study on mycobacterial cervical lymphadenitis four histological features that favoured non-tuberculous infection were identified.14 These four are presence of microabscesses, ill-defined granulomas, non-caseating granulomas, and small numbers of giant cells. Usually, as in TB, very few organisms can be identified on ZN stains. In cases of severe immunodeficiency, very few, if any, granulomas are present and numerous organisms can be identified in the distended macrophages. Leprosy Leprosy is a classical granulomatous disease and presents as two principal forms, namely lepromatous and tuberculoid leprosy. Lepromatous leprosy represents the end of the spectrum where resistance to Mycobacterium leprae is virtually non-existent and the disease is progressive. Numerous AFB can be seen in sheets of histiocytes. Granulomas are not a feature. On the other end of the spectrum is tuberculoid leprosy, where cellular immunity is pronounced and typical well-formed, non-caseating granulomas are seen. AFB are very rare, or absent. In lymph nodes, germinal centres are not prominent and histiocytes packed with organisms are not present.15
Fig. 21.3 Poorly formed granulomas with a leucocytoclastic vasculitis are visible in this section from a lung with Wegener’s granulomatosis (x100 magnification HþE).
Tertiary syphilis Scattered, small granulomas without caseous necrosis can be seen, but the hallmark of tertiary syphilis is the presence of arteritis and phlebitis with hyperplasia of the endothelium and a perivascular
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A
B
C
D
Fig. 21.4 Various organisms that may cause granuloma formation. These organisms are often found in association with necrotizing non-caseating granulomas. (A) Cryptococcus neoformans, (B) Aspergillus (C) Mucor, and (D) Schistosoma haematobium.
cuff of lymphocytes and plasma cells. In lymph nodes, prominent follicular hyperplasia is present and the follicles may often take on bizarre shapes. In isolated cases necrosis may be present in the granulomas. A Warthin–Starry stain may identify the presence of Treponema pallidum spirochaetes in the tissue, although this is a very difficult stain to interpret.16
Cat scratch disease Bartonella henselae is usually induced by a cat scratch or splinters and thorns. At the site of the scratch a vesicular lesion develops; 1–3 weeks later regional lymphadenopathy develops. Constitutional symptoms may be present. The typical granulomas in cat scratch disease show stellate central necrosis, with neutrophils, palisading epithelioid histiocytes, and only occasional giant cells. The organism may be identified on the Warthin–Starry stain, especially in necrotic areas.17 Granuloma inguinale In granuloma inguinale, caused by Calymmatobacterium granulomatis, poorly formed granulomas, consisting predominantly of histiocytes and some plasma cells, as well as scattered small abscesses, may be seen.18 Donovan bodies, small, round, encapsulated bodies in the histiocytes’ cytoplasm, can be identified on HþE stain, but are more easily demonstrated with a Giemsa or Warthin–Starry stain.17
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Foreign bodies Foreign particles often provoke a granulomatous response, usually associated with foreign body-type giant cells, with or without necrosis. Classically, these cells have haphazardly arranged nuclei as opposed to the orderly arranged peripheral nuclei of Langhans-type giant cells seen in TB. However, neither of these two is pathognomonic, and either can be seen in any of the granulomatous conditions. The most useful way to identify foreign bodies not readily visible on HþE stain is to polarize the sections, highlighting the presence of any foreign material. Some of the particles include those found in the lungs, such as beryllium, lipids, gastric content, and intravenous injection of oral drugs. Other examples include endogenous foreign bodies (keratin, lipids, urate, cholesterol, calcium) and iatrogenic foreign bodies (tattoos, paraffin, silicone, vaccination, drugs – legal and illegal – skin tests, sutures, talc). Hypersensitivity pneumonitis This pulmonary disease, associated with an extensive list of causes, including farmer’s lung and bird fancier’s disease, may present with granulomatous pulmonary disease. These granulomas are usually small, poorly formed, and interstitial, but, especially in immunocompromised patients, may be difficult to distinguish from TB.19
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21
The immune status of the patient is essential, if known to the clinician, as specimens from immunocompromised patients may show significantly altered cytomorphology compared with the classical cytomorphology of immunocompetent patients.24–27 In addition, if mycobacterial disease is suspected clinically, stains for mycobacteria should routinely be performed on these patients, and may be positive in the absence of the cytopathological changes suggestive of mycobacterial infection.
FLUIDS
Fig. 21.5 A gout tophus, represented by gout crystals, surrounded by multinucleated giant cells and macrophages.
Other Other possibilities that might provoke a granulomatous response include granulomatous inflammation associated with malignancy, e.g. malignant lymphoma and non-lymphoma malignancies, and metabolic disease, e.g. gout (Fig. 21.5). ANCILLARY INVESTIGATIONS Several ancillary techniques are now available for use on paraffinembedded wax blocks. These include immunohistochemistry, in situ hybridization, and polymerase chain reaction (PCR). These molecular techniques are described in more detail in Chapters 4, 20, and 23.
CYTOLOGICAL DIAGNOSIS OF TUBERCULOSIS SAMPLES Cytopathology specimens most appropriate for the diagnosis of TB are fine needle aspiration biopsies (FNABs). A presumptive diagnosis of TB may be suggested on other specimens such as pleural and pericardial effusion samples, ascitic fluid, cervicovaginal (Pap) smears, or sputum, but more effective methods such as fluorescent smear microscopy or culture are available to this end. These specimen types are more commonly submitted to the cytopathology laboratory to exclude or diagnose malignancy.20,21 In children the difficulty in obtaining a sputum specimen is well documented, and, although induced sputum may provide an adequate specimen, this requires skill and may be a source of nosocomial infection for health workers.22,23 Alternative specimens may be aspirates from the nasopharynx, trachea, and stomach, which may not be well tolerated.22 Hospitalized patients may undergo bronchoscopy and washings and brushings, and bronchoalveolar lavage (BAL) specimens may be submitted to the cytology laboratory. This is usually in addition to the specimens submitted to microbiology for direct microscopy and culture. Adequate clinical information including the origin of the specimen submitted, age and gender of the patient, and duration of symptoms greatly enhance the diagnosis proffered by the pathologist.
Pleural, pericardial and ascitic fluid, respiratory specimens (bronchial washings and brushings, BAL, and nasopharyngeal, tracheal, and gastric aspirates), urine, and cerebrospinal fluid (CSF) The role of cytopathology in the diagnosis of TB on fluids is primarily triage – to exclude malignancy – and then supportive, and should be assessed in conjunction with biochemistry, adenosine deaminase (ADA) levels, and microbiological culture. All fluids must be submitted in clean containers to the cytology laboratory as soon as possible after collection as it is preferable not to add alcohol or other fixative to the fluid. For reliable results CSF must reach the cytology laboratory within 1 hour after the specimen has been taken. If this is not feasible the specimen may be added to a fixative, such as equal volumes of 50% alcohol. For pleural, pericardial or ascitic taps, the full volume removed must be sent to the cytology laboratory and not a sample of the fluid withdrawn. Although catheterized urine specimens may be submitted, including selective catheterization, the preferred urine specimen received is an early morning midstream urine. Processing Pleural, pericardial, and ascitic fluid, respiratory specimens (sputum – see below) 1. Decant fluid into two labelled glass test tubes and centrifuge at 1500 rpm for 10 minutes. 2. Decant supernatant back into original container. 3. Pipette sediment onto corresponding labelled slides and place second glass slide parallel to first without pressure, allowing sediment to disperse. Rapidly pull slides apart in a horizontal direction, maintaining constant contact between slides. 4. Spray-fix one slide with commercial alcohol-based fixative within 10 seconds from a distance of 30 cm. 5. Air-dry second slide. 6. The fixed slide is stained with the Papanicolaou stain, which is a nuclear stain, and the air-dried slide with the Giemsa stain, which is a cytoplasmic stain.
Sputum 1. Homogenize sputa in Sacomanno tubes, one filled with water and one with 70% alcohol. 2. Decant homogenized specimen into glass tubes and centrifuge at 1500 rpm for 10 minutes. 3. Decant supernatant and pipette sediment onto corresponding labelled slides and place second glass slide parallel to first without pressure, allowing sediment to disperse. Rapidly pull slides apart in a horizontal direction, maintaining constant contact between slides.
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4. Spray-fix one slide with commercial alcohol-based fixative within 10 seconds from a distance of 30 cm. 5. Air-dry second slide. 6. Stain as for fluids.
Urine and CSF 1. Decant fluid into two labelled glass test tubes and centrifuge at 1500 rpm for 10 minutes. 2. Decant supernatant back into original container. 3. The sediment is then spun in a cytospin chamber as follows. 4. Pipette sediment into cytospin chambers, label slide, filter paper, and place in corresponding chamber. Add 1 drop of 1:1 ether-alcohol solution to sediment, with the exception of the chamber containing CSF for Giemsa staining. 5. Centrifuge at 1500 rpm for urine and 700 rpm for CSF for 10 minutes. 6. Remove slides, spray-fix one slide for Papanicolaou staining and air-dry the second for Giemsa staining.
Cytomorphology Pleural, pericardial, and ascitic fluid Numerous mature lymphocytes in the virtual absence of mesothelial cells in an effusion are virtually diagnostic of TB.28,29 These cells are predominantly CD4þ T cells and the CD4/CD8 ratio is increased in the fluid when compared with the peripheral blood – compartmentalization.29 All other infective inflammatory or neoplastic conditions which affect the serous cavities cause hyperplasia of mesothelial cells, which are present in the resultant effusions. This is in addition to the cells in the fluid which are dependent on the primary pathology, i.e. neutrophils in bacterial infections and neoplastic cells in malignancy. This diagnostic pattern, however, is altered in HIV-infected patients in whom large numbers of mesothelial cells have been shown to be present in tuberculous effusions.27,29 If there is direct involvement of the body cavity, such as in tuberculous pleuritis, mesothelial cells may be present, forming papillae and mimicking malignancy. In addition necrosis, epithelioid histiocytes, and giant cells may be present in the fluid.30 The presence of giant cells is not diagnostic of TB, because they may be present in effusions due to other causes such as rheumatoid arthritis.30 CSF The cellular composition in the CSF in tuberculous meningitis is essentially non-specific and dependent on the stage of the disease.30 In the early stages neutrophils predominate, followed by activated lymphocytes and macrophages and plasma cells.31 Although giant cells may be seen, they are non-specific and may be seen in meningeal sarcoidosis and reactions to foreign material.30 Urine Cytological features of granulomatous inflammation such as macrophages, epithelioid histiocytes, and lymphocytes may be seen in urine specimens from the lower or upper urinary tract,32 but patients with TB of the urinary tract may present with sterile pyuria and with numerous neutrophils on the cytological smears, and the diagnosis of mycobacterial infection may only be made on demonstration of the organism on ZN stains or culture. Sputum, gastric, nasopharyngeal, and tracheal aspirates Adequacy of the sputum specimen is assessed by the presence of carbon-laden macrophages or alveolar pneumocytes. Gastric aspirates should show the presence of normal or reactive columnar
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epithelium. In immunocompromised patients, pathology, such as opportunistic infections like cytomegalovirus (CMV), cryptococcus, and pneumocystis, as well as neoplasia, such as Kaposi’s sarcoma and lymphoma, should be actively excluded. Granulomatous inflammation such as epithelioid histiocytes in clusters or forming granulomas in a background of amorphous necrosis is classical of TB and may be seen in cavitating pulmonary disease. The presence of organisms should be confirmed on ZN and fluorescent microscopy and confirmed on culture.
BAL, bronchial brushings/washings The cytological examination is primarily to exclude pathology other than TB. If there is direct involvement of the bronchial tree the classical features of granulomatous inflammation with or without necrosis may be seen, with epithelioid histiocytes, singly, in clusters, or forming poorly formed granulomas. Confirmation of the diagnosis would be by demonstration of the organism on ZN or fluorescent microscopy, bronchial biopsy, or culture. FINE NEEDLE ASPIRATION BIOPSY FNAB is an extremely rapid, safe, and cost-effective diagnostic modality in clinically suspected extrapulmonary TB. It may be performed in radiologically demonstrated lesions in deep organs such as liver, kidney, and adrenal glands but in these instances it is more likely to be performed to exclude or diagnose malignancy. The real value of FNAB is in tuberculous lymphadenitis. TB lymphadenopathy is the commonest extrapulmonary manifestation of TB, particularly in developing countries with a high incidence of HIV. The HIV pandemic has made the diagnosis of TB more problematic.33 In a recent study in Cape Town, South Africa, lymphadenopathy was shown to be the commonest extrapulmonary manifestation of TB in children.34 FNAB of these lymph nodes is effective and is of even more value as children are more likely to be sputum smearnegative, and obtaining sputum from children is difficult.35 Obtaining other specimens such as gastric aspirates and induced sputum is laborious and the yield is disappointing.33 FNAB of superficial lesions requires virtually no infrastructure or equipment; it does not require sterile procedures and may be easily and safely performed by medical and paramedical personnel. The slides, once prepared, do not deteriorate and can be transported over distances to central cytopathology laboratories. This makes it an ideal diagnostic technique for developing countries, with a high prevalence of TB and HIV, and limited resources.36–40
FNAB technique Superficial FNAB may be performed on any palpable well-defined mass lesion. The most commonly aspirated sites are lymph nodes. In HIV-infected patients parotid masses are also often aspirated. Lymph nodes 1 cm or more in diameter, particularly in children with persistent lymphadenopathy in which a local cause has been excluded, may be successfully aspirated and provide a high diagnostic yield. At least two needle passes, each yielding two slides, should be performed on all patients. This has been shown to give a consistently acceptable adequacy rate. However, if pus or abundant necrotic material is aspirated from a patient with suspected mycobacterial infection, one needle pass will suffice. Each aspirate when correctly prepared will yield two slides: one air-dried and one fixed with alcohol-based commercial spray fixative. The air-dried slides are stained with a Romanowsky stain, which is a cytoplasmic stain allowing identification of the lineage
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21
or origin of cells. The fixed slide is stained with a Papanicolaou stain, which is a nuclear stain and allows differentiation between benign and malignant cells based on nuclear features.
Equipment
22- or 23-gauge needle. 10 mL syringe. Cytology slides. (These are glass slides with ground glass edges.) Commercial cytology spray fixative. Alcohol-based skin disinfectant. Containers to transport slides to laboratory.
Consent and analgesia It is always preferable to obtain written consent from patients for the procedure. Written consent from a parent or guardian is required for children. The patient should be informed of possible minor complications, such as tissue bleeds (haematomas) and very rare serious complications such as pneumothorax and what to do should this occur. No local anaesthetic should be given. This affects the quality of the aspirate and the morphology of the cellular material. As the needle is fine, the procedure is not particularly painful. Children under the age of 5–6 years should preferably be given oral sedation and analgesia 30 minutes prior to the procedure with the purpose of achieving amnesia for the event. In children over the age of 6 years it is preferable to obtain the cooperation of the child by explaining the procedure, stating the alternative option (admission to hospital and a surgical biopsy) and allowing the caregiver to remain with the child to provide reassurance and support. Procedure 1. Patients should wherever possible be aspirated lying down, as they are more comfortable, more stable, and more easily aspirated in this position. It is also safer in the event of a vasovagal attack, which may occur infrequently. In young children ensure adequate assistance to hold the child still during the procedure. Do not request the caregiver to assist in holding the child down. 2. Ensure the slides are clearly labelled with the patient’s details on the frosted end using a pencil. 3. Clean the skin with an alcohol swab. 4. Immobilize the mass with one hand and insert the needle into the mass at an angle that will allow access to the entire lesion, directing the needle away from the fingers. This will usually mean inserting the needle laterally into the mass. 5. If the mass is mobile, e.g. a lymph node, move the needle and syringe back and forth. The mass should move with the movement of the needle. If it does not, withdraw the needle a few millimetres and reinsert until the mass moves with movement of the needle (Fig. 21.6). 6. Pull back on the plunger of the syringe to create a vacuum of no more than 1 mL. This is to prevent capillaries being drawn into the needle tip and causing a bloody aspirate. 7. Aspirate the mass by moving the needle in a fan-like fashion throughout the mass, maintaining a constant suction (Fig. 21.7). Do not allow the needle to withdraw from the mass during the aspiration procedure. 8. When material is present in the hub of the needle, release the suction and withdraw the needle. Do not aspirate until there is material in the barrel of the syringe, as this is difficult to
1 cc of suction
Fig. 21.6 Aspiration of a cervical lymph node. Nodes beneath the sternocleidomastoid muscle should preferably be avoided.
Fig. 21.7 Needle is moved in a fanlike manner to ensure optimal sampling.
expel. If pus or fluid is aspirated, as much fluid or pus as possible should be aspirated as this may be therapeutic. 9. Apply a small cotton wool swab to the puncture wound and ask the patient or assistant to apply pressure while you prepare slides. This will minimize bleeding or bruising.
Preparation of slides 1. Slides must be prepared within 10 seconds of withdrawing the needle or the material will be too degenerated for diagnosis. 2. Remove the needle from the syringe and pull 8–10 mL air into the barrel and reattach needle. 3. Holding the needle onto the syringe (to prevent it shooting off if the needle should block), push the plunger sharply down while touching the tip of the needle onto one glass slide, 1 cm from the frosted end (Fig. 21.8). 4. Holding the slide firmly in one hand, place the second slide parallel to and face down on the first slide, exert gentle pressure to allow material to spread on the slide, and then, maintaining this pressure, pull the slides apart, keeping them parallel until the end of the slide (Fig. 21.9). 5. Spray-fix one slide holding the can 12–15 cm from the slide, until wet. 6. Air-dry the second slide. 7. Repeat the procedure using a clean needle and syringe (second pass).
Cysts Lymphoepithelial cysts in HIV-infected patients may commonly be encountered in aspirates of the parotid or masses at the angle of the mandible.41 If fluid is aspirated, the cyst should be emptied as far as
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If this is not available the needle and syringe can be rinsed in sterile saline and the saline submitted in a sterile tube to the laboratory. If pus has been aspirated, only one or two drops of pus should be inoculated into the TB culture medium and the remainder submitted in a sterile dry tube. Material can also be obtained for molecular investigations such as PCR and fluorescent in situ hybridization (FISH).
Fig. 21.8 Expression of material onto the slide.
Fig. 21.9 Spreading the material between two parallel slides.
possible. Leave the needle in the cyst, detach the syringe, empty the contents of the syringe into a clean container, reattach the syringe, and withdraw fluid. When all possible fluid has been withdrawn, remove the needle and palpate the lesion. Aspirate all residual masses for smears. Submit fluid and smears labelled ‘residual mass’ to the cytology laboratory. If no residual mass is palpated, and the fluid is clear and straw-coloured, no further aspirate is needed, and the fluid is submitted to the laboratory.
Bloody aspirates Blood obscures the cells on the smear and makes them difficult or impossible to interpret. If blood is aspirated immediately upon inserting the needle, withdraw the needle, discard the needle and syringe, and re-aspirate using a smaller needle. If blood is aspirated towards the end of an aspirate, express the bloody material onto two slides and, before preparing the smears, tilt the slides up with one end on absorbent paper and allow the excess blood to run off before preparing the smears as above. If blood is repeatedly aspirated immediately on insertion of the needle, without applying suction, particularly in lymph node aspirates, prepare smears of the bloody aspirate and ask the pathologist on the request form to exclude Kaposi’s sarcoma. Mycobacterial culture FNAB is ideal for obtaining material for microbiological culture, particularly for bacteria such as mycobacteria as well as fungal organisms such as Aspergillus. Ideally in suspected mycobacterial infections TB culture medium such as BACTEC or MGIT (Becton Dickinson, Maryland, USA) should be inoculated at the bedside. Once the slides have been prepared, the culture medium should be drawn into the needle and syringe used for the aspirate and the syringe rinsed with the TB culture medium. This provides an excellent yield and there is minimal contamination.
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Processing and staining Routine staining The fixed slides are stained with the Papanicolaou stain and the airdried slides with the Diff Quik or Giemsa stain according to standard protocols. The slides are then screened by the cytologist and a preliminary diagnosis proffered. If mycobacterial infection is suspected on cytomorphology, or in cases of clinically suspected mycobacterial infection, ZN staining is requested. This is important as studies have shown that positive identification of organisms may be made on ZN or fluorescent staining, even in the absence of diagnostic cytomorphological features of TB.42 ZN staining The technique for ZN staining may be different from that used in histopathology, as the smears are less resistant to decolourization. The Kinyoun stain, used for M. leprae, may be more successful at demonstrating the organisms on cytology specimens.1 Autofluorescence The Papanicolaou-stained slides may be screened on a fluorescent microscope using a blue filter. Mycobacteria, as well as yeasts, fungal organisms, and certain other bacteria, have the intrinsic property of autofluorescence. FNAB is ideal for this investigation as the aspirates, unlike sputum, usually have no commensal organisms other than the pathogen causing the disease. Mycobacteria can be identified by their classical cytomorphology – curved rod-shaped bacilli, 3–5 mm long showing polar enhancement (Fig. 21.10).43 Cytomorphology The diagnosis of mycobacterial infection on FNAB has become more difficult with the advent of the HIV pandemic. This is due to a number
Fig. 21.10 Autofluorescence of Papanicolaou-stained smears of a lymph node aspirate in which mycobacteria fluoresce as yellow, slightly curved, rod-like bacilli with polar enhancement.
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Histopathology and cytopathology
of reasons, including altered cytomorphology in immunocompromised patients. In addition, HIV-infected patients may present more frequently with lymphadenopathy mimicking mycobacterial infection clinically and cytologically, but which is caused by non-specific reactive hyperplasia, lymphoid and non-lymphoid malignancies, and numerous other viral, parasitic, and fungal infections. Traditionally, the classical morphological appearance of TB on FNAB is epithelioid granulomata (Fig. 21.11), with or without Langhans giant cells, in a background of lymphocytes with a small amount of amorphous necrosis. Severely immunocompromised patients such as those with AIDS show a picture of ‘dirty’ necrosis, with abundant nuclear debris and numerous neutrophils, mimicking suppurative lymphadenitis (Fig. 21.12).27,42,44,45 Between these two extremes there is a variation in cytomorphology, from a neutrophilic necrotic background with occasional epithelioid histiocytes or poorly formed granulomas (Fig. 21.13), to pure amorphous necrosis with virtually no cellular component. Foam cells, or lipid-laden macrophages, thought initially to be diagnostic of infection by Mycobacterium avium–intracellulare, may also be seen in infections by Mycobacterium bovis
21
Fig. 21.13 Papanicolaou-stained smear of a lymph node aspirate demonstrating a poorly formed granuloma in a background of necrosis with moderate numbers of neutrophils.
Fig. 21.11 Papanicolaou-stained smear of a lymph node aspirate demonstrating an epithelioid granuloma.
Fig. 21.14 Papanicolaou-stained smear of a lymph node aspirate from an
Fig. 21.12 Papanicolaou-stained smear of a lymph node aspirate in an immunocompromised child demonstrating numerous neutrophils in a background of necrotic debris.
Bacillus Calmette–Gue´rin (BCG) and M. tuberculosis (Fig. 21.14), usually in patients with a low CD4 count.24,27,41,46 The foamy cytoplasm is due to the lipid-rich membrane of the phagocytosed and destroyed mycobacteria.24 The degree of immune suppression is mirrored by the bacterial load, and a heavy load of mycobacteria has been suggested as a marker for HIV by some authors. Smears showing the necrotizing pattern of necrosis show the most numerous organisms on ZN or fluorescent stains. This pattern of dirty or suppurative necrosis is not only seen in patients with immune compromise due to HIV, but also in patients who present with advanced TB or with other immunodeficiency disorders. The bacterial load in these patients may be so heavy that the organisms may be seen on the Giemsa or Diff Quik stains as a negative imprint (Fig 21.15) – the organisms do not take up the stain and are seen against the blue background as negative images.47,48 This was initially described in patients with M. avium–intracellulare, but has since been described in other mycobacterial infections such as TB and merely reflects the bacterial load. It is, however, a useful
immunocompromised child demonstrating foamy macrophages in a background of neutrophils and necrosis.
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diagnostic aid, permitting a presumptive diagnosis of mycobacterial infection prior to special stains. Although the cytomorphology of the aspirate may be suggestive of TB, and acid- and alcohol-fast bacilli may be identified on ZN staining or on fluorescent microscopy, only a diagnosis of mycobacterial infection may be proffered. The commonest mycobacterial pathogens M. tuberculosis, M. bovis (including M. bovis BCG), and M. avium–intracellulare may all present with the same cytomorphology and the organisms are morphologically similar. Definitive diagnosis is dependent on culture and speciation of the organism. In resource-poor countries, however, the diagnosis is considered in conjunction with the clinical presentation and the prevailing pathogen in the region and therapy instituted.
Fig. 21.15 Giemsa stain of a lymph node aspirate in an immunocompromised child showing numerous mycobacteria evident in the background as a negative imprint.
REFERENCES 1. Stevens A, Francis RJ. Micro-organisms. In: Bancroft JD, Stevens A (eds). Theory and Practice of Histological Techniques, 4th edn. New York: Churchill and Livingstone, 1996: 291–307. 2. Lucas SB, Hounnou A, Peacock C, et al. The mortality and pathology of HIV infection in a west African city. AIDS 1993;7:1569–1579. 3. Drake WP, Pei Z, Pride DT, et al. Molecular analysis of sarcoidosis tissues for mycobacterium species DNA. Emerg Infect Dis 2002;8:1334–1341. 4. Ishige I, Usui Y, Takemura T, et al. Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet 1994;354:120–123. 5. Nilsson K, Pahlson C, Lukinius A, et al. Presence of Rickettsia helvetica in granulomatous tissue from patients with sarcoidosis. J Infect Dis 2002;185:1128–1138. 6. du Bois RM, Goh N, McGrath D, et al. Is there a role for microorganisms in the pathogenesis of sarcoidosis? J Intern Med 2003;253:4–17. 7. Colby T, Carrington CB. Interstitial lung disease. In: Thurlbeck W, Churg A (eds), Pathology of the Lung, 2nd edn. New York: Thieme Medical, 1995: 589–737. 8. DeRemee RA. The roentgenographic staging of sarcoidosis. Historic and contemporary perspectives. Chest 1983;83:128–133. 9. Sarno M, Hasleton PS, Spiteri MA. Sarcoidosis. In: Hasleton PS (ed.). Spencer’s Pathology of the Lung, 5th edn. New York: Mc Graw-Hill, 1996: 507–535. 10. Tanaka M, Riddell RH, Saito H, et al. Morphologic criteria applicable to biopsy specimens for effective distinction of inflammatory bowel disease from other forms of colitis and of Crohn’s disease from ulcerative colitis. Scand J Gastroenterol 1999;34:55–67. 11. Hellquist HB. Granulomatous lesions of the nose and sinuses. In: Hellquist HB (ed.). Pathology of the Nose and Paranasal Sinuses. London: Butterworth, 1990: 60–81. 12. Corrin B, Nicholson AG. Pulmonary manifestations of systemic disease. In: Corrin B, Nicholson AG (eds). Pathology of the Lungs, 2nd edn. London: Churchill Livingstone, 2006: 471–505. 13. Corrin B, Nicholson AG. Infectious diseases. In: Corrin B, Nicholson AG (eds). Pathology of the Lungs, 2nd edn. London: Churchill Livingstone, 2006: 149–261.
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Ancillary investigations In addition to culture, FNAB is ideal for obtaining material for ancillary or alternative diagnostic methods for confirmation of the diagnosis of TB. These techniques are described in more detail in Chapters 4, 20, and 23.
14. Kraus M, Benharroch D, Kaplan D, et al. Mycobacterial cervical lymphadenitis: the histological features of non-tuberculous mycobacterial infection. Histopathology 1999;35:534–538. 15. Woods GL,Gutierrez Y. Mycobacteria. In: Diagnostic Pathology of Infectious Diseases. Philadelphia: Lea and Febiger, 1993: 378–398. 16. Woods GL, Gutierrez Y. Spirochetes. In: Diagnostic Pathology of Infectious Diseases. Philadelphia: Lea and Febiger, 1993: 361–377. 17. Woods GL, Gutierrez Y. Other Gram-negative bacteria. In: Diagnostic Pathology of Infectious Diseases. Philadelphia: Lea and Febiger, 1993: 399–403. 18. Ramdial PK, Kharsany AB, Reddy R, et al. Transepithelial elimination of cutaneous vulval granuloma inguinale. J Cutan Pathol 2000;27:568–571. 19. Corrin B, Nicholson AG. Diffuse parenchymal disease of the lung. In: Corrin B, Nicholson AG (eds). Pathology of the Lungs, 2nd edn. London: Churchill Livingstone, 2006: 267–327. 20. Leiman G, Katz RL, Whitaker D, et al. Pulmonary cytology: current issues in research and practice. Pathol Int 2004;54(Supp 1):S506–S519. 21. Pereira TC, Saad RS, Liu Y, et al. The diagnosis of malignancy in effusion cytology: a pattern recognition approach. Adv Anat Pathol 2006;13:174–184. 22. Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007; 92:446–452. 23. Zar HJ, Hanslo D, Appoles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005;365:130–134. 24. Sridhar CB, Kini U, Subhash K. Comparative cytological study of lymph node tuberculosis in HIVinfected individuals and in patients with diabetes in a developing country. Diagn Cytopathol 2002;26:75–80. 25. Hesseling AC, Rabie H, Marais BJ, et al. Bacille Calmette-Gue´rin vaccine-induced disease in HIVinfected and HIV-uninfected children. Clin Infect Dis 2006;42:548–558. 26. Jeena PM, Coovadia HM, Hadley LG, et al. Lymph node biopsies in HIV infected and non infected children with persistent lung disease. Int J Tuberc Lung Dis 2000;4:139–146. 27. Kocjan G, Miller R. The cytology of HIV-induced immunosuppression. Changing pattern of disease in the era of highly active antiretroviral therapy. Cytopathology 2001;12:281–296.
28. Leiman G, Hurwitz S, Shapiro C. Mesothelial cells in pleural fluid: TB or not TB? S Afr Med J 1980;57:937–939. 29. Effusions. In: Geisinger KR, Stanley MW, Raab SS, et al. (eds). Modern Cytopathology. Philadelphia: Churchill Livingstone, 2004: 257–309. 30. Cerebrospinal and miscellaneous fluids. In: Koss L, Melamed M (eds). Koss’s Diagnostic Cytopathology and its Histopathology Correlation, 5th edn. Philadelphia: Lippincott Williams and Wilkins, 2006: 1023–1055. 31. Cerebrospinal fluid. In: Geisinger KR, Stanley MW, Raab SS, et al. (eds). Modern Cytopathology. Philadelphia: Churchill Livingstone, 2004: 313–357. 32. Mukunyadzi P, Johnson M, Wyble JG, et al. Diagnosis of histoplasmosis in urine cytology. Diagn Cytopathol 2002;26:243–246. 33. Harries A, Maher D, Graham S. TB/HIV: A Clinical Manual. Geneva: WHO, 2004. 34. Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of childhood tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006;10:732–738. 35. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area. Pediatr Infect Dis J 2006;25:142–146. 36. Wright CA, Burgess SM, Geiger D, et al. The diagnosis of mycobacterial lymphadenitis in children: is fine needle aspiration the way to go? In: Proceedings of the International Association Pathology Annual Conference, Durban, South Africa, 2006. 37. Thomas JO, Adeyi D, Amanguno H. Fine-needle aspiration in the management of peripheral lymphadenopathy in a developing country. Diagn Cytopathol 1999;21:159–162. 38. Singh UR, Bhatia A, Gadre DV, et al. Cytologic diagnosis of tuberculous lymphadenitis in children by fine needle aspiration. Indian J Pediatr 1992;59:115–118. 39. Shariff S, Thomas JA. Fine needle aspiration cytodiagnosis of clinically suspected tuberculosis in tissue enlargements. Acta Cytol 1991;35:333–336. 40. Pithie AD, Chicksen B. Fine-needle extrathoracic lymph-node aspiration in HIV-associated sputumnegative tuberculosis. Lancet 1992;340:1504–1505. 41. Ellison E, Lapuerta P, Martin SE. Fine needle aspiration (FNA) in HIVþ patients: results from a series of 655 aspirates. Cytopathology 1998;9:222–229. 42. Kumar N, Tiwari MC, Verma K. AFB staining in cytodiagnosis of tuberculosis without classical features: a comparison of Ziehl-Neelsen and fluorescent methods. Cytopathology 1998;9:208–214.
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Histopathology and cytopathology 43. Wright CA, van Zyl Y, Burgess SM, et al. Auto fluorescence of mycobacteria on lymph node aspirates - a glimmer in the dark? Diagn Cytopathol 2004;30:257–260. 44. Purohit SD, Purohit V, Mathur ML. A clinical scoring system as useful as FNAC in the diagnosis of tuberculous lymphadenitis in HIV positive patients. Curr HIV Res 2006;4:459–462.
45. Nayak S, Mani R, Kavatkar AN, et al. Fine-needle aspiration cytology in lymphadenopathy of HIVpositive patients. Diagn Cytopathol 2003;29:146–148. 46. Peart L, Schneider JWS, Jordaan HJ, et al. Fine needle aspiration biopsy of post vaccination disseminated Mycobacterium bovis infection presenting as a solitary cutaneous papule. A ‘blueberry muffin’ lesion. Acta Cytol 2005;49:230–231.
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47. Powers CN. Diagnosis of infectious diseases: a cytopathologist’s perspective. Clin Microbiol Rev 1998;11:341–365. 48. Stanley M, Horwitz C, Burton L, et al. Negative images of bacilli and mycobacterial infection. A study of fine needle aspiration smears from lymph nodes in patients with AIDS. Diagn Cytopathol 1990;6: 118–121.
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Practical approaches to ordering diagnostic tests H Simon Schaaf and Helmuth Reuter
INTRODUCTION The rapid and accurate diagnosis of TB, especially pulmonary disease, is important for both the patient and the TB control programme. For the patient it is important that the diagnosis is correct and treatment is appropriate; for the control programme it is important to limit the spread of infection and to utilize limited resources efficiently. It is ironic that the highest burden of TB is found in developing countries where special investigations are very limited. While it is in these developing settings that existing special investigations, specialized imaging, and newer diagnostics are urgently needed, these tests are mainly available in developed settings where many unnecessary diagnostic investigations are probably done in cases where the diagnosis should have been clinically obvious. In most resource-limited high-incidence countries, the diagnosis of new cases of TB is based mainly on sputum smear microscopy for acid-fast bacilli (AFB) while in developed countries with low incidences of the disease use is made of both smear results and culture for Mycobacterium tuberculosis complex, which includes M. tuberculosis sensu stricto, Mycobacterium bovis, Mycobacterium africanum, and a few other species as described in Chapter 7. The incidence of AFB smear-negative pulmonary TB has increased substantially in countries where both this disease and infection by the human immunodeficiency virus (HIV) are prevalent. Further, the diagnosis of TB in children is more difficult than in adults due to the paucibacillary nature of their disease, which usually allows for confirmation by culture in less than 40% of cases. Several new diagnostic tests have been developed, although none seem likely to revolutionize the diagnosis of TB. The aim of this chapter is to briefly discuss some of the available diagnostic tests, their role in diagnosing TB in HIV-uninfected and -infected patients and to give a practical approach to ordering diagnostic tests in both children and adults with pulmonary and/or extrapulmonary TB. Table 22.1 summarizes available side room and special investigations important in the diagnosis of TB.
MICROBIOLOGICAL DIAGNOSIS OF TUBERCULOSIS Bacteriological confirmation remains the mainstay of diagnosis but even in adults the overall sensitivity is less than 80%. The paucibacillary nature of childhood TB leads to poor bacteriological yields. Sputum smear microscopy for AFB in adults with pulmonary TB
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has a positive yield of approximately 60–70%, while in children the yield is less than 20%. Culture yields for M. tuberculosis from sputum or other lung-derived fluids (e.g. bronchial, tracheal, nasopharyngeal, or gastric aspirates) on solid or liquid media are approximately 80% in adults, but vary from < 20% to 77% in children, depending mainly on the extent of intrathoracic disease. The success of both microscopy and culture also critically depends on the quality of the specimens received by the laboratory.
COLLECTION AND HANDLING OF SPECIMENS Only clean, sterile containers should be used to collect specimens and, after collection, specimens should be kept under conditions that inhibit growth of contaminating organisms. A variety of clinical materials may be submitted for microscopy and/or culture (Table 22.2). All aerosol-producing specimen collection procedures should be done in well-ventilated areas (preferably in the open air) or, if available, in an isolation room that has adequate infection control precautions (negative pressure, ultraviolet light, and extractor fan) by staff wearing adequate respiratory protection.1,2
Sputum Adults and older children who can expectorate sputum should be instructed that the phlegm produced from the lung after a productive cough is the required material. Patients are instructed to take two deep breaths, to hold the breath for a few seconds after each inhalation, and then to exhale slowly, to breathe in a third time, and then forcefully to blow the air out and then to breathe in again and then cough. This should produce a specimen from deep within the lungs. The patient is asked to hold the sputum container close to the lips and to spit into it gently after a productive cough. The specimen container should be cleaned on the outside and the cap screwed on properly as, for reasons of safety, leaking containers must be discarded.2 Induced sputum This can be obtained with few adverse events from patients as young as 6 months who have difficulty in producing sputum.3 Patients should be fasting for 3 or more hours. Patients with severe respiratory distress, reduced level of consciousness, history of significant asthma, and bleeding tendency or low platelet counts should be excluded. Patients are pre-treated with a bronchodilator via a metered dose inhaler (with a spacer in children) and they then inhale 5 mL of nebulized 3–5% hypertonic saline (approximately 15 minutes). Chest physiotherapy is useful for mobilizing secretions. For patients who can expectorate, sputum is collected as
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22
Table 22.1 Summary of available tests in the diagnosis of tuberculosis
Table 22.2 Specimens for the bacteriological confirmation of tuberculosis
Clinical and side room tests Tuberculin skin tests, e.g. Mantoux, Heaf, tine, Monotest Erythrocyte sedimentation rate (ESR) Sputum smear staining and microscopy for AFB Rapid HIV test Laboratory-based tests Bacteriological tests Smear stain and microscopy for AFB Cultures for M. tuberculosis – solid medium or liquid-based medium Speciation of M. tuberculosis (e.g. nucleic acid amplification test – polymerase chain reaction (PCR), high-performance liquid chromatography (HPLC), niacin test, positive nitrate reduction test, distinctive morphology on Middlebrook 7H10 and 7H11 agar) Drug susceptibility testing – conventional culture-based methods or detection of genetic mutations using molecular techniques Bacteriophage-based tests for detection of M. tuberculosis and drug resistance Chemistry and biomolecular tests on body fluids Chemistry (albumin/protein, glucose, chloride) and microscopy of white cells (lymphocytes vs polymorphs) Biochemical markers: Adenosine deaminase (ADA) Interferon-gamma (IFN-g) levels Lysozyme Nucleic acid amplification (NAA) tests In-house assays Commercial kits Loop-mediated isothermal amplification (LAMP) Histopathology Histology of biopsy specimens and staining and microscopy for AFB Blood tests Haematological tests (white cell count, haemoglobin, platelet count), ESR and other acute-phase reactants Interferon-g release assays or T-cell-based (T-SPOT.TB, QuantiFERON-TB Gold) Immunological tests (serological tests) HIV – enzyme-linked immunosorbent assay (ELISA) and PCR Imaging (discussed in Chapters 24, 25 and 26) Radiographs – chest, abdominal, bone and joint radiographs, and specialized studies such as barium and other contrast studies Ultrasonography – abdominal, lung and pleura, pericardial, and lymph nodes Computed tomography (CT) scans – head, chest, abdomen, and spinal Magnetic resonance imaging (MRI) scans – mainly head and spinal MRI Other diagnostic procedures Flexible bronchoscopy Thoracoscopy or medianoscopy Endoscopy and colonoscopy Arthrocentesis and arthroscopy Laparoscopy and mini-laparotomy Fine needle aspiration biopsy (FNAB) Bone marrow aspiration/biopsy
Sputum Expectoration (adults, older children) Induced sputum Tracheal and bronchial aspirates Bronchoalveolar lavage Nasopharyngeal aspirates Gastric aspirates/washings Pleural fluid Cerebrospinal fluid Peritoneal fluid (ascites) Synovial fluid/biopsy Pericardial fluid Pus swabs Abscesses, draining skin sinuses (scrofula), ear (otorrhoea) Biopsies Peripheral lymph node biopsies or FNAB Synovial/bone biopsies Bone marrow aspirate/biopsy Tissue biopsy, e.g. lung, pleura, pericardial, peritoneal, mastoid, gastrointestinal, skin, lymph nodes (internal) Uncommon tissue biopsies, e.g. parotid, adrenal gland, scrotal mass Blood Mainly immunocompromised patients Urine (3 morning urine specimens) Stool specimens Endometrial fluid/scrapings (infertility, suspected congenital TB)
described earlier. For children unable to expectorate, the nasal passages are suctioned to remove nasal secretions and suitable specimens are collected by nasopharyngeal aspiration. All equipment must be sterilized before re-use.
Gastric aspirate/lavage Gastric aspiration is a technique used to collect gastric contents containing swallowed sputum/lung fluid in order to culture for M. tuberculosis. Smear microscopy of gastric aspirates has a low yield (< 15%) and falsely positive results may be misleading due to the presence of environmental (non-tuberculous) mycobacteria. Although the yield in hospitalized children may be slightly higher, this is not a prerequisite for the collection of a good gastric aspirate. The highest yield specimens are obtained first thing in the morning. A 4- to 6-hour fast is a prerequisite. Two or three gastric aspirates on consecutive mornings should be performed for each patient. This procedure requires two people. A nasogastric tube (10 French) is inserted through the nose and into the stomach and a syringe (5, 10, or 20 mL) is attached to the nasogastric tube to enable 2–5 mL of gastric contents to be aspirated. If no fluid is aspirated, 5–10 mL of sterile water or normal saline (0.9% NaCl) is inserted and attempts are made to aspirate again (at least 5–10 mL). Gastric fluid is transferred from the syringe to a sterile container and an equal volume of sodium bicarbonate (4%) is added to the specimen to neutralize the acidic gastric contents to prevent destruction of tubercle bacilli.2 Other specimens Bronchial aspirates, bronchoalveolar lavage, and transbronchial biopsies are obtainable by fibreoptic bronchoscopy. Tracheal aspirates can be obtained if the patient is intubated. Pleural fluid and, to a lesser extent, pericardial fluid and ascitic fluid aspirates can be obtained for microscopy and culture by needle aspiration. For examination of cerebrospinal fluid (CSF) larger volumes (> 10 mL) yield better culture results, but smaller volumes are likely to be obtained from children.
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Blood should be directly inoculated into commercially available broth media for mycobacterial culture. For the examination of urine, multiple first morning-voided midstream specimens are preferred. Tissue biopsies, fine needle aspiration, and collection of other body fluid specimens are discussed in relevant chapters. All clinical specimens must be labelled clearly and accurately. Specimens should be refrigerated or kept cool before and during transit to laboratories if immediate delivery is not possible.
STRING TEST The string test, previously used successfully to obtain enteropathogens such as Giardia lamblia and Salmonella typhi from the upper gastrointestinal tract, has now been tried as an alternative to gastric aspiration to obtain swallowed sputum from adults with a dry cough and from children.4,5 The test involves swallowing a capsule with a string attached after an overnight fast. The string remains in situ for 4 hours and is then removed by gentle traction. It was reasonably accepted by children as young as 4 years. The string test outperformed sputum induction in the adult study, but no comparative studies have been done in children to date.
STAINING AND MICROSCOPIC EXAMINATION Microscopical examination of auramine- or Ziehl–Neelsen-stained smears of specimens, mainly sputum, for AFB is the most commonly performed test for the bacteriological evidence of mycobacteria and results should be available within 24 hours (see Chapter 18). Stained smears can be prepared from almost any material, but the yield is dependent on the number of bacilli present per millilitre of specimen (5,000–10,000 bacilli/mL are necessary for positive result) (Table 22.3).6 Methods to improve the yield, such as concentration procedures, in which the liquefied specimen is centrifuged and sediment is used for staining, and the bleach method, were shown to improve the sensitivity in microscopy of sputum smears. For the bleach method, sputum specimens are left to react with an equal quantity of household bleach in the sputum container for 15 minutes. Thereafter it is transferred to conical tubes and either left to stand for sedimentation overnight or centrifuged. A bleach smear is then made from the sediment after decanting.7 The bleach method also improves the sensitivity of the microscopical examination of specimens from extrapulmonary sites of disease.8 Several factors influence the sensitivity of smear microscopy including staining technique, reader experience and work load, the presence of HIV infection (reduces sensitivity), and the availability and use of
Table 22.3 Clinical materials and suitability for microscopy and/or culture for M. tuberculosis Clinical material
Microscopy yield
Culture yield
Lung-derived fluids Sputum – natural Sputum – induced
High (50–80%) Moderate
High (> 80%) Moderate (done only when natural expectoration difficult) Moderate
Bronchial, tracheal aspirates or bronchoalveolar lavage Gastric aspirate (or washing)
Moderate (low in children)
Nasopharyngeal aspirate Other body fluids Pleural fluid Cerebrospinal fluid
Moderate (low in children)
Peritoneal fluid (ascites) Pericardial fluid Synovial fluid (arthrocentesis) Urine (first morning voided) Blood (mainly immunocompromised) Bone marrow aspirate Endometrial fluid/scrapings Biopsy and/or fine needle aspiration specimens Peripheral lymph node biopsy/FNAB Pleural biopsy (adults mainly) Pericardial biopsy Invasive tissue biopsies, e.g. lung, peritoneal, liver, lymph node Skin biopsy Pus swabs Abscesses (cold, peripheral or internal) Otorrhoea (ear swab) Scrofula Stool samples
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Low (10–15% in children)
Low (< 5–10%) Low–moderate (< 5–10%, latter with large volumes) Low (< 5%) Low No data, probably low Low Not applicable No data Moderate Low (10–< 50%) Low Low Low in pus, moderate if abscess wall included Low Low Low
Moderate (< 20–77%), related to extent of disease Moderate Low–moderate (< 25–50%) Moderate (30–90%, latter with large volumes) Low (20%) Low Moderate–high (< 80%) Low Low (mainly immunocompromised patients) Moderate–high (in disseminated TB) Low–moderate Moderate High High (50–90%) Moderate Low Low–moderate Moderate Low–moderate due to mixed infection Low Low
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smear-enhancing methods. Sputum smears may give an indication of the infectiousness of an individual with pulmonary TB so the laboratory technician should report the presence of AFB in a quantified manner. The International Union against Tuberculosis and Lung Disease (IUATLD) has a recommended grading of sputum microscopy results from 0/negative to 3+, depending on the AFB counts in a minimum number of fields.9 In many high-burden resource-limited countries new cases of pulmonary TB are diagnosed only by smear microscopy. This has essential limitations: a positive smear for AFB may represent either M. tuberculosis or other species of mycobacteria, and drug susceptibility tests cannot be performed. Specimens may be positive by smear and negative by culture, but this should be in less than 1% of cases and is mostly seen in patients already on anti-TB therapy.
CULTURE OF MYCOBACTERIA There is a new global move towards submitting all clinical specimens suspected of containing mycobacteria for culture, because of increasing HIV infection and drug resistance. Culture is over a 100–1000 times more sensitive than microscopy, the species of isolated mycobacteria can be identified, and drug susceptibility tests can be performed. Mycobacterial culture methods are described in Chapter 18. Three traditional culture media are generally in use: egg-based (Lo¨wenstein-Jensen), agar-based (Middlebrook 7H10 or 7H11 medium), and liquid (Middlebrook 7H12 and other commercially available broths). The isolation rate on Lo¨wenstein-Jensen medium is better than on agar, but growth on agar is faster. Growth in liquid media is much faster. Automated culture systems such as BACTEC 460 and mycobacterial growth indicator tubes (MGIT 960) (Beckton Dickinson Microbiology Systems, Sparks, MD, USA) and other radiometric or colorimetric systems using liquid media have dramatically improved the speed of detection of mycobacterial growth (1–3 weeks compared with 3–8 weeks on solid media). Ideally, specimens should also be inoculated on an egg-based medium, as some mycobacteria may not grow in liquid media.
IDENTIFICATION OF MYCOBACTERIAL SPECIES A specialized laboratory should be able to accurately identify mycobacteria isolated from patients at the species level. At a minimum, the morphological appearance of M. tuberculosis colonies on solid media, especially Middlebrook 7H10 and 7H11 agar, is distinctive. Positive niacin and nitrate reduction tests can also be used to identify M. tuberculosis. These tests are not completely reliable. The nitrate reduction test is positive for M. tuberculosis sensu stricto, but not for M. bovis, and is variable for M. africanum. The niacin test (in the test strip form) is simple and quick but negative strains of M. tuberculosis occasionally occur. Two methods of identification of species currently in use are nucleic acid amplification, particularly by the polymerase chain reaction (PCR), and high-performance liquid chromatography (HPLC).
DRUG SUSCEPTIBILITY TESTING Ideally, drug susceptibility tests (DSTs) should be performed on initial isolates from all patients in order to determine their correct treatment regimens. With the world-wide increase in multidrug-resistant (MDR) TB, and the recognition of extensively drug-resistant (XDR) TB, this has become even more important. Because of cost implications, DSTs
22
are often not initially conducted on new TB patients in high-burden resource-limited areas. In these cases, follow-up smear microscopy and cultures are indicated at 2–3 months treatment and again at 5–6 months after commencement of treatment and, if positive, DST should be performed. DSTs should be performed on all patients undergoing retreatment or with chronic TB, as well as those with known contact with patients with drug-resistant TB. Drug susceptibilities of M. tuberculosis can be determined by observation of growth inhibition in a medium containing antiTB drug (e.g. egg- or agar-based media) in comparison with growth on drug-free media. Various methods are in use with the agar proportion method having been the standard method of M. tuberculosis DSTs in the USA for many years for all drugs except pyrazinamide. The definition of resistance for the agar proportion is that > 1% of the bacterial population being tested in vitro is resistant.10 More rapid automated systems are based on the observation of metabolic inhibition (e.g. automated radiometric systems of detection of CO2 production, such as BACTEC 460, or oxygen consumption, such as Mycobacteria Growth Indicator Tube (MGIT) 960, both of which are broth-based media methods). Non-radiometric commercially available automated systems have now largely replaced the radiometric ones and have replaced growth inhibition on solid media as the method of choice in many countries. Bacteriophage-based techniques are in a developmental stage. Drug susceptibility can also be determined by use of molecular techniques to detect genetic mutations but, except for rpoB gene mutations which lead to rifampicin resistance, not all resistancerelated genes for the different anti-TB drugs and their sites of mutation have been identified.11
NEW DEVELOPMENTS: RAPID CULTURE SYSTEMS AND RAPID DETECTION OF DRUG RESISTANCE TK Medium TK Medium (Salubris, Inc., MA, USA) is a new rapid colorimetric culture system, currently being evaluated, which indicates growth of mycobacteria by colour change. It can be used for susceptibility testing and can allow for differentiation between M. tuberculosis and other mycobacterial species. Further studies are necessary, especially under field conditions, to establish its role.12 Microscopic observation drug susceptibility (MODS) method/assay Microscopic observation drug susceptibility (MODS) assay is a novel assay that uses a modified Middlebrook 7H9 broth medium to culture specimens, e.g. sputum and gastric aspirates, with or without antimicrobial drugs for drug susceptibility testing. Direct microscopic observation (by an inverted light microscope) is then used to detect early mycobacterial colony formation. In liquid media M. tuberculosis grows with a characteristic ‘serpentine cording’ (strings and tangles), preventing confusion with bacteria or fungi and other species of mycobacteria. MODS assay results in better and faster recovery of M. tuberculosis than with Lo¨wenstein-Jensen medium in both adults and children. It can rapidly detect drug resistance directly from sputum samples. MODS is a promising, inexpensive tool which may have applicability in high-burden, resource-limited settings.12,13 Line-probe assays Line-probe assays, a family of DNA strip-based tests that use PCR and reverse hybridization methods for the rapid detection of
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mutations associated with drug resistance, are available as commercial kits. For rifampicin resistance the assay has high sensitivity and specificity when applied to M. tuberculosis isolates or AFB smearpositive sputum specimens, but is less accurate when applied to smear-negative clinical specimens. These assays are expensive and require sophisticated laboratory infrastructures.12
Bacteriophage-based assays Assays based on mycobacteriophages have shown promise in the diagnosis of pulmonary TB. In these methods bacteriophages infect live M. tuberculosis and replicate within them so that their progeny can be detected by phage plaque detection on lawns of susceptible mycobacteria. Alternatively, the phages may carry the gene for luciferase which is transcribed in viable M. tuberculosis cells infected by the phages, enabling them to emit light when the substrate firefly luciferin is added to the system. Phage amplification assays are commercially available for identification of M. tuberculosis (FASTPlaque-tuberculosis; Biotec Laboratories Ltd, Ipswich, UK) and to detect rifampicin resistance (FASTPlaque-tuberculosisMDRi).14 A luciferase reporter phage-based test based on the ‘Bronx box’, a simple low-technology system utilizing a photographic film, is currently being developed as a commercial kit by Sequella, Inc. Phage-based assays have high specificity (0.83–1.00) but lower and variable sensitivity (0.21–0.88) according to a systematic review and meta-analysis.14 Their overall performance is equal to that of sputum microscopy and phage-based tests cannot replace conventional bacteriological tests at this time. For identification of drug resistance, on the basis of current evidence the use of phage assays is limited to the detection of rifampicin resistance in culture isolates, for which the assays have relatively high sensitivity and specificity.12 Phage-based assays have important limitations. Although relatively easy to perform, they require a laboratory infrastructure similar to that needed for mycobacterial cultures and they are more expensive than smear microscopy, which restricts their use in limited-resource settings with a high burden of TB. Transport delay and time to processing of specimens in the laboratory negatively influences sensitivity. Some other mycobacterial species are susceptible to infection by the phages and thus reduce the specificity of the tests.
IMMUNOLOGICAL DIAGNOSTIC TESTS
The Mantoux TST is performed by administering an intradermal injection, on the volar or dorsal surface of the (left) forearm, of 5 tuberculin units (TU) (0.1 mL) of tuberculin purified protein derivative (PPD)-S or 2 TU (0.1 mL) of tuberculin PPD RT-23 as these give similar reactions. Healthcare workers must be trained to perform and read a TST. A pale elevation of the skin should be seen if the injection is given correctly. The induration (swelling of the skin, not redness) is read at its largest transverse diameter after 48–72 hours and recorded in millimetres. A Mantoux TST should be regarded as positive if the induration is 10 mm (whether the individual has received a BCG vaccination or not), and in high-risk patients if the induration is 5 mm (high risk includes those HIV-infected or severely malnourished).2 One report, however, showed limited value for HIV-infected patients by reducing the cut-off from 10 to 5 mm, as loss of TST sensitivity is predominantly due to anergy (an all-or-nothing phenomenon).15
Interpretation of the TST A positive TST indicates infection with M. tuberculosis but does not necessarily indicate disease. When used in a child (or an adult in a low-TB-incidence setting) with symptoms and other evidence of TB (such as an abnormal chest radiograph), it is a useful tool in making the diagnosis. TST can be used to screen children (or adults in low-TB-incidence settings) exposed to TB source cases (e.g. from a household contact with TB), though children can still be given chemoprophylaxis if TST testing is not available.2 The TST is useful in HIV-infected patients to identify those dually infected with M. tuberculosis and HIV and as an aid in the diagnosis of TB in such persons, although significantly fewer HIV-infected patients than HIV-uninfected patients will have a positive test due to immune suppression. Sometimes it is useful to repeat the TST in children once their nutrition has improved or their severe illness (including TB) has resolved, as they may be initially TST negative, but positive after 1–3 months on treatment. A negative TST never rules out a diagnosis of TB. Both misleading positive and negative TSTs may occur (Table 22.4). The TST has many limitations, such as low sensitivity Table 22.4 Possible causes of misleading-negative or false-positive tuberculin skin test results Misleading negative TST results:
TUBERCULIN SKIN TEST (TST) Infection with tubercle bacilli is followed by the development of a delayed hypersensitivity reaction to tuberculoprotein 4–6 weeks later. A positive tuberculin skin test (TST) only indicates infection with M. tuberculosis, and does not indicate immunity to TB, the time of infection, or the presence or extent of disease. The TST is currently still the most widely used method for identifying persons who are infected with M. tuberculosis, although novel Tcell-based assays may prove to be more specific for this purpose (see below). Nevertheless, especially in children, TST is a useful adjunct in diagnosing TB, when it is used in conjunction with clinical examinations and other diagnostic tests. A number of TSTs are available, but the intradermally administered Mantoux TST is the recommended test. The multiplepuncture tests, such as the Heaf test, Tine test, and Monotest, are not as reliable as the Mantoux test.
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Viral infections, e.g. HIV, measles, mumps, varicella. Live viral vaccines (within 6 weeks). Bacterial infections, e.g. overwhelming TB, TB pleural effusion, typhoid fever, brucellosis, pertussis, leprosy. Severe malnutrition (marasmus and kwashiorkor). Severe immunosuppression, e.g. congenital immunodeficiencies, malignancy, immunosuppressive drugs. Sarcoidosis. Age (infants < 3 months, elderly with waned response). Administering error, e.g. improper placement (too deep) or too little antigen. Reader error (reading or recording). Improper handling and storage of tuberculin.
Misleading positive TST results:
Infection by other (environmental or non-TB) mycobacteria. BCG immunization, especially with adverse events/infection. Boosting due to repeated tuberculin tests. Reader error (reading or recording).
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and specificity, prior Bacillus Calmette-Gue´rin (BCG) vaccination, and immunologically effective contact with other species of mycobacteria may influence the interpretation of the TST, the need for skilled personnel to perform and interpret the test, and the need for the patient to attend on two separate occasions. New tests for the diagnosis of infection with M. tuberculosis are therefore called for.
Table 22.5 Possible advantages and disadvantages of interferon-gamma release assays compared with tuberculin skin tests Possible advantages18
T-CELL-BASED ASSAYS (INTERFERON-g-BASED ASSAYS) In persons infected with M. tuberculosis, memory T-cells produce interferon-gamma (IFN-g) in response to M. tuberculosis-specific antigens. The identification of the 6-kDa early secreted antigenic target protein (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10), both of which are absent from BCG and most other species of mycobacteria, permitted the development of potentially specific novel T-cell-based tests.16 Two new blood tests, based on the detection of IFN-g produced by T cells, are commercially available. T-SPOT.TB (Oxford Immunotec, Abingdon, UK) is based on the ex vivo overnight enzyme-linked immunospot (Elispot) assay and QuantiFERON-TB Gold (Cellestis Limited, Carnegie, Australia) is based on a whole-blood enzyme-linked immunosorbent assay (ELISA). These assays are time-dependent in that the blood samples need to be transferred to the laboratory within a few hours. A new QuantiFERON-Gold in-tube system is much less time-dependent, but appears to be less sensitive than the T-SPOT.TB system, despite an additional antigen tuberculosis 7.7 (Rv2654).17 Although in the majority of initial studies these IFN-g release assays (IGRAs) were found to have superior sensitivity and specificity to TST,18 a number of studies, especially in routine clinical settings, recorded varying results.19–21 In one study, a prospective comparison of two commercially available IGRAs in routine clinical practice showed that T-SPOT.TB and QuantiFERON-TB Gold had higher specificities than the TST and this seems to be the finding of most studies.21 Rates of indeterminate and positive results varied, however, between blood tests, with more indeterminate results in QuantiFERON-TB Gold than in T-SPOT.TB. Indeterminate results were mainly associated with immunosuppression. T-SPOT.TB performed better than QuantiFERON-TB Gold in children < 5 years of age, and sensitivity has also been reported to be higher with T-SPOT.TB in other studies.22 IGRAs may soon replace the TST in selected low-incidence highincome settings in which they will mainly be used for contact and immigrant screening. Institutions in North America and Europe are steadily replacing TSTs with IGRAs.23,24 After the US Food and Drug Administration’s (FDA) approval of the QuantiFERONTB Gold assay, the Centers for Disease Control and Prevention (CDC) has recommended that it can replace the TST in all circumstances in which the latter is currently used. T-SPOT.TB has been approved for use in Canada and Europe and is being considered by the FDA, and both assays have been included in the UK guidelines on TB published by the National Collaborating Centre for Chronic Conditions.25 The current UK guidelines recommend that a TST is done initially, followed by an IGRA on TST-positive individuals. The application of IGRAs in low-income high-burden settings is currently rather limited but simplification of laboratory methods and reduction in costs might enhance applicability in these settings.18 Where laboratories are available in these settings, subgroups such as HIV-infected patients and very young children could benefit from these tests.26 Table 22.5 summarizes the possible advantages and disadvantages of IGRAs.
22
Higher specificity than TST. Not influenced by prior BCG vaccination or infection with most environmental (non-tuberculous) mycobacteria. Improved sensitivity in young children, especially T-SPOT.TB.19,21,26 Improved sensitivity in HIV-infected patients.26 Avoids subjective measurements. Can be repeated without boosting effect. Eliminates second visit for result. May possibly detect recent infection.
Possible disadvantages
Relatively expensive, currently out of reach for high-burden, resource-limited countries. Needs laboratory infrastructure and trained laboratory personnel. Indeterminate results and uncertain thresholds for interpretation as positive. Time sensitive – blood samples need to be transferred to the laboratory within a few hours. Relatively large blood volumes necessary for tests (4–5 mL in children).
HUMAN IMMUNODEFICIENCY VIRUS (HIV) TESTS HIV infection negatively affects the ability to diagnose TB in both adults and children. Progression to disease may occur soon after infection by M. tuberculosis or latent infection may be reactivated. Further, response to treatment is often slower and outcome is worse than in HIV-uninfected patients. Therefore, in areas with a high prevalence of HIV infection in the general population (HIV prevalence > 1%) where TB and HIV infection are likely to coexist, HIV counselling and testing is indicated for all TB patients as part of their routine management.2,27 In areas with lower prevalence rates of HIV, counselling and testing is indicated for TB patients with symptoms and/or signs of HIV-related conditions and in those having a history suggestive of a high risk of exposure to HIV. A rapid test for HIV (a side room investigation) could be used as a screening test. Commercially available HIV ELISA tests are most commonly used as confirmatory tests, with HIV PCR as a confirmatory test in children less than 18 months of age.
HAEMATOLOGY AND ACUTE-PHASE REACTANTS A full blood count has no diagnostic predictive value when investigating a patient for TB. Anaemia is a common finding. Platelet counts may be high or low and the white cell count or differential white cell count does not help to distinguish TB from other diseases.28 Erythrocyte sedimentation rate (ESR) may be raised (often > 100 mm/h, Westergren method) but as it may also be normal in TB it is of little value as a diagnostic test.29 HIV-infected patients with progressive disease often have a high ESR in the absence of other infections due to hypergammaglobulinaemia; therefore an elevated ESR has limited value in HIV-infected patients.30 Both C-reactive protein (CRP) and serum procalcitonin (PCT) are poor indicators of active TB.31
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AIDS TO DIAGNOSIS MICROSCOPY FOR WHITE BLOOD CELLS (EFFUSIONS, ASCITES, AND CSF) A lymphocytic predominance is common in tuberculous effusions and in the CSF in tuberculous meningitis, although polymorphonuclear leucocytes may predominate in the early stages of tuberculous effusions. Lymphocytes predominate in pericardial effusion even in HIV-infected compared with HIV-uninfected patients, despite general lymphopaenia in the HIV-infected patients.32
BIOCHEMICAL MARKERS IN PLEURAL AND PERICARDIAL EFFUSIONS, ASCITES, AND CSF Protein, lactate dehydrogenase, glucose, and chloride Pleural and pericardial effusions and ascites caused by TB mainly present as exudates. According to the criteria of Light, pleural effusions are classified as exudates when they meet one or more of the following conditions: pleural fluid protein concentration > 30 g/L; pleural fluid-to-serum protein ratio higher than 0.5; pleural fluid lactate dehydrogenase (LDH) activity two-thirds of the upper reference limit in serum; and pleural fluid-to-serum LDH ratio higher than 0.6. If an effusion must be examined in a patient being treated with diuretics and the above criteria classify it as an exudate although clinical evidence suggest a transudate, a difference in serum albumin minus pleural fluid albumin of more than 12 g/L rules out its exudative nature.33 In CSF, the protein is almost always raised above the upper limit of normal (0.45 g/L), but levels vary greatly. The level of CSF glucose is often less than 2.2 mmol/L or less than 40% of the serum glucose level. CSF chloride assay is usually not helpful. A Pandy’s test for globulin is usually positive in TB meningitis but also in bacterial meningitis. A lymphocyte predominance, usually with less than 500 lymphocytes/mL, with high CSF protein and/or globulin levels, and a decreased glucose level, is usually indicative of TB meningitis, although variations occur. Adenosine deaminase (ADA) Adenosine deaminase (ADA) is a purine-degrading enzyme, catalysing adenosine and deoxyadenosine to produce inosine and deoxyinosine in the process. This enzyme is widely distributed in tissue and body fluids, but its most important role is in the proliferation and differentiation of T-lymphocytes and macrophages/monocytes. The presence of ADA in body fluids reflects the activity of the cellular immune response in the respective compartments and, in particular, the activation of T-lymphocytes and macrophages/monocytes.34,35 ADA has two isoenzymes, ADA1 and ADA2, and it is ADA2 that is more specific for monocyte activity. Determination of ADA in body fluids is a simple, rapid, and economical test. The enzyme is stable for at least 24 hours at < 25 C and up to 10 days at 4 C.34,36 Specimens may therefore be sent from rural areas and reliable results can still be obtained. Different methods (colorimetric, spectrophotometric, and biochemical determinations) are used to determine ADA activity (U/L or IU/L). The most commonly used method is that described by Giusti.37 This is a colorimetric method based on Berthelot’s reaction of the formation of ammonia, which is produced when ADA acts on excess adenosine. Assay of ADA is an indirect method of diagnosing TB and is advocated for the differentiation of this disease from other causes of pleural effusions, pericardial effusions, ascites, and meningitis (CSF). Cut-off values, sensitivity, and specificity of ADA values for the diagnosis of
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TB do, however, vary widely in different studies and for different body fluid compartments.
ADA in pleural effusions The most commonly used cut-off values are 40–47 U/L (range 34.6– 60 U/L).38–42 Sensitivity generally ranges from 77% to 100% and specificity from 81% to 97%.38 Although ADA is a relatively good marker for TB in high-incidence settings, it may be less useful in low-incidence settings where misleading positive results may be more common.41 As parainfective conditions may also increase ADA activity, a raised ADA level in a pleural effusion should, in settings where parainfective conditions are common relative to TB, be interpreted in conjunction with the lymphocyte/neutrophil ratio, as TB pleural effusions usually have a predominant lymphocyte count (L/N ratio > 0.75).43 As ADA levels are dependent on T-lymphocyte/monocyte activity, low levels may be found in HIV-infected or other immunocompromised TB patients with very low CD4 T-lymphocyte counts. In children, ADA levels may be raised in effusions due to rheumatoid arthritis, haematological malignancies, and empyema, and in some parapneumonic effusions. High ADA levels in a lymphocyte-predominant exudate are, however, usually associated with TB or haematological malignancies.33 ADA in pericardial effusions The most commonly used cut-off levels for ADA activity in pericardial effusions are between 35 and 40 U/L,32,44 with a range of suggested cut-off levels from 30 to 60 U/L.45 Levels of ADA > 40 U/L may occur with a number of diseases, especially septic pericarditis and malignancies.32 Patients already on anti-TB treatment and those infected with HIV may have low levels of ADA. ADA in ascitic fluid Cut-off levels for ADA activity in peritoneal fluid (ascitic fluid) range between 30 and 43 U/L. A meta-analysis suggests that the optimal cut-off point is 39 U/L and showed that sensitivity and specificity ranged from 93% to 100% and 92% to 100%, respectively, in the analysed studies.35 Malignancies and bacterial peritonitis may rarely cause high levels, while severely immunocompromised HIV-infected TB patients may have low levels. The accuracy of the ADA assay was similar to the IFN-g assay (optimal cut-off point 112 pg/mL) in differentiating TB from non-TB ascites. Because of the lower cost of the ADA assay it is the more appropriate test for peritoneal fluid analysis in resource-limited settings.46 ADA in cerebrospinal fluid Determination of ADA activity in CSF is generally not a good test as sensitivities are usually between 50% and 80%. Cut-off values vary between 6.5 and 11.4 U/L. Although ADA may differentiate between aseptic (viral) meningitis and other neurological conditions and TB meningitis, high levels of ADA are often found in cases of bacterial (septic) meningitis. Further, ADA activity is often negative in the early stages of TB meningitis, the time at which differentiation from other causes is most crucial. Many central nervous system disorders, including cryptococcal meningitis, candidal meningitis, cytomegalovirus infection, toxoplasmosis, and lymphomatous meningitis, have been associated with high ADA activity in HIV-infected patients.47–49 IFN-g assays in the diagnosis of tuberculosis effusions IFN-g assays appear to be of similar usefulness as ADA estimation in distinguishing TB from other causes of pleural and pericardial effusions, and ascites, with high specificity and sensitivity. ADA assays are, however, less dependent on human and material resources. The difference in pericardial IFN-g levels of HIVinfected and -uninfected TB patients was negligible in one study.32
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Lysozyme As with ADA and IFN-g, lysozyme levels are raised in tuberculous effusions and, depending on cut-off values used, may assist in distinguishing TB from other causes of effusion with relatively high sensitivity and specificity. For pericardial lysozyme, a value of 6.5g/dL had a sensitivity and specificity of 100% and 91.2%, respectively, in one study.50 Serological diagnostic methods These assays detect humoral immune responses, as opposed to T-cell-based assays that detect a cellular immune response. A number of mycobacterial antigens have been investigated and incorporated in relatively simple and inexpensive ELISA-based tests for detection of antibody. A number of commercial kits are available, but all currently available serological tests based on IgA, IgG, or IgM responses, alone or in multi-antigen assays, in adults or in children, have yielded poor sensitivity and specificity and are therefore not useful as confirmatory tests for TB.51–53 These assays do not have the ability to distinguish between infection and disease. Further, the sensitivity is markedly lower in HIV-infected patients.54 A newer approach that focuses on antigen rather than antibody detection and antigen-capture ELISA that detects lipoarabinomannan (LAM) in urine samples seem promising, with LAM-ELISA performing better than sputum smear microscopy in both HIVuninfected and -infected pulmonary TB patients in one study, but further evaluation is necessary.55 NUCLEIC ACID AMPLIFICATION (NAA) TESTS Nucleic acid amplification (NAA) tests are promising alternatives or additions to conventional bacteriological tests for the diagnosis of TB. They were expected to offer high sensitivity and specificity but failed to do so in most studies, especially in those cases in which diagnosis is a problem, such as in paucibacillary disease (smear-negative pulmonary TB, childhood TB) and extrapulmonary TB including pleural effusion.56,57 NAA tests, which are categorized as commercial kit-based or inhouse tests, are designed to amplify nucleic acid regions specific to M. tuberculosis. The PCR is the most widely used NAA test. Various NAA tests are commercially available, including PCR and strand displacement amplification tests.53 In-house tests are those for which investigators have designed their own protocols and are commonly used in developing countries where commercial kits may not be affordable. Such tests have been found to be highly heterogeneous in studies of mainly smear-positive TB cases. Sensitivity varied from 9.4% to 100% and specificity from 5.6% to 100% in a meta-analysis by Flores and colleagues.58 The use of the insertion sequence IS6110 as an amplification target and the use of nested PCR methods showed higher diagnostic accuracy.58 One study based on a hemi-nested PCR assay that detected IS6110 showed improved detection of M. tuberculosis in Peruvian children with pulmonary TB.59 A meta-analysis of PCR for diagnosis of smear-negative pulmonary TB found that PCR on bronchial specimens could be useful in highly suspicious smear-negative TB cases, but that PCR on sputum and gastric aspirates gave unreliable results and should neither replace culture nor be used routinely for the diagnosis of smear-negative pulmonary TB.60 Commercial NAA tests, and to a much lesser extent in-house NAA tests, probably have a potential role in the diagnosis of tuberculous pleuritis, tuberculous meningitis, and other forms of
22
extrapulmonary TB. A positive test most likely indicates (rules in) TB, but a negative test does not exclude this disease as a cause of pleuritis or meningitis, because sensitivity is relatively low (approximately 60% or less in most studies).57,61 In some centres, DNA amplification by PCR is used to identify M. tuberculosis in bacteriological cultures.62 NAA tests may be used to confirm M. tuberculosis directly in smear-positive cases. In summary, current NAA tests improve diagnostic certainty but do not replace microscopy and culture. There are concerns about accuracy and reliability. The advantage of NAA tests such as PCR is the rapidity in which test results are available. The routine use of NAA tests is limited by their expense, the need for specialized laboratories and trained staff, and the complexity of the tests. Efforts are currently being made to simplify testing protocols and to increase accuracy.12
Real-time PCR assay A real-time PCR assay was shown to be more sensitive than conventional acid-fast staining techniques and mycobacterial culturing in the detection of M. tuberculosis and other species of mycobacteria in patients with lymphadenitis, particularly on fine needle aspiration specimens.63 IMAGING This is discussed in more detail in Chapters 24–26.
Radiographs (X-rays) Chest radiography is the most common imaging method used in the diagnosis of TB and is often the mainstay of diagnosis, especially in HIV-uninfected intrathoracic childhood TB. It is less helpful in HIV-infected children, because other HIV-related lung conditions mimic ‘diagnostic’ features of TB on chest radiographs. In adults, diagnosis is often made by sputum smear microscopy and chest radiography is not always performed. In many developing regions even basic imaging equipment is not available. Bone radiographs are important in screening for osteoarticular TB, especially vertebral TB. Lytic lesions may develop in any bone. Although abdominal radiographs are often carried out when abdominal TB is suspected, the signs are very non-specific and include enteroliths, features of (partial) obstruction, evidence of ascites, perforation or intussusception, and calcified nodes or granulomas.64 Barium contrast studies (barium meal or enema) may be helpful for detecting intrinsic bowel abnormalities in gastrointestinal TB. Intravenous pyelography may show erosion and distortion of the calyxes in cases of renal TB. Ultrasonography Ultrasonography may be used to confirm pleural or pericardial effusions and to characterize the type of effusion. Gross pleural or pericardial thickening or fibrous strands crossing the pleural or pericardial spaces may indicate higher likelihood of TB but is not diagnostic.65 Ultrasonography may be used to guide pleural or pericardial fluid taps for diagnostic purposes. Abdominal ultrasound may be used to identify enlarged lymph nodes (discrete or matted), with both central caseation and calcification being suggestive of TB, ascites (free or loculated), bowel wall thickening (best seen in the ileocaecal region), and hepatic or splenic granulomas.64,66 If properly conducted, ultrasound gives similar information to computed tomography scans in abdominal TB. Neck ultrasonography is sometimes done to distinguish lymphadenopathy due to TB from that due to other causes such as malignancies, but this is not a reliable procedure.67
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Computed tomography (CT) and magnetic resonance imaging (MRI) scans These investigations are discussed in other chapters, but MRI is especially valuable in the diagnosis, and for assessing the prognosis, of tuberculous meningitis and spinal TB. CT scanning is often used in complicated intrathoracic TB cases and also in abdominal TB, although the results are usually consistent with ultrasound findings in the latter.
OTHER DIAGNOSTIC PROCEDURES FLEXIBLE BRONCHOSCOPY Flexible bronchoscopy offers a safe and rapid means of directly visualizing airway abnormalities, especially in cases in which TB is suspected. It enables specimens to be obtained for microbiological and histological investigation to exclude other diagnoses, e.g. bronchial carcinoma. Neither bronchial aspirates nor bronchoalveolar lavage, however, yield better culture results for M. tuberculosis than early morning gastric aspirates.68,69
NEW TESTS ON THE HORIZON SHOWING PROMISE MPB64 SKIN (TRANSDERMAL) PATCH TEST MPB64 is an immunogenic antigen specific to the M. tuberculosis complex and skin patches containing this antigen have been shown to elicit a definite dermal response in active, but not latent, TB. In studies in Japan and the Philippines it was confirmed that MPB64 skin patch could distinguish between infection and disease, and a skin patch containing recombinant rMPT64 is currently being commercially developed as a test by Sequella, Inc.(MD, USA).12 Although requiring further evaluation, this test has the potential to make a useful impact. A disadvantage is that the dermal reaction is difficult to evaluate in patients with dark skin.
TB-LAMP (LOOP-MEDIATED ISOTHERMAL AMPLIFICATION) TEST Loop-mediated isothermal amplification is a method for amplifying TB DNA directly in clinical samples. A positive result is indicated by fluorescence visible to the naked eye. This test is under development (Eiken Chemical Co Ltd, Japan) and is claimed to have a sensitivity comparable to that of culture.
LAPAROSCOPY AND MINI-LAPAROTOMY
BREATH DETECTION METHODS
Visual inspection of the peritoneum and other abdominal structures is often more helpful than histology or culture, although the latter helps to confirm the clinical diagnosis.
Various researchers are currently investigating the possibility of detecting volatile organic compounds in the breath of TB patients but not in controls. The advantage of such a test will be that it is non-invasive, but it may only be able to detect pulmonary TB.
COLONOSCOPY
CONCLUSION
Colonoscopy may assist the diagnosis of TB of the colon and terminal ileum in which, usually, short segments are infected. Multiple biopsies for histology and culture confirms the diagnosis in up to 60% of cases.64
Tables 22.6 and 22.7 summarize special investigations that could be carried out to assist in the diagnosis of pulmonary and extrapulmonary TB, respectively.
Table 22.6 Special investigations for suspected pulmonary tuberculosis Special investigation
Urban/rural
Qualifications
Both Both Both (rapid and/or ELISA) Both (if available) Not applicable
Children; adults in low-incidence areas All adults and older children All patients in areas where HIV prevalence > 1% or HIV clinically suspected All children. In adults when TB suspected and AFB negative Limited diagnostic value, especially in HIV-infected patients
Urban
Evaluation phase; may be used instead of TST in developed countries
Urban Urban Not applicable
Evaluate extent of disease As diagnostic procedure or to evaluate complications Not recommended
Culture for M. tuberculosis
Both (if available)
Drug susceptibility testing PCR (NAA tests) Lung biopsy
When available Urban Urban
Sputum, gastric aspirates, and other lung-derived fluids. Do when TB suspected and AFB negative All patients positive at 2–3 months of treatment or recurrent TB cases To confirm M. tuberculosis; limited value Diagnostic uncertainty in sick patient
Screening tests Tuberculin skin test Sputum microscopy for AFB HIV test Chest radiograph ESR, haematology, and acute-phase reactants T-cell-based assays Non-specific tests Computed tomography chest Bronchoscopy Serological tests Confirmatory tests
AFB, acid-fast bacilli; HIV, human immunodeficiency virus; ESR, erythrocyte sedimentation rate; PCR, polymerase chain reaction; NAA , nucleic acid amplification; ELISA, enzyme-linked immunosorbent assay; TST, tuberculin skin test.
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22
Table 22.7 Special investigations for extrapulmonary tuberculosis Special investigation
Urban/rural
Qualifications
Both Both (rapid and/or ELISA) Not applicable
Children; adults in low-incidence areas All patients in areas where HIV prevalence > 1%, HIV prevalence in TB patients is > 5% or HIV infection is clinically suspected Limited diagnostic value, especially in HIV-infected patients
Urban Both Not applicable
Evaluation phase; may be used instead of TST in developed countries When pulmonary TB is suspected (see Table 22.6) Very limited diagnostic value
Both Both Both
Pleural or pericardial effusion Spinal TB, joint/bone involvement Non-specific signs, limited value Types of gastrointestinal TB
Urban
Any body fluid, swab, or biopsy specimen including FNAB
Urban
Any specimen as above, limited additional diagnostic value
Screening tests Tuberculin skin test HIV test ESR, haematology, and acutephase reactants T-cell-based assays Sputum-microscopy/CXR Serological tests Non-specific tests Radiographs: Chest radiograph Osteoarticular Abdominal radiograph Barium meal, enema Confirmatory tests Microscopy and/or culture for M. tuberculosis PCR (NAA tests)
HIV, human immunodeficiency virus; ESR, erythrocyte sedimentation rate; CXR, chest radiograph; PCR, polymerase chain reaction; NAA , nucleic acid amplification; ELISA, enzyme-linked immunosorbent assay; TST, tuberculin skin test; FNAB, fine needle aspiration biopsy.
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47. Corral I, Quereda C, Navas E, et al. Adenosine deaminase activity in cerebrospinal fluid of HIVinfected patients: limited value for diagnosis of tuberculous meningitis. Eur J Clin Microbiol Infect Dis 2004;23:471–476. 48. Donald PR, Malan C, van der Walt A, et al. The simultaneous determination of cerebrospinal fluid and plasma adenosine deaminase activity as a diagnostic aid in tuberculous meningitis. S Afr Med J 1986;69:505–507. 49. Kashyap RS, Kainthla RP, Mudaliar AV, et al. Cerebrospinal fluid adenosine deaminase activity: a complimentary tool in the early diagnosis of tuberculous meningitis. Cerebrospinal Fluid Res 2006;3:5. Available at URL:http://www. cerebrospinalfluidresearch.com/content/3/1/5 50. Aggeli C, Pitsavos C, Brili S, et al. Relevance of adenosine deaminase and lysozyme measurements in the diagnosis of tuberculous pericarditis. Cardiology 2000;94:81–85. 51. Al Zahrani K, Al Jahdali H, Poirier L, et al. Accuracy and utility of commercially available amplification and serologic tests for the diagnosis of minimal pulmonary tuberculosis. Am J Respir Crit Care Med 2000;162:1323–1329. 52. Potturmarthy S, Wells VC, Morris AJ. A comparison of seven tests for serologic diagnosis of tuberculosis. J Clin Microbiol 2000;38:2227–2231. 53. Gray JW. Childhood tuberculosis and its early diagnosis. Clin Biochem 2004;37:450–455. 54. Perkins MD, Conde MB, Martins M, et al. Serologic diagnosis of tuberculosis using a simple commercial multiantigen assay. Chest 2003;123: 107–112. 55. Boehme C, Molokova E, Minja F, et al. Detection of mycobacterial lipoarabinomannan with antigencapture ELISA in unprocessed urine in Tanzanian patients with suspected tuberculosis. Trans R Soc Trop Med Hyg 2005;99:893–900. 56. Moon JW, Chang YS, Kim SK, et al. The clinical utility of polymerase chain reaction for the diagnosis of pleural tuberculosis. Clin Infect Dis 2005;41:660–666. 57. Pai M, Flores LL, Pai N, et al. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect 2003;3:633–643. 58. Flores LL, Pai M, Colford JM, et al. In-house nucleic acid amplification tests for the detection of
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CHAPTER
23
New diagnostics for tuberculosis Mark D Perkins
INTRODUCTION It is remarkable to reflect that since the introduction of short-course chemotherapy over 30 years ago,1 all of the technological improvements supporting TB control have come in the area of diagnostics. Fluorescence microscopy, radiometric and non-radiometric automated liquid culture systems, digital radiography, molecular methods for mycobacterial detection, species determination, and strain typing, and species-specific in vitro testing for latent infection with Mycobacterium tuberculosis have all been developed or introduced into general clinical use within the past 25 years. A much greater number of research methods for mycobacterial detection or drug resistance determination have also emerged. Unfortunately, the impact of all these advances on the effectiveness of TB diagnosis in disease-endemic countries has been limited. In fact, for many patients in the developing world, including the growing number of those infected with drugresistant strains of M. tuberculosis and those coinfected with human immunodeficiency virus (HIV), the chance of accurate and speedy diagnosis remains remote. The explanation for this paradoxical situation lies in the poor suitability of many of the new diagnostic tools for disease-endemic countries, and in the poverty of laboratory infrastructure in the settings where better diagnostics are most needed. This chapter will describe the current state of TB diagnostic testing worldwide, examine the need for better tools, and review ongoing efforts to develop them. Given the distribution of TB and its striking association with poverty, the chapter will focus on developing countries.
CURRENT STATE OF TUBERCULOSIS DIAGNOSTIC TESTING AND LABORATORY FACILITIES Laboratory testing for infection and disease from M. tuberculosis is a large global public health expense. A recently published analysis of the TB diagnostics market found global expenditures of over a billion US dollars annually,2 a much larger sum than that spent on drug treatment for TB.3 The distribution of these expenditures is striking. Three-quarters of all TB testing, but only one-third of all diagnostic spending, takes place in the developing world. Two-thirds of that money is spent evaluating symptomatic individuals for active TB, and most of the remainder is spent on purified protein derivative (PPD) skin testing, primarily in low-prevalence countries.
Sputum microscopy is by far the most common case detection test in use, with nearly 90 million patient examinations a year, only 6% of which are performed in high-income countries. Dissatisfaction with microscopy is to some degree reflected in the continued popularity of radiography: 50 million chest radiographs are performed each year, two-thirds of them in diseaseendemic countries in Asia. The use of culture for case detection is much less common, and is highly unevenly distributed. Of the 17 million TB cultures performed each year, nearly a third are done in high-income countries. Over 75% of those cultures performed in the 22 high-burden countries (HBCs) are concentrated in just two countries, Brazil and the Russian Federation. Similarly, South Africa accounts for over 90% of all culture testing on the African continent. Outside of these areas, case detection through mycobacterial culture is markedly uncommon. Of the 60–70 million patients presenting with TB-like symptoms in the high-burden countries in Africa and Asia, less than 5% are evaluated with mycobacterial culture. Drug susceptibility testing (DST) also remains relatively uncommon outside of high-income settings. Among the 22 HBCs, only half a million susceptibility tests are performed annually, two-thirds of which are accounted for by Brazil and the Russian Federation. Of the 6.5 million incident cases of TB occurring annually in the high-burden countries of Asia and Africa, only 180,000 (2.5%) are tested for drug susceptibility. The infrequency of TB culture and susceptibility testing is a result of the cost, complexity and slow yield of the test methods, but also of the poverty of laboratory infrastructure to support them. Microscopy facilities, which often lack quality control procedures or well-maintained microscopes, are generally available in TBendemic countries, with nearly 1.4 such laboratories per 100,000 population in the 22 HBCs. These 40,000 microscopy centres provide the primary TB diagnostic services for a population of nearly 4 billion people. Higher grade laboratories with the capacity for culture and DST are much less common. Strikingly, more than half of the 22 countries with the greatest number of TB cases have fewer than 10 culture laboratories and fewer than three DST-capable laboratories in the entire national public health network (see Table 23.1, reprinted from Cunningham et al.2). Clearly, highperformance TB testing will remain sharply limited in availability unless the testing methodologies are significantly simplified, so that they can be performed outside reference centres, or unless a major investment is made to strengthen laboratory infrastructure in high-burden countries.
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Table 23.1 Global estimation of tuberculosis diagnostics services and facilities Population (millions)
No. public DST labs
No. private DST labs
No. public culture labs
No. private culture labs
No. public microscopy centres
No. private microscopy centres
North America Europe Japan Other high income 22 HBCs Rest of world
327,813 459,088 127,417 29,552 3,892,273 1,382,869
71 713
253
130 1,998
1,013
600 2,230
2,279
24 629 691
9 57 138
62 2,135 785
42 299 383
160 39,198 15,340
124 5,912 3,663
Total
6,219,011
2,128
457
5,110
1,737
57,528
11,978
22 HBCs Afghanistan Bangladesh Brazil Cambodia China DR Congo Ethiopia India Indonesia Kenya Mozambique Myanmar Nigeria Pakistan Philippines Russian Fed. South Africa Thailand Uganda Tanzania Viet Nam Zimbabwe
22,930 143,809 176,257 13,810 1,294,867 51,201 68,961 1,049,549 217,131 31,540 18,537 48,852 120,911 149,911 78,580 144,082 44,759 62,193 25,004 36,276 80,278 12,835
1 1 61 1 50 2 2 70 50 1 1 2 1 3 6 350 13 8 2 1 2 1
1 2 563 1 578 5
2 2 252
344 569 2,333 207 3,500 768 430 8,000 3,000 381 210 733 487 620 2,600 12,000 341 846 400 544 692 193
75 18 791 25
2 15
10 10 4
8 3 5 0
0
50 50 1 1 5 7 8 6 730 14 90 2 3 16 1
1 2 0 10 4 0 1 10 3 0 9 2 0 1
90 200 3,500 300 161 2 95 125 100 10 0 115 80 150
75
DST, drug susceptibility testing; HBC, high-burden country. This table is reprinted from reference 2 (Cunningham WHO).
THE NEED FOR BETTER TUBERCULOSIS DIAGNOSTICS In the absence of an effective vaccine, TB control relies almost exclusively on the detection and treatment of cases to interrupt transmission. Unfortunately, a billion dollars of annual spending on TB diagnostic testing has not resulted in rapid improvements in TB control, largely because of the weakness of the diagnostic tools in use. In 1991 the World Health Assembly ratified the goal of detecting 70% of new infectious (smear-positive) TB cases and curing 85% of them under the DOTS strategy by the year 2005. Despite dramatic successes in establishing and expanding DOTS implementation over the past decade, case detection targets have yet to be met. Currently, roughly 60% of the expected smear-positive cases, and fewer than 30% of all cases, are currently detected and reported as smear positive.4 Moreover, during the past 15 years the incidence of TB has risen significantly in Africa and Eastern Europe, and little progress has been made in South-east Asia. Despite improved TB control in regions with established market economies (the Americas, Central Europe and the Western Pacific), the annual incidence rate of TB globally has grown more than 10% since case detection and treatment success targets were set. Our inability to yet meet case detection targets, which are defined on the basis of smear-positive cases only, wholly reflects
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the logistic difficulty of ensuring good access to quality microscopy in resource-limited settings. Microscopy is a cumbersome technique that requires significant effort on the part of the technologist, and a willingness to meticulously examine dozens of microscopic fields. Many technologists find working with sputum unpleasant, and tire quickly of reading slides, most of which are negative. Maintaining functioning microscopes and trained microscopists at the more peripheral health posts where patients have the greatest access to care has proven difficult. The effectiveness of diagnostics to interrupt transmission depends not only on the fraction of all cases diagnosed, but also on the speed with which they are detected. Undetected cases, including those that are smear negative,5 continue to transmit disease, and many smearnegative cases progress to smear-positive disease if left untreated. The estimated prevalence of TB, at over 14 million, is nearly twice that of the estimated incidence, suggesting that many patients are detected only after delays of many months. Operational research on TB diagnostics have confirmed that such delays are commonplace.6,7 The speediness with which patients are diagnosed and treated depends on a combination of factors, including the availability of diagnostic services, the quality of those services, the sensitivity of the testing performed, and the likelihood that a positive test will result in the initiation of treatment. Delays in result reporting,
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either for logistical reasons or because of the inherent slowness of testing, such as for mycobacterial culture, increase the likelihood of patient dropout and loss to follow-up. Early case detection is hampered by the relatively low sensitivity of microscopy. Direct sputum smear microscopy detects cases in which the sputum bacillary load is heaviest (greater than 10,000 organisms per millilitre of sputum) and therefore which are those most likely to transmit the infection. The average sensitivity of sputum microscopy for pulmonary TB in immunocompetent individuals is less than 60% compared with culture, even in research settings.8–17 For certain patient subgroups, including children,18 and of course patients with paucibacillary disease, the sensitivity is much lower. This has become a particularly important problem in the wake of the HIV pandemic. HIV-mediated immunosuppression impairs granuloma formation, reduces host capacity to contain bacilli and diminishes the formation of pulmonary cavities. Clinically, this manifests as frequent extrapulmonary disease,19 atypical chest radiographic findings20,21 and lower concentrations of bacteria in sputum.8 The sensitivity of microscopy in HIV-associated TB varies with the degree of immunosuppression, the length of TB illness and the local diagnostics capacity, but is often 10–20 percentage points lower than the sensitivity of microscopy in similar populations not infected with HIV.22–26 This inherent low sensitivity is exacerbated by poor work conditions, and, in many settings where workloads are high and HIV is prevalent, the proportion of cases detected by microscopy may be as low as 20–35%.27–29 The rapid progression of TB disease in HIV coinfected individuals has highlighted the need for early diagnosis. Up to 20% of all TB patients started on treatment in sub-Saharan Africa die within a year, and two-thirds of these deaths may occur in the first 2 months, reflecting the advanced state of illness at the time of final diagnosis.30 In fact, many HIV individuals coinfected with TB die prior to detection. In Malawi, half of TB suspects in whom a diagnosis was not readily made died while under investigation.31 Autopsy studies in several African countries and in India have found TB as the leading cause of death in patients dying with HIV.32–37 These studies also showed that the accuracy of diagnosis prior to death was poor.38,39 Thus, HIV coinfection decreases the sensitivity of microscopy at the same time that it elevates the need for rapid diagnosis and treatment. Outbreaks of drug-resistant TB in HIV-infected cohorts reported in the United States in 1991 and in South Africa 15 years later with high and rapid mortality underscored the lethality of untreated or 1.0 0.9
Proportion surviving
0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0
30
60 90 120 150 Days since sputum collected
180
210
Fig. 23.1 High mortality in HIV-associated extensively drug-resistant cases in KwaZulu Natal, 2005–2006.
23
Table 23.2 High mortality in HIV-associated multidrugresistant outbreaks in US facilities 1990–92 Facility
HIV infection (%)
Mortality (%)
Median interval TB diagnosis to death (weeks)
Hospital A Hospital B Hospital C Hospital D Hospital E Hospital F Hospital I Hospital J Prison system
93 100 95 91 14 82 100 96 98
72 89 77 83 43 82 85 93 79
7 16 4 4 4 4 4 4 4
mistreated TB in patients with advanced immunocompromise (Fig. 23.1 and Table 23.2), and thus the urgency of early diagnosis.40,41 They also highlight the need for rapid and effective detection of drug resistance to guide therapy in settings where multidrug-resistant (MDR) TB has even moderate prevalence. In summary, though microscopy remains the cornerstone of TB diagnostic testing in disease-endemic countries, it is incompletely available, cannot operationally be performed as a point-of-care test and has very low sensitivity except in cases of advanced pulmonary disease. Mycobacterial culture shows much higher sensitivity. However, conventional culture on solid media is not widely available because of the significant laboratory infrastructure required, and is inherently slow, so overall impact on TB control is limited. Drug susceptibility testing is not widely performed, and, when available, often yields results too delayed to be useful in directing therapy.
GENERATION OF NEW TECHNOLOGIES In the past, many of the tools needed to support public health programmes, including highly successful vaccination campaigns, came from national research institutes. The conventional microbiological methods currently used to detect TB in most developing countries had their origins in public health institutes, including acid-fast staining (1882) and egg-based culture media (1903).42,43 In the past halfcentury, public institutes have been less heavily engaged in product development, and the commercial sector has taken complete predominance in this area. Some of the specific features of private sector industry, including product development focus, strict project management, quality assurance mechanisms and manufacturing and distribution capacity, enable the efficient development and delivery of highly sophisticated biotechnologies in ways that public sector institutes are no longer structured to do. The primary role of the private sector in technology development has prioritized work on products likely to be profitable, often to the exclusion of poverty-associated diseases. Mindful of this, in the mid-1990s a new group of non-profit agencies emerged, often with instrumental funding from the Rockefeller Foundation and the Bill and Melinda Gates Foundation, which worked in partnership with the private sector to harvest their product development capacity and put it to use for public good. More than two dozen of such product development partnerships (PDPs) have been established, including three with substantial programmes in TB vaccines (the Aeras Global TB Vaccine Foundation), drugs (the Global
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Discovery Fund targeted reagent research
Proof of principle
Development Facilitate, co-fund, co-develop
Product in box
Demonstration Large-scale projects Efficacy measuring Effectiveness Data Data feasibility and impact on disease control programs
Evaluation Regulatoryquality lab and field trials
Policy International and national Normative policy change Guidelines
Access Distribution and implementation
Fig. 23.2 Diagnostic development pathway.
improvement in the quality of laboratory infrastructure and services; increased availability of existing tests of proven performance; and development of new tests to meet specific public sector needs.
The TB programme in FIND, initiated in late 2003, has built a portfolio of diagnostic tests at different stages of development. Many of the tests in later stages of development are incremental advances over current tests. In earlier stages of development are a range of technologies with the potential to revolutionize the diagnosis of TB. The final section of this chapter will describe methodologies in the FIND TB portfolio, as well as other technologies not currently under development at FIND.
PRIORITIZATION OF TUBERCULOSIS DIAGNOSTIC TEST DEVELOPMENT There are multiple indications for diagnostic testing for TB, including case detection, drug susceptibility testing, detection of latent infection with M. tuberculosis and therapeutic monitoring. In addition to the variety of testing indications, there are a variety of settings in which tests might be used, from sophisticated central laboratories to remote or rural primary health clinics. This combination of test indications and settings of use means that a variety of different diagnostic tests for TB are needed. The diagnostic priorities for TB testing in terms of public health are determined by the size of the population that would be affected and the impact of testing. As shown in Table 23.3, the greatest need is for tests to detect active TB, both smear positive and paucibacillary disease. Less critical to TB control, though important for TB management in settings in which there is a significant risk of drug resistance, is drug susceptibility testing. Detection of latent infection in order to offer preventive therapy with isoniazid is a key feature of TB control in low-prevalence countries and is known to be effective
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Purpose
Priority test indications
Test population
Detection of active TB
1. Detect pulmonary TB with high bacterial load (ssþ) 2. Detect pulmonary TB with low bacterial load (ss, Cxþ) 3. Detect extrapulmonary and paediatric TB 4. Detect MDR-TB for treatment 5. Detect MDR-TB for surveillance
100–200 million 100–200 million 5–50 million 10 million 100,000
6. Detect LTBI for surveillance 7. Detect LTBI for treatment
Unknown Testdependent
Drugsusceptibility testing Latent TB infection Ancillary tests
8. Screening to rule out TB 9. Monitoring response to treatment
MDR-TB, multidrug-resistant TB.
in reducing the incidence of TB in HIV coinfected populations. Lastly, tests to monitor the effectiveness of treatment and screening tests that could be used to rule out TB, especially in the overstretched clinics of disease-endemic countries, could be very useful, even if less critical to overall TB control efforts. As mentioned earlier, in addition to test indication, the needs for TB diagnostics can be described in terms of the levels of the health system in which they will be used. Though the sophistication of health services varies widely around the world, the settings in which patients undergo diagnostic testing can usefully be divided into several discrete levels, as shown in Fig. 23.3. At the higher levels of the health system, greater sophistication is possible, in terms of both the type of technology that could be used and the type of diagnostics information obtained. A minority of patients receive care at higher levels of the health system, and the overall
Reference laboratory Regional or referral laboratory
Microscopy laboratory
Greater sophistication
Table 23.3 Priority setting for the diagnostic indications for tuberculosis
Greater patient access
Alliance for TB drug development (GATB)) and diagnostics (the Foundation for Innovative New Diagnostics (FIND)). FIND is a non-profit organization dedicated to developing diagnostics for poverty-related infectious diseases. FIND works to identify technologies with characteristics likely to meet public health needs and, in partnership with academic and commercial agencies, drives their development. Once development is complete, products are evaluated in regulatory-quality clinical trials. If performance targets are met, the feasibility and impact of programmatic use is demonstrated in large-scale projects carried out in collaboration with national disease control programmes (see Fig. 23.2). The results of such demonstration projects can ideally be used to drive national and international testing policies. In partnership with other agencies, FIND is working to implement an overall strategy to improve the quality of diagnostic testing that recognizes the need for:
Health clinic
Fig. 23.3 Schematic representing levels of the health system.
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public health impact of technologies used at this level, even if performance characteristics are excellent, will be limited. Mathematical modelling exercises have shown that access to testing has a much greater impact than test performance.44 Thus, new TB diagnostics that would have the greatest impact would be case detection tests that are simple enough to use that they could be deployed at the periphery of the health system, such as in primary care clinics.
DIAGNOSTIC TECHNOLOGIES This section will provide an overview of diagnostic testing methods in development or under study for wide use in disease-endemic countries. The focus will be on case detection methods, but phenotypic and genotypic drug susceptibility testing methods will also be covered. Tests for latent infection are covered in detail elsewhere in this volume.
MICROSCOPY From a test development perspective, improving microscopy is an attractive approach as it takes advantage of an existing network of laboratories and technologists, and requires no change in case definition. Moreover, microscopy is inexpensive, relatively rapid to perform, and, in countries where TB is endemic, is highly specific. Though in many industrialized countries a significant fraction of acid-fast bacilli (AFB)positive specimens represent non-tuberculous mycobacteria (NTM),45 in disease-endemic countries microscopy remains specific for TB, even in settings where NTM may commonly be recovered in culture.46 In TB programmes, microscopy is performed much as it was 100 years ago, and remains a laborious task. Prototype devices for automated microscopy have been developed, but no successful product has yet been developed.47–49 Two methods for increasing the performance of AFB microscopy have been well documented in the existing scientific literature: processing of sputum prior to slide preparation and examination, and fluorescent staining techniques. AFB microscopy using fluorescent staining techniques was invented around the time of the Second World War,50,51 but has only been widely deployed in industrialized countries in the past two decades. Fluorescent AFB microscopy allows slide examination with 25–40 objectives, yielding a viewing field much larger than that with the conventional 100 oil immersion objectives used for carbol fuchsin-stained slides. Though the primary advantage touted for this method is increased speed, which is primarily attractive in laboratories with high workload, a recent systematic review of 45 studies comparing the fluorescent and conventional methods confirmed that fluorescence microscopy yielded an average increase in sensitivity of 10%, with no loss in specificity.52 Fluorescent microscopy is not widely used in disease-endemic settings, primarily because of the high equipment costs, the short bulb-life of expensive light sources such as high-pressure mercury lamps, and the need for a darkroom. Ultrabright light-emitting diodes (LEDs), which consume low amounts of energy and have a lifespan of over 10,000 hours, have now seen widespread application in such things as automotive parts and traffic lights. Industrial scale-up has resulted in low costs and improved reproducibility in manufacture, and a number of medical applications have been developed. Preliminary data on the utility of fluorescent microscopes using ultrabright LEDs in the royal blue wavelength for
23
TB detection have been published,53 and work is ongoing at FIND and elsewhere to develop a high-performance and inexpensive fluorescent microscope exploiting these principles. Most sputum microscopy is performed directly on smeared and stained preparations of unprocessed sputum. Many studies have examined sputum-processing methods that promise to improve the yield, safety or ease of microscopy by concentrating bacilli with gravitational force or filtration, by improving their dispersion in sputum, or by decreasing their viability with chemical or thermal treatment.54 A recent systematic review examined 83 studies comparing the yield of direct microscopy with a variety of sputum-processing methods. Procedures for digestion/liquefaction of sputum followed by centrifugation, prolonged gravity sedimentation or filtration increased the sensitivity of microscopy by 13–33% over direct methods.55,56 The variability in trial design between published studies makes it impossible to determine which method is optimal. Inexpensive household bleach (5% sodium hypochlorite), which is easily available and is microbicidal, is one of the more commonly studied processing reagents, and multicentre studies for examining standardized bleach-processing methods are in progress.57 Beyond processing and staining methods, simply altering the collection and examination procedures may significantly improve diagnosis. Recent studies have shown, for example, that improving communication between patients, clinics and laboratories,58 or offering to instruct patients on the proper collection of sputum, can result in significant improvements in the yield of microscopy.59 Though serial examination of multiple specimens can also improve sensitivity, additional yield accrued beyond the second sputum examined is small.60 Decreasing the required number of sputum samples examined from three to two has been suggested as a way of increasing efficiency, reducing workload and increasing time available to examine remaining specimens and reduce patient dropout, an important problem especially for patients with positive, but delayed, microscopy results.61,62
MYCOBACTERIAL GROWTH DETECTION The most sensitive way to detect mycobacteria is through cultivation of processed specimens on enriched media. Unfortunately, M. tuberculosis replicates slowly, and 6–8 weeks are needed to rule out growth of visible colonies on conventional solid media. Most laboratories in disease-endemic countries are currently performing culture using egg-based media (e.g. Lo¨wenstein-Jensen or Ogawa) invented at the turn of the past century. Adding or substituting culture in a liquid medium that includes a growth indicator method can improve sensitivity slightly and speed significantly, roughly halving the time to detection of positive cultures, especially if automated continuous monitoring is used.63–74 Pairing automated liquid culture with DST using the same system can reduce the overall time to culture and DST results from a median of 2 months to 2 weeks.75 Culture, and more importantly the specimen processing that precedes it, is a relatively complex procedure, and is not commonly performed outside of a limited number of reference centres in most high-burden countries. Automated liquid systems, which have much higher capital and reagent costs, have in the past been rarely used in national programmes of developing countries, with the notable exception of South Africa. Over the past 2 years, FIND mounted large demonstration projects involving tens of thousands of patients to examine the feasibility and public health impact of
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wider use of liquid culture in developing countries, both for case detection and for DST, and has negotiated lower prices for the public sector in such countries with the major manufacturer of this type of media system. The initial data from those projects, presented to the Seventh Scientific and Technical Advisory Group (STAG) of the World Health Organization’s Stop TB Department in 2007, resulted in recommendations on the wider use of such culture media in settings with appropriate infrastructure and quality control. As liquid culture is highly sensitive for the growth of a large number of mycobacterial species, many developing country laboratories implementing liquid culture will detect NTM with much higher frequencies than they had with solid media. Thus, species determination of culture isolates becomes very important in this setting, especially because NTM are often resistant to many of the drugs used to treat TB and can lead the unsuspecting technologist to falsely report MDR-TB. Rapid test methods for detecting MPT-64, a protein specific to M. tuberculosis complex organisms, in culture isolates from solid or liquid media have recently been developed.76–79 This makes rapid and inexpensive species determination of M. tuberculosis possible where previously only very slow phenotypic or very expensive genotypic speciation tests would have been available. This may be of particular importance in areas where HIV co-prevalence is high. The use of these rapid speciation tests in association with liquid culture was among the recommendations of the 2007 WHO STAG report. Many non-commercial culture methods for speeding the detection of mycobacterial growth on solid and liquid media have been developed, and most have also been applied to DST. Thin layer culture on agar, a method decades old, has been shown to provide reliable and rapid culture results at a speed similar to that of commercial liquid systems and has also been applied to DST.80–82 Similarly, direct inoculation of processed clinical specimens into rehydrated commercial liquid media in multi-well plates with or without antibiotics, followed by repeated microscopic examination using an inverted microscope, has demonstrated speed of detection that is as fast or faster than commercially prepared liquid culture. This method, called microscopic observation drug susceptibility (MODS), also gives concomitant isoniazid and rifampin susceptibility results with good accuracy compared with standard methods.83 Unlike methods that depend on oxygen consumption or the accumulation of metabolites, microscopic detection appears to be minimally delayed with lower concentrations of bacteria in the inoculum, with median difference in time to detection between smear-positive and smear-negative samples of only 1–4 days in two different studies.83,84 Direct inoculation of processed sputum into commercially prepared liquid media75,85,86 or eggbased solid media,87,88 with and without antibiotics, give similar results, albeit a few days later. Colorimetric indicators may allow simpler readout of results in non-commercial DST methods. Good preliminary data exist for the nitrate reductase assay in solid media as either an indirect or direct DST method.89,90 Similarly, reazurin or MTT assays have been used in liquid media for indirect or direct DST.91,92 None of these methods, all of which require repetitive examination and relatively labour-intensive pre-inoculation processing steps, have become widely used, despite low reagent costs. Sputum swab methods that use cetrimide decontamination, which removes the need for a centrifugation step, has been experimentally applied for cultivation and direct DST, but has not been widely implemented.93,94
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Improvements in culture-based methods can thus reduce the time to bacterial detection, and even of susceptibility testing, from 1–3 months down to 1–3 weeks. To further speed detection, methods that use readouts for other than detection of M. tuberculosis growth are necessary. Mycobacteriophages have been used as bacterial reporters by a number of groups. One method first published in 1993 used phages expressing firefly luciferase to determine the susceptibility of M. tuberculosis strains to antibiotics.95 This method, which requires a pre-test culture step and repeated addition of luciferin for readout, has not been commercially developed. Another phage-based method, which uses a conventional plaque assay on a lawn of rapidly growing mycobacteria as the readout, gives results at a set time of 48 hours, and has been commercialized as the FASTPlaqueTB™ test (Biotec, UK). Variability in the susceptibility of TB strains to phage infection, especially after harsh treatment such as with NaOH for decontamination, limits the sensitivity of the assay for case detection, especially in samples with a lower bacterial concentration. The current version of the commercialized test detects 29–87% of smear-positive patients and 13–78% of smear-negative patients within 2 days.15,96–100 The capacity of the D29 phage to replicate in NTM has not impaired clinical specificity, which remained high (99.1%) even in a study in which 30% of all culture isolates were NTM.74 In collaboration with FIND, Biotec adapted the method for rifampin susceptibility testing to work directly from sputum in smear-positive samples. Though interesting as an alternative to molecular amplification, the feasibility of the FASTPlaque-Response™ test for use in national TB control programmes could not be demonstrated. In summary, mycobacterial growth detection and drug susceptibility testing may be performed by a wide variety of methods, each with arguable advantages. Thus far, most culture and DST in diseaseendemic settings has used solid media and indirect DST, with long delays in result reporting. Except for the commercial test systems, few of the many alternative and faster methods have been subjected to rigorous multicentre evaluations. The feasibility of universal access to DST, including commercial systems, is in doubt unless laboratory infrastructure can be substantially improved, or unless much simpler methods of proven effectiveness can be developed.
NUCLEIC ACID AMPLIFICATION TESTING (NAAT) Molecular detection of M. tuberculosis genes from clinical materials would appear to be an ideal application for polymerase chain reaction (PCR) and other amplification methods, as culture methods are so slow, and as early and appropriate therapy improves outcome. Great excitement greeted the development of a range of commercial and non-commercial NAAT assays for TB some 15 years ago. These tests have shown excellent performance for mycobacterial detection in terms of speed and specificity. Though analytical sensitivity is extremely good, clinical sensitivity approaches 100% only in samples with substantial bacterial concentrations (e.g. smear-positive samples). The reported sensitivity of NAAT in samples that are smear negative varies, but is generally in the range of 50–80% compared with dual-media culture.101,102 The additional cost of these tests, which have not yet been able to compete with culture in terms of sensitivity or drug resistance detection, as well as their considerable complexity, has resulted in relatively low implementation globally. Only 2.5 million commercial NAAT assays are performed each year for TB world-wide, compared with 18 million cultures and nearly 90 million sputum smears for microscopy. The vast majority of this testing is in developed countries. Even in established molecular laboratories in resource-limited
CHAPTER
New diagnostics for tuberculosis
countries, performance is highly variable, suggesting that much greater assay robustness or much more laboratory support will be needed before NAA testing could be implemented more widely.103 Work to simplify sample processing and molecular amplification is underway in a number of groups. FIND has been collaborating with Eiken Chemical Corporation (Tokyo, Japan) to develop a simple, manual molecular TB detection test based on their loopmediated, isothermal amplification (LAMP) platform. The advantages of this technology, which uses six specifically designed primers and a single polymerase with strand displacement activity, are that it requires no thermocycler, is a closed system, with no need ever to open the reaction tube after amplification, and gives a visual readout interpretable by the naked eye.104 Eiken and FIND recently developed a prototype test for TB with a simplified specimen-processing method that could be performed at the bench-top by microscopy technologists in resource-limited settings. Preliminary data suggest that the simplified system may perform similarly to commercial instrumented systems, detecting essentially all smear-positive specimens and half of smear-negative specimens.105 The requirement for specimen processing and DNA extraction is an important obstacle to the implementation of any molecular amplification method in laboratories without substantial technical infrastructure. FIND is working with Cepheid (Sunnyvale, CA, USA) to develop a real-time PCR assay for TB on its GeneXpertW platform that automates sputum processing, DNA extraction, gene amplification and target detection into a single, hands-free test. The assay, which is being developed in collaboration with the University of New Jersey Medical and Dental Schools, will use molecular beacons to detect the presence of both TB and rifampin resistance in under 2 hours.106 Clinical trials are expected to start in 2008. Molecular mechanisms for resistance to isoniazid and rifampin, and assays to test for these mutations, were first reported in the early 1990s.107,108 Since that time, a broad array of non-commercial methods for detecting drug resistance-associated mutations have been developed. The limited number of genetic mutations responsible for rifampin resistance has been exploited by two currently available commercial molecular assays, GenoTypeW MTBDRplus (Hain LifeScience, Nehren, Germany) and INNO-LiPA.Rif TB (Innogenetics, Gent, Belgium), both of which use conventional PCR followed by amplicon hybridization onto a series of oligonucleotide probes on nitrocellulose strips to detect rifampin resistance with 1-day turnaround. Several trials of these tests, performed on culture isolates or directly on smear-positive sputum, have shown good correlation with conventional rifampin susceptibility testing.109–116 Based on these studies and evidence collected in FIND demonstration projects, recommendations for the selected use of these tests for MDR screening in smear-positive samples were issued in a 2008 WHO STAG report. The GeneXpertW system described earlier uses similar gene targets for rifampin resistance, but, by automating processing and amplification and detection steps, aims to greatly simplify the detection of resistant strains, making point-of-care detection possible.105
DETECTION OF ANTIBODY RESPONSES TO TUBERCULOSIS INFECTION The pursuit of a simple test that could detect diagnostic humoral responses to TB is over 100 years old.117 In most people, progressive TB does generate easily detectable levels of antibody directed at a variety of M. tuberculosis protein and non-protein antigens.
23
On this basis, dozens of companies, many of them small, have developed lateral flow or other immunochromatographic tests for TB. Unfortunately, humoral responses to TB disease are quite heterogeneous in man, and many confirmed TB patients do not have detectable antibodies against the limited number of antigens that have been included in commercial assays. The clinical performance of these tests has proven poor, especially in HIV coinfected patients.118–120 Efforts to use modern methods to expand the pool of target antigens are less than a decade old, but have already shown that novel antigens may offer improved performance.121,122 Recently, protein microarrays using fractionated native M. tuberculosis proteins or high-throughput cloning and expression systems that allow examination of the diagnostic potential of large numbers of potential targets have been developed.123,124 In collaboration with Immport, Inc. (Irvine, CA, USA) and the Public Health Research Institute at the University of New Jersey Medical and Dental Schools, FIND has recently completed development of protein microarrays that include over 96% of the entire TB proteome. Interrogation of these arrays with large numbers of well-characterized patient sera may make it possible to identify a set of antigens that together show sufficient diagnostic utility to be put into an assay for point-of-care testing intended to support TB control in high-burden countries.
ANTIGEN DETECTION Detection of bacterial antigens is an attractive approach to TB diagnosis, with the theoretical benefits of high specificity, correlation to bacterial burden and independence from immune function. Assays using serum or urine might have particular application in HIV-associated TB, where extrapulmonary disease is common and a large total body burden of bacilli may not be reflected in the sputum. This approach has been successfully applied for clinical diagnosis of a number of pathogens using relatively simple formats (e.g. respiratory syncytial virus, influenza, Streptococcus pneumoniae, Legionella pneumophila, Cryptosporidium parvum, Plasmodium sp.). A number of studies examining the potential detection of protein and non-protein antigens in clinical samples from TB patients, including blood, cerebrospinal fluid or urine, have been published.125–128 Monoclonal antibodies have been used to detect proteins and glycolipids found to be abundant in culture filtrate, such as MPT32,129 the antigen 85 complex,130–132 the 38-kDa protein,131,133 and lipoarabinomannan (LAM). LAM is a high-molecular-weight, heat-stable, glycolipid present in the cell wall of mycobacteria. It has been found in measurable concentrations in the urine, sputum and serum of TB patients.134–141 A number of groups are working to develop highly sensitive assays to detect LAM and other antigens.
DETECTION OF TUBERCULOSIS-SPECIFIC ORGANIC COMPOUNDS Chromatography and mass spectrometry have been used to identify organic compounds specific to TB for many years, and clinical applications of these methods were proposed in the 1970s and 1980s for the detection of meningeal and pulmonary TB.142–149 The instrumentation required to detect these compounds, however, was much too expensive and complex to be deployed in settings where TB is common. These proposals have resurfaced recently as detection technologies improve.150,151 More recently, there have been efforts to develop more compact sensing technologies such as the electronic nose that could detect characteristic volatile compounds or patterns
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of compounds in exhaled air or headspace gas over sputum or bacterial cultures. These technologies are simpler both to manufacture and to use, and hold the promise of a reagent-free method for TB detection.152,153 Promising preliminary data using a non-optimized sensor array of 14 conductive polymer sensors (Bloodhound, Scensive, Inc.) to differentiate M. tuberculosis, Mycobacterium avium and Pseudomonas aeruginosa in headspace gas over spiked sputum with an analytical sensitivity for M. tuberculosis of 104 colony-forming units per millilitre have been published. Clinical performance of the Bloodhound eNose for M. tuberculosis was reasonably good, though not adequate for implementation without further optimization.154 One approach being explored by FIND is optimization of an eNose to detect specific volatile organic compounds (VOCs) identified by more complex methods. For example, gas chromatography/mass spectroscopy (GC/MS) analysis has identified VOCs in headspace gas over TB culture,155 with similar VOCs found in air exhaled by patients with pulmonary TB.
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Tanzanian patients with suspected tuberculosis. Trans R Soc Trop Med Hyg 2005;99(12):893–900. Pereira Arias-Bouda LM, Nguyen LN, Ho LM, et al. Development of antigen detection assay for diagnosis of tuberculosis using sputum samples. J Clin Microbiol 2000;38(6):2278–2283. Cho SN, Shin JS, Kim JD, et al. Production of monoclonal antibodies to lipoarabinomannan-B and use in the detection of mycobacterial antigens in sputum. Yonsei Med J 1990;31(4):333–338. Sada E, Aguilar D, Torres M, et al. Detection of lipoarabinomannan as a diagnostic test for tuberculosis. J Clin Microbiol 1992;30:2415–2418. Mardh PA, Larsson L, Hoiby N, et al. Tuberculostearic acid as a diagnostic marker in tuberculous meningitis. Lancet 1983;1(8320):367. Craven RB, Brooks JB, Edman DC, et al. Rapid diagnosis of lymphocytic meningitis by frequencypulsed electron capture gas-liquid chromatography: differentiation of tuberculous, cryptococcal, and viral meningitis. J Clin Microbiol 1977;6(1):27–32. Brooks JB, Choudhary G, Craven RB, et al. Electron capture gas chromatography detection and mass spectrum identification of 3-(20 -ketohexyl) indoline in spinal fluids of patients with tuberculous meningitis. J Clin Microbiol 1977;5(6):625–628. Odham G, Larsson L, Mardh PA. Demonstration of tuberculostearic acid in sputum from patients with pulmonary tuberculosis by selected ion monitoring. J Clin Invest 1979;63(5):813–819. French GL, Teoh R, Chan CY, et al. Diagnosis of tuberculous meningitis by detection of tuberculostearic acid in cerebrospinal fluid. Lancet 1987;2(8551):117–119. Larsson L, Odham G, Westerdahl G, et al. Diagnosis of pulmonary tuberculosis by selected-ion monitoring: improved analysis of tuberculostearate in sputum using negative-ion mass spectrometry. J Clin Microbiol 1987;25(5):893–896. French GL, Chan CY, Cheung SW, et al. Diagnosis of pulmonary tuberculosis by detection of tuberculostearic acid in sputum by using gas chromatography-mass spectrometry with selected ion monitoring. J Infect Dis 1987;156(2):356–362. Muranishi H, Nakashima M, Tsunematsu H, et al. [Rapid diagnosis of pulmonary tuberculosis by detection of tuberculostearic acid with gas chromatography/mass spectrometry]. Kekkaku 1987;62(12):627–633. [In Japanese] Stopforth A, Tredoux A, Crouch A, et al. A rapid method of diagnosing pulmonary tuberculosis using stir bar sorptive extraction-thermal desorption-gas chromatography-mass spectrometry. J Chromatogr A 2005;1071(1–2):135–139. Daikos GL, Brooks JB, Michos A, et al. Detection of tuberculostearic acid in serum and other biological fluids from patients with tuberculosis by electron capture-gas chromatography and chemical ionisation-mass spectrometry. Int J Tuberc Lung Dis 2004;8(8):1027–1031. Deisingh AK, Stone DC, Thompson M. Applications of electronic noses and tongues in food analysis. Int J Food Science Technol 2004;39(6): 587–604. Pavlou AK, Turner AP. Sniffing out the truth: clinical diagnosis using the electronic nose. Clin Chem Lab Med 2000;38:99–112. Fend R, Kolk AHJ, Bessant C, et al. Early detection of M. tuberculosis in culture and sputum using electronic nose technology: Prospects for clinical application. J Clin Microbiol 2006;44:2039–2045. Phillips M, Cataneo RN, Condos R, et al. Volatile biomarkers of pulmonary tuberculosis in the breath. Tuberculosis (Edinb) 2007;87(1):44–52.
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Imaging of tuberculosis in adults Charles L Daley and Michael Gotway
Imaging has played a central role in the evaluation of patients with mycobacterial infections since radiography was first developed at the turn of the twentieth century. Since that time, the sophistication of imaging has increased substantially, and new non-invasive modalities for anatomical and physiological investigation, particularly cross-sectional methods, such as computed tomography (CT), magnetic resonance imaging (MRI) and 18F-fluoro-2deoxy-D-glucose positron emission tomography (FDG-PET), have been introduced and are widely employed. Nevertheless, the chest radiograph still plays a central role in the evaluation of patients suspected of mycobacterial infections, and familiarity with the findings of mycobacterial infection on chest radiography, as well as the limitations of chest radiography and cross-sectional methods for the evaluation of mycobacterial infections, is critical for physicians caring for patients at risk for these diseases. Mycobacterial infections have traditionally been broadly classified into infections related to Mycobacterium tuberculosis and non-tuberculous mycobacterial (NTM) infections. Research regarding the imaging appearances of M. tuberculosis and NTM infections has been reported along these lines, and the manifestations of mycobacterial infections discussed later will follow in the same vein.
mediastinal lymph nodes, where a similar histopathological reaction may occur. The combination of the lung parenchymal and lymph node infection has been termed the Ranke complex (Fig. 24.2). Simon foci are apical lung nodules, often calcified, that are the result of haematogenous dissemination at the time of initial infection.1 Organisms within the Ghon focus often gain access to the bloodstream and may disseminate to extrathoracic organs, but typically host defences prevent overt infection from developing in extrathoracic sites. However, although the pulmonary, lymphatic and extrathoracic foci of infection Box 24.1 Mycobacterium tuberculosis: primary infection
MYCOBACTERIUM TUBERCULOSIS
Clinical infection following first exposure. Ghon focus: local infection. Ranke complex: local infection with lymph node spread. Often asymptomatic in children. Adults: weight loss, fever, cough, haemoptysis. Radiographs possibly normal in 15%. Air-space consolidation, often lobar; slow to clear. Atelectasis in children. Cavitation and miliary spread uncommon. Lymphadenopathy characteristic in children, uncommon in adults. Pleural effusion possibly seen, uncommonly without lung disease, more so in older patients than children.
The imaging manifestations of TB are strongly dependent on a number of factors, including prior exposure to M. tuberculosis, age at time of infection and, in particular, host immunity.1 Several different patterns of TB have been described in immunocompetent patients, each differing in pathological, clinical, and radiological manifestations. These patterns include primary TB, progressive primary TB, and postprimary TB. The imaging appearances of these forms of TB are often distinctly different and familiarity with each is important for proper image interpretation.
PRIMARY TUBERCULOSIS Primary TB refers to disease that occurs following the first exposure to M. tuberculosis (Box 24.1). While primary TB is often considered a primarily paediatric disease, this pattern may be encountered in adults, particularly in severely immunocompromised patients. The host, in normal circumstances, will sequester M. tuberculosis by granuloma formation. This initial infection has been termed the Ghon focus, and usually heals by the development of a fibrous capsule around the focus of infection, which often calcifies (Fig. 24.1). Shortly after the initial infection, organisms may spread through the lymphatics to hilar and
Fig. 24.1 TB: Ghon lesion. Detail chest radiograph shows small, circumscribed dense nodule (arrow), consistent with nodule calcification.
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Primary TB in children is asymptomatic in up to 65% of patients, and may be detected only with testing for infection. In contrast, approximately 95% of adults with primary TB are symptomatic, commonly presenting with weight loss, anorexia, failure to thrive, fever, cough, night sweats and haemoptysis.2
Fig. 24.2 TB: Ranke complex. Detail chest radiograph shows circumscribed dense nodule (arrow) associated with calcified right hilar lymph nodes (arrowhead).
are usually inactive shortly after primary infection, organisms remain viable and may serve as the nidus for reactivation of disease when favourable circumstances occur.
Imaging findings The most common manifestation of primary TB is lymphadenopathy. Enlarged intrathoracic lymph nodes are seen in 83–96% of paediatric patients with TB,1,3,4 with the frequency of lymphadenopathy decreasing with age. Immunocompetent adults with TB have a prevalence of lymphadenopathy ranging from 43% in those under the age of 35 to less than 10% of patients with a median age in the sixth decade of life.1,5,6 Lymphadenopathy is most commonly seen in the right paratracheal (Fig. 24.3A and B) and right hilar stations in patients with primary TB.1 However, lymphadenopathy may be encountered in any lymph node station within the chest or in various combinations, including involvement of both hila in up to 31% of patients, hilar without mediastinal lymphadenopathy and isolated mediastinal lymphadenopathy.1,3,4,7 Lymphadenopathy is more readily detectable with CT or MRI than radiography, and lymph nodes affected with TB characteristically show central low attenuation with contrast-enhanced CT, particularly if the lymph nodes exceed 2 cm in diameter (Figs. 24.3C).1,3,7 In the proper clinical context,
Fig. 24.3 Primary TB in a child: lymphadenopathy. (A) Chest radiograph shows right paratracheal lymphadenopathy (arrow). (B) Chest radiograph taken 1 year prior to (A) shows normal right paratracheal region. (C) CT shows low-attenuation subcarinal lymphadenopathy (arrow) narrowing right lower lobe bronchus (curved arrow).
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lymph nodes showing central low attenuation with peripheral rim enhancement are highly suggestive of TB, but they are not specific for that diagnosis as they also can be seen with metastatic squamous cell carcinoma, metastatic testicular carcinoma, lymphoma and Whipple’s or Crohn’s disease.1 Patients with primary TB may show no pulmonary parenchymal abnormalities in 15% of patients, particularly infants and young children.8 When radiographic abnormalities are present, the pattern is usually one of parenchymal opacification. These parenchymal opacities are ill-defined, are segmental in nature or involve an entire lobe, frequently extend to the pleural surface, may contain air bronchograms and resemble other causes of air-space pneumonia (Fig. 24.4).9 Patchy linear and nodular opacities resembling a bronchopneumonia pattern (Fig. 24.5), and mass-like areas of opacity may also be seen.1,10,11 Occasionally parenchymal opacity will produce a bulging fissure (Fig. 24.4), particularly in the presence of endobronchial obstruction.4,9,12 Multifocal opacities will be seen in 12–25% of patients.1,4,9,13 The right lung is more commonly affected than the left, possibly reflecting the larger volume
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of aerated lung on the right side.1 No definite zonal predominance is clearly demonstrable – various investigators have described upper, lower and no zonal predominance for parenchymal opacities due to primary TB.1,4–6,13 Parenchymal opacities are located ipsilateral to enlarged lymph nodes in two-thirds of patients.4 Because lymphadenopathy is commonly present in children with primary TB, the presence of parenchymal opacities without lymphadenopathy is a very uncommon pattern.4 However, this pattern has been reported in 38–81% of adults with primary TB and should therefore be an expected finding in this patient population.1,5,6 Miliary dissemination in primary TB is seen in 2–6% of patients, usually occurs within 6 months of primary infection and is more commonly encountered in young children, immunocompromised adults or the elderly.12–15 Early in the course of miliary TB, chest radiography may appear normal. Later, miliary infection presents on chest radiography as circumscribed nodules measuring 1–3 mm in size diffusely distributed throughout the upper, middle and lower lung zones (Fig. 24.6). CT, in particular high-resolution CT (HRCT), is well suited for the detection and characterization of small pulmonary nodules such as those encountered with miliary infection. Miliary nodules on HRCT appear as circumscribed 1–3 mm nodules, distributed throughout the lung parenchyma evenly, in contact with visceral pleural surfaces and in the
Fig. 24.4 Primary TB in a child: air-space consolidation. Chest radiograph shows consolidation in right upper lobe. Note bulging fissure.
Fig. 24.5 Primary TB in a child: bronchopneumonia. Chest radiograph shows patchy consolidation (arrows).
Fig. 24.6 TB: miliary pattern. (A) Chest radiograph shows multiple randomly scattered circumscribed nodules. (B) HRCT shows randomly disseminated nodules (arrowheads, centrilobular nodules; arrows, subpleural nodules), representing the miliary pattern. (Continued)
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Fig. 24.7 Primary TB in a child: airway involvement and volume loss. Chest radiograph shows patchy consolidation in right upper lobe associated with volume loss, evidenced by cranial retraction of the right minor fissure (arrows).
Fig. 24.6—cont’d (C) Gross specimen shows randomly disseminated nodules (arrows), correlating with HRCT findings.
centrilobular regions of lung (Fig. 24.6B and C). Miliary disease is characteristic of processes caused by haematogenous dissemination to the lung, but is not unique to mycobacterial infection, and can be seen with fungal or viral infections and metastatic disease. Lymphadenopathy may be encountered in patients with miliary disease, particularly children. Uncommonly, the adult respiratory distress syndrome may complicate miliary disease.9 With appropriate therapy, miliary disease often resolves in 2–6 months, usually more rapidly in children than in adults.9,16 Miliary TB usually does not calcify.9,17 Atelectasis and, less commonly, hyperinflation are often encountered on thoracic imaging studies in children with primary TB (Fig. 24.7), and may be related to airway compression by enlarged lymph nodes (Fig. 24.3C). Less commonly, rupture of an infected lymph node into an adjacent bronchus may cause endobronchial dissemination of infection and produce atelectasis or pulmonary overinflation. Most commonly, anterior segment upper lobe or medial segment right middle lobe bronchi are involved.9 Airway involvement in patients with primary TB often affects the distal trachea and bronchi simultaneously, presenting as irregular or smooth circumferential airway thickening or occlusion.18 These findings may normalize following treatment, although airway irregularities may remain.18 Pleural effusion is a common manifestation in adults with primary TB, and has been reported in 29–38% of patients.1,5,6 Pleural effusions in primary TB are usually unilateral and ipsilateral to parenchymal abnormalities and are commonly small,1,19 but may be moderate (Fig. 24.8) to large in size.9,13,20 Bilateral pleural effusions are seen in approximately 12–18% of patients,1,4,6,13 whereas
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Fig. 24.8 Primary TB: pleural effusion. CT shows bilateral pleural
effusion (arrows) and lingular consolidation (arrowheads). M. tuberculosis was recovered from pleural biopsy.
pleural effusion is the sole radiographic abnormality in 5% of patients,6 although it is possible that occult parenchymal foci may be present and only readily detectable with CT.9,21 Pleural effusions in primary TB are less commonly seen in children, particularly children under the age of 2 years;1,19 the prevalence increases with age, and is approximately 6–11% in young children and as high as 38% in adolescents and adults.1,4,5,9,12,13,22 Pleural effusions with primary TB often resolve quickly with the institution of appropriate therapy,9,12 although pleural thickening and calcification may occur.9 When pleural thickening exceeds a thickness of 2 cm on the chest radiograph, CT frequently will show pleural liquid, and the fluid may contain viable tubercle bacilli.9,21,23 Parenchymal opacities completely resolve without sequela in twothirds of patients.4,9 However, radiographic abnormalities in primary TB are often slow to resolve, even with the institution of prompt treatment. Air-space opacities often take 6–24 months to clear completely.4,9 In the remaining one-third of patients, primary TB will resolve, leaving a residual scar.9 Resolution of parenchymal opacities is usually more rapid in the presence of anti-TB treatment, although ‘paradoxical worsening’ in the first 3 months following initiation
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Fig. 24.9 Pericardial TB: calcific pericarditis. (A) Chest radiograph shows irregular, linear calcification projected over heart (arrows). (B) CT shows calcification involves anterior and posterior pericardium (arrows).
of treatment may be seen.4,9 Lymphadenopathy may take longer to resolve than parenchymal opacities, often resolving without sequelae, although nodal calcification may persist. Nodal calcifications usually develop 6 months or longer following the initial infection.9,17 Uncommonly, tuberculous lymphadenitis results in tuberculous mediastinitis, with the subsequent development of superior vena caval compression, airway compression, oesophageal fistula formation or pericarditis.9 When the pericardium is involved, constrictive pericarditis may develop in 10% of patients,9,12 and typically manifests on chest radiography as pericardial calcification (Fig. 24.9A) and cross-sectional imaging as pericardial calcification (Fig. 24.9B) and pericardial thickening. Focal nodules or masses, referred to as tuberculomas, are often considered a manifestation of healing of primary TB.9,12 Tuberculomas are encountered in 7–9% of patients with TB, and are usually discovered in asymptomatic adults.9,13 Tuberculomas vary in size, with most lesions measuring less than 3 cm, but some investigators have reported lesions exceeding 5 cm in size.9,12,24 Tuberculomas are located in the upper lobes in 75% of patients, and may be multiple in 20% of cases.9,24 Cavitation may occur and has been reported in 10–50% of tuberculomas.9,12 Surrounding ‘satellite’ nodules (smaller nodules in the immediate vicinity of a dominant nodule) have been reported in nearly 80% of patients.9 Ultimately, tuberculomas calcify in 50% of patients.9,12,14 Cavitation is uncommon in patients with primary TB (Fig. 24.10); some investigators have reported a frequency ranging from 7% to 29%,6,9,13 but it is possible that some of these patients actually had progressive primary TB, and the true incidence of cavitation in primary TB may be lower.9
PROGRESSIVE PRIMARY TUBERCULOSIS
Fig. 24.10 Primary TB: cavitation. Chest radiograph shows patchy consolidation in right lower lobe associated with cavitation (arrow).
Rarely a parenchymal focus of primary TB may become rapidly progressive, both at the site of initial infection and at the secondary foci of haematogenous dissemination into the upper lobes. Extensive consolidation and cavitation occur, either at the site of the initial pulmonary parenchymal infectious focus or in the apical and
posterior segments of the upper lobes, or both locations. Opacities consistent with endobronchial spread of infection may be seen, and miliary disease may occur. Thus, progressive primary TB closely resembles postprimary TB.9,17
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POSTPRIMARY (REACTIVATION) TUBERCULOSIS Postprimary TB usually occurs as a result of previously latent infection (Box 24.2). During the initial infection, organisms may be transported by the bloodstream to the apical and posterior segments of the upper lobes and to the superior segments of the lower lobes. Later, often when host defences become impaired, reactivation of infection in these regions may be favoured by the relatively high oxygen tension or decreased lymphatic clearance in these lung segments.9 Unlike the healing that commonly occurs with primary TB, postprimary TB is often associated with progressive disease. As the inflammation mounts, tissue destruction occurs and caseous material liquefies and may acquire communication with the tracheobronchial tree, producing the characteristic pathological and radiological finding of postprimary TB: cavitation. The presence of cavitation tends to promote worsening infection by allowing more oxygen to reach the inflammatory focus, and also creates the opportunity for endobronchial spread of infection and transmission of infection to others. As the bacteria proliferate, erosion of infected material into the airways, producing endobronchial spread of infection; into the pleura, creating a bronchopleural Box 24.2 Postprimary (reactivation) tuberculosis
Reactivation of latent infection. Usually involves apical and posterior segments of upper lobes and superior segments of the lower lobes. Often associated with progressive disease without treatment. Cavitation common; endobronchial spread may occur. Clinical: fatigue, night sweats, weight loss, low-grade fever, haemoptysis. Imaging findings: ○ poorly defined consolidation; ○ cavitation visible in 40-87%; ○ centrilobular nodules often with ‘tree-in-bud’ on HRCT; ○ lymphadenopathy and effusions uncommon; ○ miliary spread; ○ airway stenosis; ○ tuberculoma.
fistula; into the pulmonary arteries, producing a Rasmussen aneurysm and fatal haemoptysis; and into bronchial arteries, resulting in systemic dissemination, is possible.9 If host defences prevail, cavities in postprimary TB usually heal by scar formation. Bronchiectasis, airway strictures, volume loss and areas of emphysema are common sequelae. Chronic cavities, often very thin-walled, may persist. Tuberculomas may also result from postprimary TB.9
Imaging findings Postprimary TB almost always occurs in adolescent or adult patients. The characteristic radiographic finding of postprimary TB is poorly defined areas of consolidation favouring the apical and posterior segments of the upper lobes (Figs 24.11 and 24.12A), and to a lesser extent the superior segments of the lower lobes. These opacities have previously been referred to as ‘exudative’ lesions.9,12 Isolated anterior or basilar segmental opacities are seen in only 2–6% of patients.9,25 Multiple segments are involved in most patients, and bilateral disease is found in 32–64% of patients.9,13,26 Often small poorly defined opacities, or satellite nodules, are seen on the periphery of the dominant foci of consolidation (Fig. 24.12B). On HRCT, postprimary TB manifests as consolidation (Figs 24.12B and 24.13B), poorly defined nodules, some of which show branching configurations (Fig. 24.13B), and interlobular septal thickening. Small, branching nodules detected at HRCT have often been referred to as ‘tree-in-bud’ opacities (Fig. 24.13), owing to the resemblance of the nodules to a tree budding in springtime. These branching opacities represent impaction of small airways with pus and caseous material. Variably sized cavities are also seen (Fig. 24.12B). Following treatment, these findings are gradually replaced by coarser areas of linear bands and architectural distortion, bronchiectasis and areas of lobular air trapping or irregular air-space enlargement (previously known as paracicatricial emphysema).27 Some areas of lobular air trapping are thought to be the result of lobular bronchiolar stenoses.27 If the infection in patients with postprimary TB is not checked, rapid destruction of a lobe or even the entire lung is possible (Fig. 24.14), usually manifest as extensive bronchiectasis and volume loss.
Fig. 24.11 Postprimary TB: consolidation in characteristic location (post-thoracotomy patient). (A) Chest radiograph shows apical and posterior upper lobe consolidation (arrow) associated linear and nodular opacities. (B) Chest radiograph at completion of treatment shows regression of consolidation with prominent linear opacity and volume loss, evidenced by ipsilateral tracheal shift.
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Fig. 24.12 Postprimary TB: consolidation, cavitation and small nodules. (A) Chest radiograph shows patchy upper lobe consolidation (arrow) and small nodules. (B) CT shows posterior segmental right upper lobe cavitary consolidation (arrowhead) and small centrilobular nodules (arrows).
Fig. 24.13 Postprimary TB: HRCT findings. (A) Gross specimen shows bronchiolar impaction, the pathological correlate of tree-in-bud opacity (arrows). (B) HRCT shows numerous small nodules with branching configurations (arrows), representing bronchiolar impaction with mucus, pus and debris (‘tree-in-bud’ opacity).
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Fig. 24.14 Postprimary TB: rapid lung destruction. (A) CT focused on left lower lobe shows bronchiectasis and lung destruction. Lingular bronchiectasis (arrow) is also evident. (B) CT obtained months after (A) shows further left lower lobe destruction. Note left major fissure is posteromedially retracted (arrows); essentially no functional left lower lobe parenchyma remains. (C) Chest radiograph obtained several months after (B) shows nearly complete destruction of left lung with extensive shift of cardiomediastinal structures into the left thorax. Patient was persistently sputum-positive, and left pneumonectomy was performed. (D) Gross specimen of left lower lobe following resection shows extreme volume loss and bronchiectasis. Note resemblance to CT image in (B).
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Areas of cavitation are seen in 40–87% of chest radiographs of patients with active postprimary TB (Figs 24.15 and 24.16A),9,13,26,28 but small cavities are more easily appreciated with CT and HRCT (Fig. 24.16B). Cavities are usually multiple and range in size from a few millimetres to several centimetres.9,12,13,28 Pulmonary cavitation in patients with postprimary TB is often found in areas of consolidation and the cavities are initially thick-walled and irregular (Fig. 24.16), and then evolve to relatively thin-walled
Fig. 24.15 Postprimary TB: cavitation. Chest radiograph shows right upper lobe consolidation, linear and nodular opacities and cavitation (arrows). Small nodules in left upper lobe represent ‘acinar’ nodules due to endobronchial spread of infection (arrowheads).
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lesions. As they heal, the cavities may become progressively more thin-walled, resembling emphysematous bullae.9,27 Air–fluid levels are relatively uncommon in postprimary TB cavities, with a reported frequency of 9–22%.9 The presence of an air–fluid level in a TB cavity can indicate the presence of bacterial superinfection.9,12,28 With healing, pulmonary cavities in patients with postprimary TB involute and may leave no sequelae, although linear scars and architectural distortion are common. The presence of pulmonary cavitation indicates the communication of infected parenchymal opacities with the tracheobronchial tree, and the material expelled from the cavities may be spread through smaller airways, representing endobronchial spread of infection.9,26,27 Endobronchial spread of infection appears on chest radiographs as 4- to 8-mm poorly defined nodules, often referred to as ‘acinar’, ‘acino-nodose’,27 or ‘air-space’ nodules (Fig. 24.15), and is seen in about 20% of chest radiographs of patients with postprimary TB.13,27,28 These nodules often become confluent and create the appearance of larger areas of opacity on the chest radiograph due to superimposition. For this reason, CT, in particular HRCT, is much more sensitive for the detection and characterization of these small nodules.9,27 On HRCT, endobronchial spread of infection appears as 2- to 10-mm nodules that approach, but usually do not contact, visceral pleural surfaces, and possess branching ‘Y’ shapes often referred to as tree-in-bud opacity (Figs 24.13 and 24.17). Such nodules are commonly seen in the setting of active TB (as high as 98% of patients in one series27), and slowly resolve during treatment. Rapid coalescence of small poorly defined opacities into larger areas of consolidation has been referred to as ‘galloping consumption’.9
Fig. 24.16 Postprimary TB: cavitation. (A) Chest radiograph shows right upper lobe cavitation (arrows). (B) CT image shows dominant right upper lobe cavity has moderately thick, irregular wall.
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Fig. 24.17 Postprimary TB: endobronchial spread of infection. CT shows bronchiectasis and cavitation in right upper lobe, associated with centrilobular nodules (arrowheads).
The initial opacities seen on chest radiography in patients with postprimary TB evolve into coarser linear and nodular opacities, and the two types of pulmonary parenchymal opacities usually coexist (Figs 24.18A and B).9,13 These coarser linear and nodular opacities have often been referred to as ‘fibroproductive’ lesions.9,12 Over time these opacities continue to evolve and, with healing, are eventually replaced by traction bronchiectasis, architectural distortion, irregular air-space enlargement and parenchymal volume loss. In more severe cases of scarring various combinations of volume loss (ipsilateral shift of the trachea, hilar retraction), pleural thickening, calcified parenchymal nodules and tracheomegaly are seen (Fig. 24.18C).9,12,13 Pleural involvement in patients with postprimary TB is uncommon, reported in 6–19% of patients.1,9,26,29,30 When pleural effusions are seen in patients with postprimary TB, the effusions are usually small and often associated with ipsilateral pulmonary parenchymal disease.13,20 The development of an air–fluid level in the pleural space suggests the presence of a bronchopleural fistula (Fig. 24.19).
Fig. 24.18 Postprimary TB: serial chest radiography of active infection and treatment response. (A) Chest radiograph during active TB shows bilateral hilar retraction consistent with upper lobe fibrosis and scarring with patchy consolidation and numerous small nodules (arrowheads) and right upper lobe cavity (arrow). (B) Chest radiograph 6 months into treatment shows fewer nodules and consolidation within left upper lobe and decreased size of right apical cavity. (C) Final film shows involution of right apical cavity and clearing of consolidation and nodules in left upper lobe. Apical pleural thickening has increased.
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Spontaneous pneumothorax (Fig. 24.20) in patients with postprimary TB is reported in 5% or less of patients with cavitary lung disease.30 When an effusion is large, associated with mass effect, and assumes a convex shape, empyema should be suspected (Fig. 24.21).
Fig. 24.19 Postprimary TB: bronchopleural fistula. CT shows numerous air–fluid levels in right pleural space and site of bronchopleural fistula (arrows).
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Tuberculous empyema is an uncommon complication of postprimary TB, reported in 1–4% of patients.13,30 Tuberculous empyemas are often accompanied by extensive, cavitary parenchymal abnormalities.9,30 Occasionally, tuberculous empyema may erode into the chest wall, creating a pleurocutaneous fistula, a condition referred to as empyema necessitans.9,20,30 Tuberculous empyemas often heal with calcification, but the development or persistence of fluid within a calcified fibrothorax should suggest the possibility of chronic tuberculous empyema and active infection (Fig. 24.22).1,21,23 In contrast to primary TB, hilar and mediastinal lymphadenopathy is an uncommon manifestation of postprimary TB, seen in no more than 5% of patients with postprimary infection.13 The miliary pattern and the development of tuberculomas (Figs 24.23 and 24.24) may be seen in patients with postprimary TB. The imaging appearance is identical to the miliary pattern that may be seen in patients with primary TB (Fig. 24.6). Tuberculosis may affect the main or lobar bronchi in 10–40% of patients, and airway abnormalities are usually the result of direct extension of inflammation from adjacent tuberculous lymphadenitis, endobronchial dissemination of disease or possibly lymphatic spread of infected material to the airways.9,10,31 Occasionally erosion of adjacent calcified lymph nodes into the airways, referred to as broncholithiasis, may occur (Fig. 24.25). Chest radiographic findings of tuberculous involvement of the airways include volume loss and collapse, hyperlucency secondary to lobar overinflation, mucoid impaction and post-obstructive pneumonia or collapse (Fig. 24.26A);9,10 CT is more sensitive for the demonstration of these findings and also allows direct visualization of the abnormal airways, revealing airway wall
Fig. 24.20 Postprimary TB: spontaneous pneumothorax. CT shows pneumothorax (*) and right lung consolidation (arrows).
Fig. 24.21 Postprimary TB: tuberculous empyema. CT shows a large
Fig. 24.22 Postprimary TB: tuberculous empyema. CT shows pleural
right pleural fluid collection with non-dependency, suggesting loculation. Note ‘split-pleura’ sign – thickened, enhancing visceral and parietal (arrow) pleura – a finding consistent with empyema.
calcification (arrows) and large pleural fluid collection. Pleural fluid detection within calcified fibrothorax should raise suspicion for chronic tuberculous empyema.1
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Fig. 24.23 Postprimary TB: tuberculoma. (A) Chest radiograph shows left apical nodule (arrow). (B) CT shows left apical lesion (arrow) does not enhance and is not calcified. (C) Chest radiograph shows partial regression of nodule (arrow) following anti-TB therapy.
Fig. 24.24 Postprimary TB: cavitary tuberculoma and regional endobronchial infection spread. CT shows cavitary nodule and small satellite nodules (arrows) representing local endobronchial spread of infection.
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Fig. 24.25 Postprimary TB: broncholithiasis. CT shows patchy consolidation in lateral segment right middle lobe due to partially obstructing broncholith (arrow).
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Fig. 24.26 Postprimary TB: bronchostenosis. (A) Chest radiograph shows left upper lobe volume loss (note hazy left upper lobe opacity with left cardiac border obscuration). (B) Coronal volume rendered image shows left main bronchostenosis (arrow).
thickening, long segment strictures (Fig. 24.26B), endobronchial obstruction and/or extrinsic airway compression by adjacent lymphadenopathy. Postprimary TB involvement of the trachea often exceeds 3 cm in length and commonly affects the distal trachea, and is usually accompanied by bronchial disease.18 Once fibrosis develops within the airway wall, the strictures are usually not reversible.32 Among the potential airway complications related to TB, bronchiectasis is the most common (Fig. 24.14). Bronchial dilation may result from fibrosis due to healing of the parenchymal inflammation, a process referred to as traction bronchiectasis. Direct airway inflammation with destruction of the bronchial walls (true bronchiectasis) and bronchostenoses may also produce bronchial dilation.
MULTIDRUG-RESISTANT TUBERCULOSIS The imaging appearances of drug-susceptible and multidrugresistant TB (MDR-TB) are essentially identical.33,34 Kim et al.35 has suggested that MDR-TB is more commonly associated with extensive cavity formation (Fig. 24.27) than is drug-susceptible TB, although it is unlikely that this observation will alter the diagnostic approach or clinical management of TB patients.
RADIOGRAPHIC MANIFESTATIONS OF SURGICAL TREATMENT FOR TUBERCULOSIS Surgical therapy is occasionally employed in the modern era for patients with TB. Surgical intervention has historically been employed as a treatment for pulmonary and pleural TB prior to the advent of effective anti-TB drugs. A number of surgical procedures, whose common goal was compression and collapse of pulmonary cavities, promoting healing and preventing spread of infection to uninvolved regions of lung, have been developed for this purpose. Successful treatment produced fibrosis with encapsulation of the diseased portion of lung. Surgical procedures employed for pulmonary collapse therapy include plombage with methyl-methacrylate (Lucite) spheres or paraffin, induction of pneumothorax, phrenic nerve crush or thoracoplasty. Plombage was often favoured over thoracoplasty because
Fig. 24.27 Multidrug-resistant TB. CT shows consolidation and cavitation (arrow). Findings are consistent with TB but not specific for multidrugresistant TB.
it allowed selective collapse of the most diseased portion of the lung, minimizing adverse impacts on pulmonary function. While these procedures are rarely used these days, patients who have undergone such procedures are occasionally encountered and recognition of the radiographic appearances of these therapies is important to prevent misdiagnosis or for the detection of complications. The plombage method involved creation of an extrapleural space filled with an inert material, such as polymerized Lucite spheres, plastic (polystan) packs or mineral/vegetable oils.9,36 Lucite sphere plombage appears as multiple smoothly marginated lucent round spheres usually projecting over the upper thorax (Fig. 24.28).9,36 Occasionally air–fluid levels develop within the spheres, suggesting superinfection.9,36 Other forms of plombage, such as polystan packs and oleothorax, appear as circumscribed opacities projected over the upper hemithorax that may show peripheral calcification.9,36 These opacities can occasionally expand over time as a result of bacterial superinfection, tuberculous infection or sterile exudation around the plomb material.9
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Fig. 24.28 TB collapse therapy: Lucite sphere plombage. Chest radiograph shows several regular lucencies (arrows), representing Lucite sphere plombage in a patient with left upper lobe TB.
Thoracoplasty was performed by removing portions of the second to eighth ribs, but is permanently disfiguring and has adverse effects on pulmonary function. Chest radiographs in patients who have undergone thoracoplasty show deformity of the upper thorax associated with pleural thickening and severely reduced volume in the affected regions of lung (Fig. 24.29).9,36 The pleural thickening may occasionally calcify, and thoracic CT may show the presence of residual loculated pleural fluid collections which may contain viable bacilli.9,21
UNUSUAL MANIFESTATIONS OF TUBERCULOSIS Unusual manifestations of TB are summarized in Box 24.3. Although a number of studies have reported variable prevalences of these findings, in general, ‘atypical’ imaging manifestations occur in 30% or less of patients with TB.11,25,28,29
Fig. 24.29 TB collapse therapy: thoracoplasty. Chest radiograph shows deformity of right upper thorax (arrows), consistent with prior thoracoplasty. Note calcified fibrothorax.
11,28,29
Box 24.3 Unusual manifestations of tuberculosis
Atypical parenchymal locations, such as parenchymal opacities predominating within the anterior segments of the upper lobes or lower lobes unaccompanied by lymphadenopathy in patients with postprimary TB. Lymphadenopathy with or without parenchymal opacity in patients with postprimary TB. Diffuse opacities related to TB. Air–fluid levels within pulmonary cavities. Mass-like opacities or tuberculomas. Primary TB pattern in a patient older than 40 years of age Isolated pleural effusion.
COMPLICATIONS OF TUBERCULOSIS Complications of TB include colonization of residual upper lobe cavities with Aspergillus organisms, resulting in aspergilloma, tuberculous erosion of a pulmonary artery (Rasmussen aneurysm), broncholithiasis, tracheoesophageal and oesophageal–mediastinal fistulas, pericarditis, fibrosing mediastinitis, pneumothorax and bronchopleural fistula, and spinal osteomyelitis, among other conditions (Box 24.4).37 Aspergilloma typically presents as thickening of a pre-existing cavity with the subsequent development of an intracavitary, mobile mass. Rasmussen aneurysm is a rare complication of pulmonary TB, usually developing months or years after the initial infection. Rasmussen aneurysms are present in 5% or less of patients at autopsy, although rarely encountered clinically.9 Rasmussen aneurysms present on contrast-enhanced thoracic CT
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Box 24.4 Complications of tuberculosis
Aspergilloma. Rasmussen aneurysm. Broncholithiasis. Bronchiectasis and lung destruction. Airway stenoses. Tracheoesophageal and oesophagomediastinal fistula. Pneumothorax and bronchopleural fistula. Empyema. Pericarditis. Fibrosing mediastinitis. Chest wall abscesses. Spinal osteomyelitis
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as intensely enhancing lesions equivalent in opacity as the enhanced pulmonary arterial circulation, possibly surrounded by consolidation and ground-glass opacity, representing pulmonary haemorrhage. Treatment with pulmonary arterial catheterization and coil embolization may be life-saving because the mortality associated with Rasmussen aneurysms is high.9 Tracheoesophageal or oesophagomediastinal fistulas usually result from airway inflammation and tuberculous mediastinitis, respectively. Oesophageal TB involvement may result in oesophageal strictures or diverticula. Tracheoesophageal fistula may present with recurrent pulmonary infection and aspiration of oral contrast during oesophagography; CT may show the site of fistula directly. Oesophagomediastinal fistula will present as a localized gas collection within the mediastinum that may communicate with the oesophagus on contrast oesophagography.37 Fibrosing mediastinitis is more commonly the result of histoplasmosis than TB. Patients may present with cough and low-grade fever and symptoms related to compression of the airways, superior vena cava and oesophagus.37 Imaging manifestations of fibrosing mediastinitis include mediastinal widening with the development of numerous collateral venous channels resulting from superior vena cava or great vein occlusion. Narrowing of the airways and pulmonary arteries by abnormal tissue infiltrating throughout the mediastinum is commonly seen. Pulmonary opacities in patients with fibrosing mediastinitis result from obstructive atelectasis or pneumonia and pulmonary venous infarction.37
OTHER IMAGING MODALITIES IN PATIENTS WITH TUBERCULOSIS Other imaging modalities that may occasionally be employed in the course of assessment of patients with TB primarily include MRI and FDG-PET. Most often, these imaging studies are not used to evaluate patients with known TB; rather, MRI or FDGPET will be obtained in the evaluation of patients with indeterminate opacities or nodules on chest radiography or thoracic CT. MRI may effectively show thoracic lymphadenopathy in a fashion similar to that of CT, although CT is far superior to MRI for the characterization of pulmonary opacities and airway abnormalities. MRI may show pleural abnormalities effectively, although there are no data to suggest that MRI provides any additional diagnostic benefit to CT for the evaluation of pleural disease. The main role for MRI for patients with TB is for the assessment of complications due to TB, such as tuberculous brain or spine abscesses or osteomyelitis. FDG-PET examinations in patients with TB are usually performed in the course of evaluation of an indeterminate nodule. Active tracer uptake will be seen in the majority of patients with active TB, both within the lung parenchyma and within infected mediastinal lymph nodes. This tracer accumulation may create diagnostic confusion because the tracer uptake may simulate carcinoma.38 The presence of metabolically active satellite lesions may suggest that an inflammatory lesion is more likely than malignancy, but this pattern is not specific for TB and is often seen in patients with fungal infections as well. In contrast, active tracer accumulation is not invariably encountered in patients with TB. While some investigators have suggested that active FDG-PET accumulation could have a role in disclosing unsuspected sites of disease, FDG accumulation is not always synonymous with transmissible pulmonary infection, and the utility of FDG-PET in patients with TB is speculative.
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EXTRATHORACIC MANIFESTATIONS OF TUBERCULOSIS (ALSO SEE CHAPTER 25) M. tuberculosis is capable of disseminating to practically any organ. The most common sites of extrathoracic dissemination may be broadly classified as spread to the central nervous system, skeletal system, genitourinary system and gastrointestinal system. In all cases, the principal route of entry for M. tuberculosis is through the respiratory system, but radiographic evidence of active intrathoracic TB is lacking in more than 50% of patients with extrathoracic TB.39
M. tuberculosis infection in the central nervous system Tuberculous meningitis and intracranial tuberculoma are the most common manifestations of central nervous system TB, and usually result from prior haematogenous dissemination to the subependymal or subpial regions (referred to as Rich foci).39 Rupture of a Rich focus into the cerebrospinal fluid is thought to be the cause of tuberculous meningitis.39 Cerebritis, miliary brain infection and brain abscesses may also occur. Tuberculous meningitis most commonly affects the basal cisterns and produces intense basal enhancement following intravenous contrast administration. Hydrocephalus may be present.39,40 Areas of infarction in the basal ganglia and internal capsule may result from occlusion of small perforating vessels.39 Spinal meninges may also be affected. The brain parenchyma may be affected by TB with or without coexistent meningitis. Cross-sectional imaging studies, such as CT or MRI, will show nodular lesions most commonly affecting the frontal and parietal lobes.39,40 Homogeneous (Fig. 24.30) or
Fig. 24.30 Central nervous system TB: tuberculomas. MRI shows several homogeneously enhancing lesions (arrows).
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nodular ring enhancement patterns with surrounding vasogenic oedema are commonly observed. Miliary TB in the brain is usually accompanied by meningeal TB, and appears as numerous, small homogeneously enhancing lesions centred at the grey–white junction.39,40
Tuberculosis in the skeletal system The spine is the most common osseous structure involved in patients with disseminated TB, a condition referred to as tuberculous spondylitis, or Pott’s disease.39,40 The vertebral body itself is affected more commonly than the posterior elements, and usually more than one vertebral body is affected.39,40 Infection begins within the superior or inferior vertebral body end plates and spreads to involve the adjacent intervertebral disc spaces.40 Bone resorption occurs, with loss of the normal white cortical end plate margin, eventually progressing to vertebral body collapse.40 This progressive vertebral body collapse eventually produces kyphotic angulation and the gibbus deformity characteristic of tuberculous spondylitis.39,40 Characteristically, the affected vertebral bodies do not show sclerosis,39,40 and, due to the indolent nature of the infection, the intervertebral disc spaces are relatively maintained compared with the rapid disc space destruction usually seen in patients with pyogenic discitis.39 Subligamentous spread of infectious material and paravertebral abscesses, including psoas abscesses, are commonly present.39,40 Tuberculous osteomyelitis commonly affects the epiphyses of the femur, tibia, and small bones of the hands and feet,39,40 the latter referred to as tuberculous dactylitis. In skeletally immature patients, tuberculous osteomyelitis may affect the metaphyses of long bones, which is distinct from other pyogenic infections.40 The radiographic appearance of tuberculous osteomyelitis consists of areas of osteopenia, bone destruction and periosteal reaction, similar to that of pyogenic osteomyelitis. Unlike pyogenic infections, however, tuberculous osteomyelitis may readily cross the growth plate, although fungal infections may exhibit the same behaviour.39 A peculiar form of osteomyelitis that more commonly affects children than adults, referred to as cystic tuberculosis, manifests as a circumscribed area of lucency within the metaphysis with surrounding sclerosis.39,40 Tuberculous dactylitis presents as soft-tissue swelling and periosteal reaction, eventually followed by bone destruction and sequestrum formation.39,40 As the bone is destroyed, the remaining bone may show a ballooned appearance, a condition referred to as spina ventosa (Fig. 24.31).39,40 Tuberculous arthritis usually involves one joint, usually the hip or the knee.39 The Phemister triad suggests the diagnosis of tuberculous arthritis: periarticular osteoporosis, peripherally located osseous erosions and gradual narrowing of the joint space.39,40 Relative preservation of the joint space is characteristic of tuberculous arthritis, as opposed to the rapid cartilage and joint space destruction more typical of septic arthritis.39 Untreated, tuberculous arthritis will produce complete joint space destruction and result in ankylosis, more commonly fibrous than bony, of the affected joint.39,40 Tuberculosis in the genitourinary system Genitourinary system TB is one of the most common sites of extrathoracic dissemination of M. tuberculosis infection. The kidneys, prostate and seminal vesicles are usually involved by haematogenous dissemination, whereas the bladder and other lower genitourinary structures are more commonly involved by ascending or descending infection.41
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Fig. 24.31 Musculoskeletal TB: spina ventosa. Left-hand radiograph shows second digit soft-tissue swelling with cystic destruction (arrows).
Renal TB manifests in a number of patterns. The earliest manifestation of renal TB is erosion of a calyx, creating a ‘moth-eaten’ appearance, followed by papillary necrosis.40,41 Infundibular strictures, creating a dilated calyx that incompletely opacifies, as well as ureteropelvic strictures, producing hydronephrosis, may occur.40,41 Decreased renal function with decreased enhancement on contrast-enhanced imaging studies, such as intravenous urography, CT and MRI, may be seen, and irregular pools of renal parenchymal contrast due to areas of cavitation may be present.40,41 Advanced renal TB results in cortical scarring and dilation and distortion of the calyceal system and obstructive uropathy that may ultimately lead to autonephrectomy.41 Lobar renal calcification resulting from TB has been referred to as ‘putty’ kidney (Fig. 24.32).40 Adrenal TB may present at cross-sectional imaging with unilateral or bilateral irregular adrenal masses, but is more commonly encountered as adrenal calcification after the infection has healed.40 Ureteral TB produces a ragged, dilated ureter with mucosal irregularity, and eventually results in stricture formation.39 Ureteral shortening, ulceration, filling defects and calcification may occur.39 Tuberculosis of the bladder produces a small volume bladder with wall thickening.39 When severe, the bladder volume may be extremely small and irregular.40 Vesicoureteral reflux may occur, but the bladder wall will rarely calcify.39,40 Female genital TB usually manifests as salpingitis, usually bilateral, with or without tubo-ovarian abscess.39,40 Endometrial adhesions may occur, and pelvic lymph node calcifications are often seen.40 Male genital TB usually affects the prostate, seminal vesicles, epididymis or testicles. Areas of necrotic fluid, tissue cavitation and calcification may be seen with cross-sectional imaging studies.40
Tuberculosis in the gastrointestinal system Gastrointestinal TB involves the ileocaecal region in 80–90% of patients,39 and may result from haematogenous dissemination or
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Fig. 24.33 Gastrointestinal TB: caecal TB. Abdominal CT shows small, thickened, enhancing caecum (arrow).
Hepatic and splenic TB is usually the result of haematogenous dissemination and manifest on cross-sectional imaging studies as numerous variably sized nodules. Small nodules, or micronodular TB, may be thought of as a form of miliary disease, whereas larger nodules, or macronodular TB, may be considered a form of tuberculoma. These nodules have low attenuation on CT and may occasionally show central enhancement early and calcification later.39,40
ACTIVE VERSUS INACTIVE TUBERCULOSIS
Fig. 24.32 Genitourinary TB: putty kidney: single abdominal radiograph from an intravenous urogram shows right upper quadrant amorphous, reniform calcification (arrow).
regional spread from adjacent tuberculous osteomyelitis or soft-tissue abscesses.40 Gastrointestinal TB first produces thickening and gaping of the ileocaecal valve, which may be associated with narrowing of the terminal ileum.39,40 The caecum may be shortened, rigid and amputated, or even obliterated.40 Linear, stellate or oval ulcers may be seen in the terminal ileum, often associated with extensive bowel wall thickening. Unlike Crohn’s disease, fistulas and sinus tracts are rare in TB.41 Bowel fibrosis, shortening, obstruction, retraction and pouching are common with advanced disease.41 CT imaging may show circumferential caecal (Fig. 24.33) and terminal ileum wall thickening associated with mesenteric lymphadenopathy. Thickening of the caecum is characteristically asymmetric, affecting the medial wall and ileocaecal valve, and the adjacent lymphadenopathy may show necrosis.40 Peritoneal TB usually occurs in the setting of widely disseminated abdominal TB, and has traditionally been described in three major forms. ‘Wet’ peritoneal TB produces a large amount of ascites that may show high attenuation at CT due to the large protein and cellular composition, possibly with loculation.40 ‘Dry’ peritoneal TB is characterized by fibrous adhesions, peritoneal retraction and caseous nodules.40 The third variety of peritoneal TB, called the ‘fibrotic-fixed’ type, is characterized by matted loops of mesentery and bowel associated with omental masses, and, occasionally, loculated ascites.40 Infiltration of the mesentery and tethering and angulation of bowel loops may be seen as well.40
A question that inevitably surfaces in the care of patients suspected of TB is whether active disease is present. In general, one must have prior radiographs for comparison to determine disease activity, and the radiographic pattern should be stable for 6 months or more before suggesting that disease is not active. Imaging is not a proxy for the exclusion of active infection by examination of sputa and, ultimately, culture. However, certain imaging findings are more often associated with active disease and may warrant a more aggressive management posture, whereas certain other findings are associated with a low prevalence of positive sputa or cultures. Radiographic patterns that suggest the presence of active TB include lymphadenopathy (Fig. 24.3), air-space or lobular consolidation (Figs 24.4, 24.5, 24.7, 24.8, 24.10–24.13, 24.20), endobronchial spread patterns (Figs 24.12, 24.13, 24.15, 24.17), such as centrilobular nodules, often with branching configurations, on HRCT studies (Figs 24.13A and 24.17), the miliary pattern (Fig. 24.6) and pulmonary cavities (Figs 24.10, 24.15, 24.16, 24.24, 24.27), and these findings are usually encountered in the absence of architectural distortion or other findings suggesting pulmonary fibrosis. Im et al.27 found that all 28 patients with active newly diagnosed TB showed centrilobular nodules with branching configurations on HRCT, and these findings resolved in the ensuing 5–9 months following appropriate therapy. They also reported that centrilobular nodules and nodules with tree-in-bud opacity were seen in 92% and 67%, respectively, of patients with postprimary TB.27 Poey et al.42 also found that poorly marginated nodules, centrilobular nodules and ground-glass opacity and consolidation are relatively specific to patients with active TB, an observation echoed by other investigators.43 However, other investigators reported that air-space consolidation, ground-glass opacity and pulmonary cavitation, not pulmonary nodules, occur more frequently than other HRCT findings in patients with smear-positive TB.44 Matsuoka et al.45 reported
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that the frequency of consolidation and cavitation increased with the number of acid-fast bacilli (AFB), and, while small nodules tend to predict active pulmonary TB, the frequency of small nodules could not predict the number of AFB in sputum smears. Combining the results of these various studies allows the conclusion that HRCT can, in most patients at risk for TB, distinguish active from inactive disease: if consolidation, nodules (especially those with branching patterns) and ground-glass opacity are present, active infection is likely (Figs 24.4–24.8, 24.10, 24.11A, 24.12, 24.13, 24.15–24.17, 24.18A, 24.20, 24.24, 24.27). In contrast, when these findings are absent, active disease is unlikely,27,43,45,46 but the ability to predict active or inactive disease is not 100% when compared with sputum smears and culture. The HRCT determination of disease activity may be most useful for those patients in whom chest radiographic findings are indeterminate or prior films are not available for comparison, and to assess the effectiveness of anti-TB therapy,42 but the role of HRCT in the assessment of patients with TB is not well established. Certainly HRCT is not a substitute for sputum examination and culture, and HRCT cannot reliably predict whether a given patient is capable of transmitting M. tuberculosis. Findings more often associated with inactive disease include bronchiectasis, linear and reticular opacities, architectural distortion and calcified nodules. However, these findings may be seen in patients with active disease as well, but usually in combination with air-space consolidation, nodules, ground-glass opacity and bronchial wall thickening. Because of the difficulties in determining whether active pulmonary disease is present in patients with tuberculous infection, some investigators have advocated reporting chest radiographs as ‘stable’ rather than ‘active’ or ‘inactive’.9,13
TUBERCULOSIS IN THE IMMUNOCOMPROMISED PATIENT Mycobacterium tuberculosis infection is frequently encountered in immunocompromised patients, particularly those with HIV/AIDS. The radiographic presentation of TB in HIV-infected patients is dependent on the patient’s level of immunosuppression as assessed by the patient’s CD4 T-cell count. Patients with relatively preserved immunity (CD4 counts > 200 cells/mL) usually present with the postprimary TB pattern typically encountered on thoracic imaging
studies of immunocompetent patients, such as apical and posterior segmental upper lobe air-space consolidation, cavitation and nodules, usually unaccompanied by pleural effusion or lymphadenopathy.47 With progressive immunosuppression, particularly when the patient’s CD4 count falls below 200 cells/mL, extrapulmonary dissemination of M. tuberculosis infection becomes increasingly common and the thoracic manifestations of TB in this patient group resemble the pattern associated with primary TB in immunocompetent patients, such as air-space consolidation (Fig. 24.34B), lymphadenopathy and pleural effusion (Fig. 24.34A). The miliary pattern on chest radiography has been reported to occur more frequently in severely immunosuppressed patients than in relatively immunocompetent patients.47 Often lymphadenopathy is the dominant or only finding in severely immunosuppressed patients, and the affected lymph nodes may show low central attenuation with peripheral enhancement following contrast administration (Fig. 24.35B). In HIV-infected patients the presence of low-attenuation lymph nodes with peripheral rim enhancement is strongly suggestive of mycobacterial infection. Jasmer et al.48 found HIV-infected patients with necrotic lymphadenopathy on thoracic CT were 26 times more likely to have mycobacterial infection than HIV-infected patients without necrotic lymphadenopathy. Lymphadenopathy in patients with severe immunosuppression typically involves multiple stations, usually the right paratracheal region in combination with other nodal stations. A normal chest radiograph may be seen in HIV-infected patients with TB in 14–40% of patients.34,49,50 The use of highly active antiretroviral therapy (HAART) has been shown to decrease the risk of developing TB among HIV-infected patients.51 Patients treated with HAART are more likely to develop TB at higher CD4 counts, and are more likely to show a postprimary pattern of infection on thoracic imaging studies.51 This observation may reflect the partial reconstitution of cell-mediated immunity as a result of HAART. The institution of HAART has also resulted in a new clinical and radiographic entity in HIV-infected patients, referred to as the immune reconstitution (inflammatory) syndrome (Fig. 24.36).52 This syndrome has been defined as an exacerbation of symptoms, signs or radiological manifestations of a pathogenic antigen that are not the result of relapse or recurrence.52 With the institution of HAART, the HIVinfected patient’s cellular inflammatory response to mycobacteria
Fig. 24.34 TB in HIV/AIDS: primary TB pattern. (A) Chest radiograph shows left lower lobe consolidation with left pleural effusion (arrow). (B) CT confirms left lower lobe consolidation, which resembles other causes of lobar bacterial pneumonia and is not specific for TB.
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Fig. 24.35 TB in HIV/AIDS: primary TB pattern. (A) Chest radiograph shows right paratracheal lymphadenopathy (arrow). (B) CT confirms right paratracheal lymphadenopathy (arrows). Lymph nodes possess central low attenuation, indicating necrosis.
Fig. 24.36 Immune reconstitution syndrome in HIV/AIDS and HAART. (A) Chest radiograph prior to institution of HAART shows minimal, perihilar non-specific changes. (B) Chest radiograph several months after initiation of HAART shows new right paratracheal lymphadenopathy (arrow).
is restored, resulting in clinical and radiographic abnormalities. Such patients may present with fever, weight loss and respiratory failure, and thoracic imaging studies may show new or worsening lymphadenopathy, parenchymal opacities such as nodules, and pleural effusion.47,52 This response tends to be most profound among those patients with CD4 counts less than 100 cells/mL prior
to the initiation of HAART. Rajeswaran et al.52 evaluated 11 patients with immune reconstitution syndrome who underwent thoracic CT: eight had new or worsening lymph node enlargement (seven with necrosis) and small (< 3 mm) parenchymal lung nodules were seen in six patients, of whom three had worsening of previously noted opacities and three developed new opacities. Immune reconstitution
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syndrome usually begins within 1–3 months, but as late as 12 months, following the initiation of HAART.52 The diagnosis of immune reconstitution syndrome is one of exclusion, and requires careful elimination of numerous competing infectious, inflammatory and neoplastic diagnoses. Patients with other forms of immunocompromise, such as steroid therapy, haematopoietic stem cell transplantation and solid organ transplantation, are at increased risk for developing TB once infected. Patients with non-HIV-related immunocompromise undergoing steroid therapy and those with collagen vascular disease may have a higher prevalence of miliary and extrapulmonary TB.53 Some investigators have suggested that diabetic and non-HIVrelated immunocompromised patients may have a higher prevalence of atypical presentations of postprimary TB,25,54,55 but other reports have not confirmed this observation.1,2,54 Patients with solid organ transplantation, particularly lung transplantation, may develop TB. Tuberculosis is less common than other infections, such as viruses, other bacteria and fungi, in solid organ transplant recipients, but the incidence of TB is elevated compared with the general population, albeit still at a fairly low rate.56–58 Tuberculosis in lung transplant recipients may occur as a result of postprimary/reactivation of latent infection within the donor lung or recipient, or, less commonly, because of a new primary infection.58 The radiographic findings are nonspecific, and include multiple nodules, cavitary lesions with or without lymphadenopathy, air-space consolidation in various locations (including basilar disease), pleural effusion, chest wall abnormalities or even no radiographic findings at all.58,59 Often the radiographic findings of TB in lung transplant recipients are minimal.59 Tuberculosis may occur in haematopoietic stem cell transplant recipients, although less often than in solid organ transplant recipients because the duration of immunosuppression is shorter in the former, and stem cell transplantation is more often performed in developed countries, where the prevalence of M. tuberculosis infection is comparatively lower.60 The lung is most commonly involved, although disseminated disease to the kidneys, bone marrow and central nervous system may occur. The imaging findings of TB in haematopoietic stem cell transplantation include air-space consolidation (patchy or segmental/lobar in configuration), multiple variably sized nodules (Fig. 24.37) and an interstitial pattern, diffuse opacities resembling diffuse alveolar damage and, uncommonly, a normal chest radiograph.60 Upper lobe fibrocavitary disease is reported to be an unusual appearance of TB following haematopoietic stem cell transplantation.60
NON-TUBERCULOUS MYCOBACTERIA More than 125 species of NTM have been described,61 and relatively little is known about the imaging manifestations of the vast majority of these organisms. Pulmonary disease is most often caused by Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium abscessus, Mycobacterium xenopi, Mycobacterium malmoense and Mycobacterium chelonae, although other species are occasionally implicated in human disease. There is a good deal of overlap in the imaging appearances of NTM pulmonary infection, although certain patterns of disease have been recognized: fibrocavitary disease, previously referred to as ‘classical’ infection, and the nodular bronchiectasis, or ‘non-classical’ NTM pattern of infection (Box 24.5).62 Patients with oesophageal motility disorders may present with a pattern resembling aspiration pneumonia, and, recently, a hypersensitivity pneumonitis pattern has been ascribed to NTM acquired from hot tubs. Recently, NTM infections in patients with cystic fibrosis has been recognized; these patients are typically much younger than those with fibrocavitary disease (usually children and young adults), they are non-smokers and no gender predilection is observed.63 Finally, disseminated NTM infection may occur, usually in the setting of immunodeficiency.63 Fibrocavitary, or classical, NTM infection closely resembles postprimary TB, and tends to be encountered in older patients, often smokers, with underlying structural lung abnormalities, such as pneumoconioses, chronic obstructive pulmonary disease, bronchiectasis, prior TB, pulmonary alveolar proteinosis and aspiration lung disease related to oesophageal disorders.61,62 Fibrocavitary NTM disease presents on chest radiography as segmental or multifocal linear and nodular opacities predominating in the apical and posterior segments of the
Box 24.5 Non-tuberculous mycobacterial infection: thoracic imaging patterns
Fig. 24.37 TB following haematopoietic stem cell transplantation. HRCT shows small subpleural right apical nodule (arrow), new compared with CT 1 month earlier. Culture from bronchoscopy performed 3 weeks earlier grew M. tuberculosis.
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Fibrocavitary (‘classical’) pattern ○ Chest radiography: upper lobe linear and nodular opacities, thin-walled cavitation. ○ CT/HRCT: upper lobe thin-walled cavities, air-space opacities, nodules, pleural thickening. Nodular bronchiectatic (‘non-classical’) pattern: ○ Chest radiography: linear and nodular opacities with air-space opacity. ○ CT/HRCT: bronchiectasis, small nodules (some with branching configurations), consolidation predominating in the right middle lobe and lingula. Hypersensitivity-like pattern ○ Chest radiography: diminished lung volumes with normal appearance or vague hazy increased opacity; later, diminished volumes with coarse linear and reticular opacities. ○ CT/HRCT: ground-glass opacity, hazy ground-glass attenuation centrilobular nodules, air trapping; later, linear and reticular opacities with architectural distortion and traction bronchiectasis, sparing the extreme costophrenic sulci. Aspiration pattern: lower lobe air-space opacity. Disseminated disease ○ Chest radiography: normal, lymphadenopathy, focal opacities (single or multiple). ○ CT/HRCT: focal or multifocal nodules or masses, single nodule, extrathoracic dissemination (focal liver and splenic lesions, lymphadenopathy).
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upper lobes, often associated with cavitation (Figs 24.38A). Cavities associated with fibrocavitary disease tend to be small and thin-walled (Fig. 24.38B),62 possibly associated with small nodules, reflecting endobronchial spread of infection. Lymphadenopathy and pleural effusion are uncommon in patients with the fibrocavitary pattern of NTM infection, and both of these findings are almost never found in the absence of parenchymal abnormalities.62 Lower lobe disease is uncommon.61,62 The parenchymal opacities in patients with the fibrocavitary pattern of NTM infection have a tendency to slowly progress over time, producing volume loss, architectural distortion and traction bronchiectasis. Apical pleural thickening may occur. The imaging appearance of the fibrocavitary pattern of NTM infection closely resembles postprimary TB, and the two conditions are very difficult to distinguish on imaging studies. Several
Fig. 24.38 Fibrocavitary NTM infection: MAC. (A) Chest radiograph shows several cavitary lesions (arrow and arrowhead). (B) HRCT through the lung apices shows two relatively thin-walled cavitary lesions with few surrounding nodules.
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features are more commonly associated with fibrocavitary NTM disease than with postprimary TB:61,62 1. relatively thin-walled, smaller cavities with fewer surrounding parenchymal opacities (Fig. 24.38B); 2. fewer features suggesting endobronchial spread of infection, but a greater tendency for local contiguous spread of disease; 3. more profound pleural thickening adjacent to the parenchymal disease focus and; 4. lower prevalence of calcified lung nodules and hilar lymph nodes. Unfortunately, the above features usually will not allow NTM fibrocavitary infection to be distinguished from postprimary TB in the majority of patients.61 MAC is the predominant NTM species associated with the fibrocavitary pattern of disease, although other organisms, such as M. abscessus, M. chelonae, Mycobacterium simiae and M. kansasii, have also been associated with this pattern.61 The nodular bronchiectasis pattern of NTM infection, or nonclassical NTM infection, is nodular in nature, predominating in the mid- and lower lungs, and associated with bronchiectasis in more than 90% of patients.61 This pattern of NTM infection is most commonly seen in older, non-smoking white women, otherwise healthy, and has also been referred to as ‘Lady Windermere syndrome’ or ‘nodular bronchiectatic disease’. Bronchiectasis in patients with the non-classical pattern of NTM infection is the dominant imaging feature, and tends to predominate in the right middle lobe and lingula (Fig. 24.39A and B), although other lung segments and lobes may be affected to a lesser extent. Bronchiectasis is often cylindrical, but may be severe and cystic. Bronchial wall thickening is prominent, and variably sized nodules, some larger than 1 cm and many subcentimetre in size (Fig. 24.39B and C), are commonly seen. The nodules in patients with non-classical NTM infection are the result of peribronchiolar inflammation, bronchiolar impaction and granuloma formation (Fig. 24.39C).61,64 Foci of consolidation are also seen in patients with the nodular bronchiectasis NTM infection pattern and often reflect areas of organizing pneumonia (Fig. 24.39C). Cavitation, usually small foci, may also be encountered with the nodular bronchiectasis pattern of NTM infection. The cavitation may, at least in part, be the result of bronchial wall inflammation, destruction and, eventually, bronchial dilation and frank bronchiectasis.65 Lymphadenopathy is mild if present, usually only detectable with CT. Pleural effusion is rare. Antimicrobial therapy may produce improvement in these imaging findings, although the structural lung disease (bronchiectasis) will not improve once present. Furthermore, frequent relapses are common and often little change, or frank progression, is seen on serial imaging studies. The nodular bronchiectasis pattern may be associated with a number of different organisms, including MAC, M. abscessus and M. chelonae. Several reports of the CT appearances of M. abscessus and M. chelonae pulmonary infection indicate that bronchiectasis, nodules (often with tree-in-bud opacity), consolidation and cavities are the common findings, but, unlike pulmonary MAC infection, the bronchiectasis does not predominate in the right middle lobe and lingula.66–69 Pulmonary NTM infection has been reported in patients with oesophageal motility disorders, particularly achalasia, often associated with M. fortuitum.62 Thoracic imaging studies usually show basilar, dependent air-space opacities consistent with aspiration pneumonia. A pulmonary disease closely resembling hypersensitivity pneumonitis resulting from NTM exposure from contaminated water in hot tubs, spas and similar devices has been recently recognized. This condition is more frequently encountered in patients younger than those typically affected by other forms of NTM infection. The exact cause is unclear,
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Fig. 24.39 Nodular bronchiectatic NTM infection: MAC. (A) Chest radiograph shows extensive bilateral perihilar linear opacities representing bronchial wall thickening, nodules (arrow), and bronchiectasis. (B) HRCT image shows extensive right middle lobe and lingular bronchiectasis associated with tree-in-bud opacity (arrowhead). (C) Gross specimen shows small nodules (arrows) representing granulomas and bronchiectasis (arrowhead).
and the condition may be the result of a combination of NTM infection, other exposure factors and certain host susceptibility features.61 The imaging findings of NTM-induced hypersensitivity-like disease are essentially identical to other forms of hypersensitivity pneumonitis, and include bilateral linear or reticular opacities on chest radiography without pleural effusion or lymphadenopathy. The lung opacities seen on chest radiography with hypersensitivity pneumonitis or NTM-induced hypersensitivity-like lung disease are very non-specific and the diagnosis is usually quite difficult to make on chest radiography. HRCT, however, may show findings very suggestive of hypersensitivity pneumonitis, including multifocal ground-glass opacity, poorly defined, hazy, ground-glass attenuation centrilobular nodules (Fig. 24.40) and air trapping. The combination of ground-glass attenuation nodules and air trapping is fairly suggestive of hypersensitivity pneumonitis, or, in the proper clinical setting, NTM-induced hypersensitivity-like disease. With more chronic exposure, coarse reticulation (Fig. 24.41),
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Fig. 24.40 Hypersensitivity-like NTM infection: subacute disease. HRCT shows ground-glass opacity and micronodules (arrowheads).
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traction bronchiectasis and even honeycombing may be seen. Often these will spare the extreme costophrenic sulci, unlike usual interstitial pneumonia/idiopathic pulmonary fibrosis. Several other patterns of NTM infection that are uncommon but have been occasionally encountered include single or multiple nodular pulmonary opacities and the miliary pattern. The imaging features of these patterns of NTM infection are non-specific and resemble TB or fungal infections and, in the cases of NTM infection producing a solitary pulmonary nodule, lung carcinoma.
NON-TUBERCULOUS MYCOBACTERIAL INFECTION IN IMMUNOCOMPROMISED PATIENTS
Fig. 24.41 Hypersensitivity-like NTM infection: chronic disease. HRCT shows patchy ground-glass opacities and reticulation (arrows), and bronchiolectasis (arrowhead).
Immunocompromised patients, such as HIV-infected patients, solid organ transplantation patients, patients undergoing steroid therapy, patients with malignancy and rare immunodeficiency syndromes, such as severe combined immunodeficiency, are at risk for NTM infection.63 In HIV-infected patients, NTM infection is usually encountered at CD4 counts less than 25 cells/mL.61 The chest radiograph in NTM infection may be normal in HIV-infected patients with low CD4 counts. When radiographic abnormalities are encountered, mediastinal and hilar lymphadenopathy (Fig. 24.42) may be seen, with or without parenchymal opacities, such as single or multiple small nodules, masses or even the miliary pattern.62 Lung involvement is uncommon in patients with advanced HIV disease and disseminated NTM infection, and the condition often manifests on imaging studies as abdominal lymphadenopathy and hepatosplenomegaly. The involved lymph nodes may show central necrosis (Fig. 24.42B). The organisms usually associated with disseminated NTM infections in HIV/AIDS include MAC (usually M. avium)
Fig. 24.42 NTM infection in AIDS: MAC. (A) Chest radiograph shows bilateral hilar (arrows) and mediastinal (arrowhead) lymphadenopathy. (B) CT confirms lymphadenopathy, and shows that aortopulmonary lymphadenopathy has minimal central necrosis (arrow). This finding usually favours M. tuberculosis infection, but may occasionally be encountered in MAC infection.
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Fig. 24.44 NTM infection following lung transplantation: MAC. CT shows mildly thick-walled cavity (arrows) in native fibrotic right lung.
Fig. 24.43 NTM infection in AIDS: M. kansasii. Chest radiograph shows thin-walled cavities (arrows), linear opacities and left lower lobe nodules (arrowhead). Findings are consistent with NTM infection, but not specific for a particular organism.
and, less commonly, M. kansasii (Fig. 24.43) and a host of other NTM species.61 The immune reconstitution syndrome may also be triggered by MAC infection in patients with advanced HIV infection who have recently begun HAART. NTM infection may occur in lung transplant recipients, typically late following transplantation and often associated with chronic rejection.61 MAC and M. kansasii are most often isolated from pulmonary NTM infection. Chest radiographic findings usually do not allow a specific diagnosis, and may show multiple small nodular
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opacities, cavities (Fig. 24.44), patchy air-space opacities, linear or reticular abnormalities (suggesting fibrosis) associated with pleural thickening, normal findings or, rarely, pleural effusion.59 Among pulmonary infections commonly encountered in lung transplant recipients, NTM are less common than opportunistic viral and fungal infections and Pneumocystis jiroveci pneumonia. NTM infection in lung transplant recipients responds readily to appropriate treatment with little or no reduction in immunosuppression.59 NTM infection may rarely occur in patients who have undergone haematopoietic stem cell or solid organ transplantation. NTM infection most commonly presents as venous catheter infection in stem cell transplant recipients, whereas solid organ transplant recipients (renal, lung, heart and liver) typically present with cutaneous disease. Pleuropulmonary disease may occur in both haematopoietic stem cell and solid organ transplant recipients, and is usually non-specific in appearance, manifesting as multiple nodules, cavities, progressive air-space opacities and multifocal bronchiectasis.70 Disseminated disease may occur in these settings but is more common in immunosuppression due to AIDS.61
8. Miller WT, Miller WT Jr . Tuberculosis in the normal host: radiological findings. Semin Roentgenol 1993;28:109–118. 9. McAdams HP, Erasmus J, Winter JA. Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 1995;33:655–678. 10. Lee KS, Kim YH, Kim WS, et al. Endobronchial tuberculosis: CT features. J Comput Assist Tomogr 1991;15:424–428. 11. Miller WT, MacGregor RR. Tuberculosis: frequency of unusual radiographic findings. AJR Am J Roentgenol 1978;130:867–875. 12. Palmer PE. Pulmonary tuberculosis–usual and unusual radiographic presentations. Semin Roentgenol 1979;14:204–243. 13. Woodring JH, Vandiviere HM, Fried AM, et al. Update: the radiographic features of pulmonary tuberculosis. AJR Am J Roentgenol 1986;146: 497–506. 14. Buckner CB, Walker CW. Radiologic manifestations of adult tuberculosis. J Thorac Imaging 1990;5: 28–37. 15. Lee KS, Im JG. CT in adults with tuberculosis of the chest: characteristic findings and role in management. AJR Am J Roentgenol 1995;164:1361–1367.
16. Reed MH, Pagtakhan RD, Zylak CJ, et al. Radiologic features of miliary tuberculosis in children and adults. J Can Assoc Radiol 1977;28:175–181. 17. Stansberry SD. Tuberculosis in infants and children. J Thorac Imaging 1990;5:17–27. 18. Kim Y, Lee KS, Yoon JH, et al. Tuberculosis of the trachea and main bronchi: CT findings in 17 patients. AJR Am J Roentgenol 1997;168:1051–1056. 19. Wallgren A. The time-table of tuberculosis. Tubercle 1948:245–251. 20. Epstein DM, Kline LR, Albelda SM, et al. Tuberculous pleural effusions. Chest 1987;91: 106–109. 21. Hulnick DH, Naidich DP, McCauley DI. Pleural tuberculosis evaluated by computed tomography. Radiology 1983;149:759–765. 22. Weber AL, Bird KT, Janower ML. Primary tuberculosis in childhood with particular emphasis on changes affecting the tracheobronchial tree. Am J Roentgenol Radium Ther Nucl Med 1968;103:123–132. 23. Schmitt WG, Hubener KH, Rucker HC. Pleural calcification with persistent effusion. Radiology 1983;149:633–638. 24. Steele JD. The solitary pulmonary nodule. J Thorac Cardiovasc Surg 1963;46:21–39.
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Imaging of tuberculosis in adults 25. Spencer D, Yagan R, Blinkhorn R, et al. Anterior segment upper lobe tuberculosis in the adult. Occurrence in primary and reactivation disease. Chest 1990;97:384–388. 26. Christensen EE, Dietz GW, Ahn CH, et al. Initial roentgenographic manifestations of pulmonary Mycobacterium tuberculosis, M. kansasii, and M. intracellularis infections. Chest 1981;80:132–136. 27. Im JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings—early active disease and sequential change with antituberculous therapy. Radiology 1993;186:653–660. 28. Hadlock FP, Park SK, Awe RJ, et al. Unusual radiographic findings in adult pulmonary tuberculosis. AJR Am J Roentgenol 1980;134:1015–1018. 29. Krysl J, Korzeniewska-Kosela M, Muller NL, et al. Radiologic features of pulmonary tuberculosis: an assessment of 188 cases. Can Assoc Radiol J 1994;45:101–107. 30. Winer-Muram HT, Rubin SA. Thoracic complications of tuberculosis. J Thorac Imaging 1990;5:46–63. 31. Choe KO, Jeong HJ, Sohn HY. Tuberculous bronchial stenosis: CT findings in 28 cases. AJR Am J Roentgenol 1990;155:971–976. 32. Moon WK, Im JG, Yeon KM, et al. Tuberculosis of the central airways: CT findings of active and fibrotic disease. AJR Am J Roentgenol 1997;169:649–653. 33. Fishman JE, Sais GJ, Schwartz DS, et al. Radiographic findings and patterns in multidrug-resistant tuberculosis. J Thorac Imaging 1998;13:65–71. 34. Greenberg SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994;193:115–119. 35. Kim HC, Goo JM, Lee HJ, et al. Multidrug-resistant tuberculosis versus drug-sensitive tuberculosis in human immunodeficiency virus-negative patients: computed tomography features. J Comput Assist Tomogr 2004;28:366–371. 36. Shepherd MP. Plombage in the 1980s. Thorax 1985;40:328–340. 37. Kim HY, Song KS, Goo JM, et al. Thoracic sequelae and complications of tuberculosis. Radiographics 2001;21:839–858; discussion 859–860. 38. Goo JM, Im JG, Do KH, et al. Pulmonary tuberculoma evaluated by means of FDG PET: findings in 10 cases. Radiology 2000;216:117–121. 39. Engin G, Acunas B, Acunas G, et al. Imaging of extrapulmonary tuberculosis. Radiographics 2000;20:471–488; quiz 529-430, 532. 40. Harisinghani MG, McLoud TC, Shepard JA, et al. Tuberculosis from head to toe. Radiographics 2000;20:449–470; quiz 528-449, 532. 41. Engin G, Balk E. Imaging findings of intestinal tuberculosis. J Comput Assist Tomogr 2005;29:37–41.
42. Poey C, Verhaegen F, Giron J, et al. High resolution chest CT in tuberculosis: evolutive patterns and signs of activity. J Comput Assist Tomogr 1997;21:601–607. 43. Hatipoglu ON, Osma E, Manisali M, et al. High resolution computed tomographic findings in pulmonary tuberculosis. Thorax 1996;51:397–402. 44. Kosaka N, Sakai T, Uematsu H, et al. Specific highresolution computed tomography findings associated with sputum smear-positive pulmonary tuberculosis. J Comput Assist Tomogr 2005;29:801–804. 45. Matsuoka S, Uchiyama K, Shima H, et al. Relationship between CT findings of pulmonary tuberculosis and the number of acid-fast bacilli on sputum smears. Clin Imaging 2004;28:119–123. 46. Lee KS, Hwang JW, Chung MP, et al. Utility of CT in the evaluation of pulmonary tuberculosis in patients without AIDS. Chest 1996;110:977–984. 47. Saurborn DP, Fishman JE, Boiselle PM. The imaging spectrum of pulmonary tuberculosis in AIDS. J Thorac Imaging 2002;17:28–33. 48. Jasmer RM, Gotway MB, Creasman JM, et al. Clinical and radiographic predictors of the etiology of computed tomography-diagnosed intrathoracic lymphadenopathy in HIV-infected patients. J Acquir Immune Defic Syndr 2002;31:291–298. 49. Leung AN, Brauner MW, Gamsu G, et al. Pulmonary tuberculosis: comparison of CT findings in HIV-seropositive and HIV-seronegative patients. Radiology 1996;198:687–691. 50. Fournier AM, Dickinson GM, Erdfrocht IR, et al. Tuberculosis and nontuberculous mycobacteriosis in patients with AIDS. Chest 1988;93:772–775. 51. Busi Rizzi E, Schinina V, Palmieri F, et al. Radiological patterns in HIV-associated pulmonary tuberculosis: comparison between HAART-treated and nonHAART-treated patients. Clin Radiol 2003;58:469–473. 52. Rajeswaran G, Becker JL, Michailidis C, et al. The radiology of IRIS (immune reconstitution inflammatory syndrome) in patients with mycobacterial tuberculosis and HIV co-infection: Appearances in 11 patients. Clin Radiol 2006;61:833–843. 53. Kim HY, Im JG, Goo JM, et al. Pulmonary tuberculosis in patients with systematic lupus erythematosus. AJR Am J Roentgenol 1999;173:1639–1642. 54. Ikezoe J, Takeuchi N, Johkoh T, et al. CT appearance of pulmonary tuberculosis in diabetic and immunocompromised patients: comparison with patients who had no underlying disease. AJR Am J Roentgenol 1992;159:1175–1179. 55. Khan MA, Kovnat DM, Bachus B, et al. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 1977;62:31–38. 56. Arslan O, Gurman G, Dilek I, et al. Incidence of tuberculosis after bone marrow transplantation in a single center from Turkey. Haematologia (Budap) 1998;29:59–62.
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57. Bravo C, Roldan J, Roman A, et al. Tuberculosis in lung transplant recipients. Transplantation 2005; 79:59–64. 58. Morales P, Briones A, Torres JJ, et al. Pulmonary tuberculosis in lung and heart-lung transplantation: fifteen years of experience in a single center in Spain. Transplant Proc 2005;37:4050–4055. 59. Kesten S, Chaparro C. Mycobacterial infections in lung transplant recipients. Chest 1999;115:741–745. 60. Akan H, Arslan O, Akan OA. Tuberculosis in stem cell transplant patients. J Hosp Infect 2006;62:421–426. 61. Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367–416. 62. Erasmus JJ, McAdams HP, Farrell MA, et al. Pulmonary nontuberculous mycobacterial infection: radiologic manifestations. Radiographics 1999; 19:1487–1505. 63. Waller EA, Roy A, Brumble L, et al. The expanding spectrum of Mycobacterium avium complex-associated pulmonary disease. Chest 2006;130:1234–1241. 64. Jeong YJ, Lee KS, Koh WJ, et al. Nontuberculous mycobacterial pulmonary infection in immunocompetent patients: comparison of thinsection CT and histopathologic findings. Radiology 2004;231:880–886. 65. Kim TS, Koh WJ, Han J, et al. Hypothesis on the evolution of cavitary lesions in nontuberculous mycobacterial pulmonary infection: thin-section CT and histopathologic correlation. AJR Am J Roentgenol 2005;184:1247–1252. 66. Han D, Lee KS, Koh WJ, et al. Radiographic and CT findings of nontuberculous mycobacterial pulmonary infection caused by Mycobacterium abscessus. AJR Am J Roentgenol 2003;181:513–517. 67. Hazelton TR, Newell JD Jr , Cook JL, et al. CT findings in 14 patients with Mycobacterium chelonae pulmonary infection. AJR Am J Roentgenol 2000;175:413–416. 68. Hartman TE, Swensen SJ, Williams DE. Mycobacterium avium-intracellulare complex: evaluation with CT. Radiology 1993;187:23–26. 69. Swensen SJ, Hartman TE, Williams DE. Computed tomographic diagnosis of Mycobacterium aviumintracellulare complex in patients with bronchiectasis. Chest 1994;105:49–52. 70. Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Dis 2004;38:1428–1439.
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Imaging for tuberculosis in children Savvas Andronikou and Nicky Wieselthaler
INTRODUCTION Imaging TB in children is challenging and has numerous objectives. It is often the only means of making the diagnosis in children when other methods fail or are unreliable.1 It can be used to detect complications of the disease and assist in making management decisions including planning surgery.2 Imaging can also be used to prognosticate outcome3 and to follow response to therapy – both for diagnosis and for management decisions.4 Tuberculosis can affect any part of the body and can have a multitude of presentations and appearances. The imager must therefore call on all the modalities available, keeping in mind that reducing radiation and invasiveness is of major importance when imaging children.
PULMONARY TUBERCULOSIS Making the diagnosis of pulmonary TB in children is difficult because of non-specific radiological signs and interobserver variation in the interpretation of radiographs and even computed tomography (CT) scans.5,6
PRIMARY PULMONARY TUBERCULOSIS The hallmark of primary pulmonary TB is mediastinal and hilar adenopathy with a variety of accompanying features that include a focal nodule, air-space disease, collapse, miliary nodules and pleural disease.1,5,7,8 Normal appearance of hila and mediastinum are shown in Fig. 25.1.
COMPLICATIONS OF PULMONARY TUBERCULOSIS Complications are those of direct progression of the disease in the parenchyma and of bronchial stenosis due to lymphadenopathy (30–50%).5,7,8 Features include bronchial narrowing with airtrapping, collapse, expansile pneumonia and necrotizing pneumonia/liquefaction with or without cavitation.5,8 Breakdown of a lymph node and erosion into a bronchus may result in widespread bronchial distribution while erosion of the oesophagus or a vessel may cause complications that require urgent surgery. Fibrothorax and chest wall involvement are less common longer term complications.1
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UNUSUAL FORMS OF PULMONARY TUBERCULOSIS There are some unusual forms of TB in children such as the adult form of the disease (with fibrocavitatory changes in the apices) and progressive primary disease with breakdown of the primary focus of infection in the lung – the latter being more common in infants.
IMAGING PULMONARY TUBERCULOSIS LOOKING FOR NODES Plain radiographs are not sensitive or specific enough for detecting lymphadenopathy in children with suspected pulmonary TB,5,7,9 but there are patients in whom the radiographic findings are unequivocal. Lobulated, oval, dense masses filling the hilar point (outwardly convex) on the frontal radiograph (Fig. 25.2) and making a full ring on the lateral (much like a ‘doughnut’; Fig. 25.3) are characteristic of TB lymphadenopathy.1,8 Calcification is uncommon (1% on plain radiographs) and requires approximately 6 months to develop (Fig. 25.4).5,8 Airway compression is an indirect feature of lymphadenopathy, especially in children less than 6 months of age,1,5,8 but is very useful. High kilovolt (kV) radiographs are not useful as routine practice, but in the absence of CT scanning they may demonstrate bronchial compression in keeping with the presence of lymphadenopathy.5 CT scanning demonstrates lymphadenopathy to great advantage in addition to parenchymal changes and complications of bronchial compression. Liquefaction necrosis (non-enhancing parenchyma with or without visible vascular and bronchial detail), cavity formation, and pleural and pericardial disease are also well demonstrated by CT. Two-thirds of TB nodes show enhancement, which sometimes has the characteristic low-density ring-enhancing appearance, but more often shows fine curvilinear enhancement in the central part of a matted group of nodes. This has been likened to the appearance of a group of cartoon ghosts, hence the term ‘ghost-like enhancement’ (Fig. 25.5).1,7 The subcarinal group is most commonly enlarged but other sites such as the paratracheal region and the hila and the azygo-oesophageal extension of the subcarinal group are also commonly involved. Multifocal lymph node involvement is usually present, making it easier to confirm the diagnosis.7 High-resolution CT (either performed specifically or as a reconstruction from multidetector scans called ‘combi-scans’) can be used to confirm lymphadenopathy (Fig. 25.6) or miliary TB better when plain radiographs are equivocal.
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Fig. 25.1 Frontal and lateral radiographs: normal appearances of the hila and mediastinum. (A) Normal frontal radiograph in a child less than 1 year of age demonstrating masked hilar points, trachea to the right of the midline and the wide mediastinum as a result of the normal thymus. (B) Normal frontal radiograph in a child of 4 years of age demonstrating the now narrow mediastinal width and visible hilar points which have concave outer margins. (C) Normal lateral radiograph in a child less than 1 year of age. The bronchus intermedius is only seen for a short length and there are no oval dense masses posterior to it. (D) Normal lateral radiograph in a child of 4 years of age. The only lobulated oval densities are the right main pulmonary artery anteriorly and the arches of the left main pulmonary artery and aortic arch forming an upside-down horseshoe. The markings posterior to the bronchus intermedius are radiating and linear and are in keeping with normal vessels.
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Fig. 25.2 Frontal radiographs: lymphadenopathy. (A) Lobulated, dense right hilar region with an outwardly convex hilar point, consistent with lymphadenopathy. (B) Outwardly convex right hilar point consistent with hilar adenopathy. (C) An oval lobulated density is present posterior to the cardiac shadow on the left with an outwardly convex margin, consistent with left hilar lymphadenopathy. Also note the tracheal displacement to the left by the right paratracheal lymphadenopathy and compression of both left and right main bronchi (and bronchus intermedius). (D) High kV view of airway compression predominantly involving the bronchus intermedius and the left main bronchus due to TB lymphadenopathy.
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Fig. 25.3 Lateral radiographs – lymphadenopathy. (A) There is an oval density at the hilum likened to a ‘doughnut’, representing lymphadenopathy. Anteriorly and superiorly this is formed by normal anatomical structures (the right main pulmonary artery, left main pulmonary artery and aortic arch). Inferiorly the hilar and subcarinal groups of lymph nodes are implicated in the completion of this ‘ring’. (B) Oval densities posterior to the bronchus intermedius represent lymphadenopathy and may cause the appearance of an ‘air-bronchogram’ of this structure. (C) Variations on the ‘doughnut’ sign.
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Fig. 25.4 Calcified lymphadenopathy. (A) Frontal and (B) lateral radiographs of calcified right paratracheal and right hilar lymphadenopathy with an associated calcified right basal parenchymal focus. In addition there is a thin-walled cystic cavity in the left lower lobe.
Fig. 25.5 CT – lymphadenopathy. (A) Multiple anterior mediastinal ring-enhancing lymph nodes with low-density centres displacing the thymus to the left. Bilateral para- and pretracheal lymphadenopathy compressing the trachea from right and left is also present. (B) A large ring-enhancing lymph node with a low-density centre is seen in the pretracheal region. There are also anterior mediastinal lymph nodes with homogeneous enhancement seen. These are distinguished from thymic tissue by the presence of cleavage planes between them. The right upper lobe is consolidated and shows wide areas of necrosis. (C) ‘Ghost-like’ enhancement (curvilinear enhancement not forming full rings; much like the cartoon representation of a ghost) is present in the anterior mediastinum and right paratracheal position. (D) Ring calcification of right paratracheal lymphadenopathy.
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Fig. 25.6 Reconstruction correlated with plain radiography – lymphadenopathy. (A) Axial CT with contrast – subcarinal and left hilar lymphadenopathy. (B) Coronal–oblique reconstruction of (A) shows both subcarinal and left hilar lymphadenopathy. (C) Sagittal reconstruction at the mid-subcarinal position. The oval density formed by the lymphadenopathy is demonstrated. (D) Lateral radiograph. The superimposed lymph node densities form the ‘doughnut’ sign. (Continued)
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Fig. 25.6—cont’d (E) Coronal oblique reconstruction. The ring-enhancing left hilar lymphadenopathy is well demonstrated. (F) Sagittal reconstruction at the left hilum demonstrating the oval density formed by the left hilar nodes which contribute to the ‘doughnut’ density on the lateral radiograph in (D).
Magnetic resonance imaging (MRI) using short tau inversion recovery (STIR) sequences are useful for detecting lymphadenopathy without ionizing radiation. Currently, however, the need for anaesthesia/sedation presents an unnecessary risk for these patients, who may have airway compromise, and, in addition, this modality is not widely available in countries where TB is most prevalent.1
WHAT DOES THE PARENCHYMAL DISEASE LOOK LIKE? Air-space disease, oval focal granuloma, air-trapping, collapse, expansile pneumonia, liquefaction necrosis (drowned lung), cavitation and miliary interstitial nodules are the features of parenchymal disease (Figs 25.7–25.12).5,7,8
Fig. 25.7 Frontal radiograph – air-space disease/expansile pneumonia. (A) Frontal radiograph. Right middle lobe air-space disease and left hilar lobular density are consistent with lymphadenopathy. There is also compression of both the bronchus intermedius and left main bronchus, probably due to lymphadenopathy. (B) Frontal radiograph of right upper and middle lobe expansile pneumonia with an inferiorly convex bulging margin. All the major airways are compressed (probably due to TB lymphadenopathy) but the right main bronchus and bronchus intermedius are affected the most, accounting for the right upper and middle lobe findings.
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Fig. 25.8 Radiographs and CT – miliary interstitial nodules. (A) Frontal and (B) lateral radiographs of bilateral symmetrical diffusely distributed small nodules representing miliary TB. The lateral view also demonstrates the hilar lymphadenopathy. (C) High-resolution CT of bilateral symmetrical, diffusely distributed, small nodules of miliary TB.
IMAGING ABDOMINAL TUBERCULOSIS Abdominal TB manifests much like pulmonary TB on imaging, with ring-enhancing lymphadenopathy being characteristic and the most common finding.10 Other features include ascites, multifocal organ lesions (in the liver, spleen and pancreas), omental ‘cakes’, bowel wall thickening and complex masses involving a combination of bowel, lymph nodes and omentum.10 The lymphadenopathy is commonest in the para-aortic region and porta hepatis and is equally likely to be low density with rim enhancement or calcified. Mesenteric nodes show a typical stellate appearance of splaying the mesenteric vessels and displacing bowel to the
periphery.10 Organ lesions may be solitary or multiple, may be low density and ring-enhanced or may be calcified.10 Ultrasound is excellent for diagnosing ascites and some of the other features but CT detects all the features in one study to better advantage (Fig. 25.13).10 Retroperitoneal disease affects the adrenals and kidneys with calyceal and ureteric stricturing, papillary necrosis and cavitation and eventually fibrosis, calcification and autonephrectomy.1,10–12 Pelvic involvement including the ovaries is also encountered.1 Imaging is primarily with ultrasound and CT, but MRI has some advantages and intravenous pyelography (IVP) may still be useful for evaluation of the renal collecting system, particularly the ureters (Figs 25.14, 25.15).11,12
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Fig. 25.9 (See legend on page 271)
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Fig. 25.9 Radiographs and CT – drowned lung/breakdown/cystic changes. (A) Frontal and (B) lateral radiographs of thin-walled air-filled cysts within the parenchyma interspersed with normal lung parenchyma in the lung apices. These may result from bronchial obstruction but their upper lobe distribution suggests post primary, ‘adult-type’, reactivation TB. (C) Frontal radiograph of an exudative-type expansile air-space disease in the right upper lobe. An area of breakdown is also present. The narrow calibre airways are in keeping with the TB lymphadenopathy. (D–F) Axial CTs with contrast of different children demonstrating varying stages and degrees of post-bronchial obstructive lung consolidation with exudation, necrosis and breakdown. (D) The patient’s right upper and middle lobe do not enhance and there are no air-bronchograms visible, only blood vessels. This is termed a ‘drowned’ lung. (E) A ‘drowned’ right middle lobe but the left lower lobe is vital and even though it shows volume loss and air-space disease, the lung is enhancing and air-bronchograms are still visible. (F) The lung necrosis has resulted in breakdown and cavity formation. The lung necrosis and cavitation resulted from bronchial obstruction by TB lymphadenopathy in all cases.
Fig. 25.10 CT – collapse/air trapping. (A) Axial CT of consolidation and volume loss in the right lower lobe in a child with confirmed TB. (B) Axial CT of a child demonstrating miliary nodules in both lungs. The left lung also shows lower density overall, and fewer and more widely dispersed vessels and nodules as a result of air-trapping due to bronchial obstruction by lymphadenopathy.
IMAGING TUBERCULOSIS OF THE CENTRAL NERVOUS SYSTEM Tuberculosis can affect the brain and spinal cord both focally and diffusely.1,2,13 It is one of the commonest referrals for brain imaging for acquired epilepsy/seizure and it is the commonest cause for bacterial meningitis in some developing countries. Imaging often makes the diagnosis of TB where other methods have failed but also detects complications which require either medical or surgical management and dictate prognosis.1–3 Follow-up imaging may demonstrate new diagnostic features and monitor management (especially shunting of hydrocephalus) and the development of new infarctions.4 Even though CT is the more available modality, the most practical to use (because of its speed and patient monitoring capacity) and the most widely researched, MRI is probably more sensitive in demonstrating both the diagnostic features and complications of tuberculous meningitis.3,4 In particular, diffusion weighted imaging (DWI) is particularly well suited for confidently identifying infarction early on, and perfusion imaging may help us distinguish salvageable tissue. These techniques and MRI assessment of cerebrospinal fluid (CSF) flow are currently under investigation and may do away with procedures such as the air-encephalogram, which is still the only reliable means of distinguishing communicating
from non-communicating hydrocephalus. MRI is also the modality of choice for demonstrating TB involvement of the spinal cord and its meningeal coverings.1
LOOKING AT FOCAL LESIONS: TUBERCULOMAS, TUBERCULOSIS ABSCESSES, LOCALIZED MENINGITIS Tuberculomas are the commonest focal TB lesions resulting in seizure (> 95%). They have a typical iso- or hyperdense centre on CT, and are usually < 2 cm in size with ring or discoid enhancement and moderate surrounding oedema (Fig. 25.16). On MRI the characteristic feature is low signal on T2. On T1 they are iso-intense to cortex and the ring or discoid enhancement is also present.1 The alternative to a tuberculoma is a tuberculous abscess. This type of lesion is rare (< 5%), is > 2 cm in size, has a low-density centre with ring enhancement and on MRI is of low signal on T1 and high signal on T2. In short these lesions are inseparable from pyogenic abscesses and most tumours.1 Tuberculosis meningitis may also present focally, resulting in confusion. This is not uncommon and usually presents as focal basal enhancement with or without associated infarction/border zone necrosis and even meningeal-based tuberculomas.1,13
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Fig. 25.11 Radiographs and CT – airway compression. (A) Zoomed and cropped frontal radiograph of right main bronchus, bronchus intermedius and left main bronchus demonstrating severe narrowing as a result of lymphadenopathy. (B) Unilateral and (C) bilateral airway narrowing as a result of TB lymphadenopathy demonstrated by high kV technique using specialized filters. It has been shown that routine use of this technique is not warranted but when applied selectively it is useful in areas where CT is unavailable. (D) Axial CT with contrast of the bronchus intermedius markedly compressed from left and right by low-density-ring enhancing nodes. There is resultant expansile pneumonia of the right middle lobe. There are no air-bronchograms; the parenchyma does not enhance and has a homogeneous low density with outwardly convex margins. (Continued)
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Fig. 25.11—cont’d (E) Axial CT with contrast of narrowing of the bronchus intermedius and right main bronchus with resultant right middle and lower lobe air-space disease. Early areas of breakdown are present in the apical segment of the lower lobe as focal low densities with air-pockets within them. (F) Coronal–oblique reconstruction of a post-contrast CT chest showing large subcarinal and left hilar pathological lymph nodes of low density causing compression and narrowing of the left main bronchus. (G,H) Pre-lymph node enucleation. (G) Frontal radiograph demonstrates a lobulated right cardiac and mediastinal margin as well as compression of the bronchus intermedius and left main bronchus. There is corresponding right middle and lower lobe air-space disease. (H) The axial CT with contrast confirms the bronchus intermedius compression between two low-density ring-enhancing lymph nodes.
LOOKING AT MORE DIFFUSE DISEASE: MENINGITIS AND ITS COMPLICATIONS The most characteristic and well-known feature of TB meningitis is the basal enhancement, which is often meningeal but is also seen within the cisterns at the base of the brain (Fig. 25.17). This cisternal enhancement may represent leakage of contrast material into the CSF or may represent enhancement of vascularized granulation tissue which has organized and replaced CSF within the cisterns at the base of the brain. It is therefore best to refer to ‘basal enhancement’ rather than ‘basal meningeal enhancement’. On CT basal enhancement is the most sensitive finding and is
reported in between 75% and 93% of children with TB meningitis. Sometimes the basal enhancement can be predicted by the pre-contrast study which shows hyperdensity in the cisterns in about half of patients with proven TB meningitis. This is a very specific finding for TB meningitis and is useful when resources for contrast material are limited. MRI appears to be more sensitive for the detection of basal enhancement (currently being investigated) and demonstrates the flow voids of the vessels to stand out against the cisternal enhancement.1 On CT the determination of the presence of basal enhancement is not as easy. This has led to the development of nine objective features for determining its presence (some of which are demonstrated below)
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Fig. 25.12 Radiographs and CT – pleural and pericardial disease. (A) In addition to the bilateral basal air-space disease and bronchial compression (in keeping with lymphadenopathy), the patient demonstrates in this frontal radiograph a right-sided effusion. Note that in children an effusion is more likely to track alongside the chest wall and into the fissures rather than blunt the costophrenic angle. (B) Axial CT with contrast of bilateral pleural effusions (right worse than left) and pericardial thickening on the right. (C) Axial CT with contrast of a pericardial abscess. This was proven to be due to TB from a surgical specimen. (D) Axial CT without contrast of the left pleura showing thickening throughout as well as calcification and volume loss of the underlying lung. There is also multifocal pleural disease on the right. This is demonstrated early on in the progression to fibrothorax where the calcification will increase and volume of the lung and thorax will decrease.
and we refer the reader to the publications by Przybojewski and Andronikou for these.1,14 Tuberculosis meningitis results in complications detectable by imaging. Hydrocephalus is the most important clinically as there are treatment solutions.1,2 Sometimes air may be visible within the ventricles and sometimes this is concentrated only at the basal cisterns with no air in the ventricles. These findings are due to air which has deliberately been injected during lumbar puncture (LP) for CSF collection (air encephalogram). These two pictures differentiate communicating hydrocephalus (air reaches the ventricles), which can be treated medically or by serial LP, from non-communicating hydrocephalus (air stuck at the cisterns), which requires ventricular drainage to relieve the CSF being produced that cannot escape the ventricles (Fig. 25.18). Infarctions dictate prognosis and usually involve the basal ganglia and internal capsules.2,3 Bilateral basal ganglia involvement has the worst prognosis but almost any infarction results in some disability
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with more extensive bilateral infarcts resulting in death. Current research with DWI and perfusion MRI is attempting to show whether there is recoverable tissue and also searches to identify why some patients with no infarcts on CT do badly. Brainstem infarcts are better demonstrated by MRI and may hold the key to clinical findings. Tuberculomas assist in making the diagnosis of TB but are seen in less than 15% of children with TB meningitis (Figs 25.19, 25.20).2
IMAGING TUBERCULOSIS OF THE MUSCULOSKELETAL SYSTEM Skeletal TB is uncommon and represents only 10–20% of all extrapulmonary TB and 1–2% of all TB cases.15 The main route of infection is haematogenous spread from a primary source. Concurrent pulmonary TB is seen in less than 50% of cases.15
Fig. 25.13 (See legend on page 276) (Continued)
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Fig. 25.13 (A) Transverse abdominal ultrasound of low-density lymphadenopathy at the porta hepatis characteristic of TB. (B) Longitudinal abdominal ultrasound at the level of the inferior vena cava of lymphadenopathy adjacent to the porta hepatis and gall bladder. In addition there are multiple hepatic abscesses consistent with TB. (C) Abdominal ultrasound of ascites evident throughout the abdomen. This is often termed ‘wet’ abdominal TB. (D) Longitudinal abdominal ultrasound of a calcified lesion in the liver casting an echo-shadow. (E) High-resolution ultrasound (high-frequency linear probe) of multiple focal low-density lesions in the liver consistent with miliary TB. (F) Transverse ultrasound of the right iliac fossa of a mass consisting of matted low-density nodes, bowel and omentum which cannot be distinguished. (G) Longitudinal ultrasound of the kidney where upper and lower pole scarring at the fornices has resulted in focal calyceal dilation often inseparable from hydronephrosis. In addition necrosis and cavitation also resemble hydronephrosis on imaging. (H) Longitudinal ultrasound of the kidney shows urothelial thickening at the renal pelvis characteristic of TB. (I) Transverse ultrasound of the kidney of increased echogenicity at the renal pelvis is a reported feature of renal TB. (J) Transverse ultrasound of bilaterally enlarged ovaries in keeping with TB.
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Fig. 25.14 Radiographs, contrast studies, IVP – TB of the gastrointestinal system and renal tracts. (A) Contrast studies of the bowel are rarely used to make the diagnosis of abdominal TB in children but bowel involvement is well demonstrated as wall thickening separating bowel loops, luminal narrowing and ulceration, all demonstrated here. (B) Frontal abdominal radiograph of calcifications bilaterally in the renal areas. In regions with a high incidence of TB this is the most likely diagnosis. (C) Intravenous pyelogram, excretory phase, of scarring at the midpole fornix resulting in focal calyceal dilation typical of renal TB. (D) Intravenous pyelogram, excretory phase, of calcification of the right kidney and non-function consistent with autonephrectomy in TB. On the left there is a ureteric stricture resulting in hydroureter and hydronephrosis.
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Fig. 25.15 CT – ascites, organ lesions, lymphadenopathy, masses, omental cakes. (A) Axial CT with contrast of ascites, which is commonly reported in abdominal CT and is termed ‘wet’ TB. The density of the ascitic fluid is often higher than water density. Bowel dilation is also common with abdominal TB. (B) An initial CT demonstrates hepatic and splenic low-density TB abscesses/granulomas as well as calcified para-aortic lymphadenopathy. (C) Follow-up CT scans in the same patient (without contrast) and (D) progressive multifocal calcification of the organ lesions. (E) Axial CT with contrast of low-density ring-enhancing mesenteric lymphadenopathy. Characteristically in abdominal TB this results in splaying of the mesenteric vessels and displacement of the bowel peripherally. (F) Axial CT with contrast of low-density ring-enhancing lymphadenopathy in the para-aortic region with anterior displacement of the pancreas and inferior vena cava. (Continued)
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Fig. 25.15—cont’d (G) Axial CT with contrast of low-density ring-enhancing lymphadenopathy in the mesentery as well as bilateral psoas abscesses. (H) Axial CT with contrast of the omentum showing lesions of low density just deep to the abdominal wall. These are known as omental cakes and even though not seen regularly they are characteristic of abdominal TB. In addition there is bowel wall thickening of the caecum and ascending colon as well as mesenteric lymphadenopathy. (I) Axial CT with contrast of delayed contrast excretion by the right kidney, hydronephrosis, cavitation and multifocal calcification consistent with TB. (J) Axial CT without contrast of focal calcification in the right kidney consistent with TB. (K) T1 coronal MRI of an enlarged right kidney with focal upper and lower pole calyceal dilation due to cavitation at the medullary pyramids.
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Fig. 25.16 CT – tuberculomas, TB abscesses, focal meningitis. (A) Axial CT with contrast of a ring-enhancing isodense lesion with surrounding oedema in the right frontal lobe typical of a tuberculoma. (B) Axial CT with contrast of a discoid/nodular enhancing lesion in the right parietal lobe with surrounding oedema: another typical presentation of a tuberculoma on CT. (C) Axial CT with contrast of a larger isodense, ring-enhancing lesion with surrounding oedema present in the right cerebellar hemisphere. This patient also has features of TB meningitis, including basal meningeal enhancement and hydrocephalus. (Continued)
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Fig. 25.16—cont’d (D) Axial CT with contrast of multiple ring- and discoid-enhancing granulomas clustered at the right thalamus with surrounding oedema. There is another group clustered at the right tentorial edge. This patient also has right caudate and lentiform infarcts in keeping with a vasculitis associated with meningitis. (E) Axial CT with contrast of nodular meningeal enhancement at the suprasellar. (F) Axial CT with contrast of a single discoidenhancing granuloma in the prepontine suprasellar cistern. There is accompanying hydrocephalus even though no basal enhancement is noted. (G) Axial CT with contrast of both parenchymal (predominantly right-sided) and meningeal-based tuberculomas which are of discoid- and ring-enhancing varieties. In addition there is bilateral meningeal enhancement of the Sylvian fissures consistent with TB meningitis. (Continued)
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Fig. 25.16—cont’d (H, I) Axial CT with contrast of patients demonstrating focal meningeal enhancement. In (H) this involves the Sylvian fissure on the left and there is low density of the surrounding parenchyma representing oedema and possible necrosis; a process also known as ‘border-zone necrosis’. In (I) there appears to be formation of an abscess/empyema in the left middle cerebral artery cistern.
Fig. 25.17 CT – TB meningitis, meningeal enhancement. (A–D) Axial CT with contrast of numerous objective features of abnormal basal enhancement including (A, D) ‘double lines’ in the middle cerebral artery cistern; (A, B) ‘Y-on the side’ at the suprasellar cistern; (C) ‘joining of the dots’ in the Sylvian cistern; (A, B) linear enhancement over more than one slice; (A, D) enhancement posterior to the third ventricle recess; (A, B) ‘fuzzy margins’ to the vessels; and (B, C) asymmetry. The cisterns are normally non-enhancing other than the vessels of the circle of Willis contained there. These are usually symmetrical, seen as horizontally enhancing lines on one slice only, have sharp margins and are not nodular. The vessels in the Sylvian fissures are usually separate from each other and seen as dots in cross-section. (Continued)
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Fig. 25.17—cont’d (B, C) Asymmetry. The cisterns are normally non-enhancing other than the vessels of the circle of Willis contained there. These are usually symmetrical, seen as horizontally enhancing lines on one slice only, have sharp margins and are not nodular. The vessels in the Sylvian fissures are usually separate from each other and seen as dots in cross-section. (E, F) Axial CT without and with contrast of the suprasellar and middle cerebral artery cisterns filled with a hyperdense content which enhances post contrast. This may represent granulation tissue, which is vascularized, or exudate with leaking of contrast into it. The pre-contrast finding has been shown to be specific for TB meningitis. (Continued)
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Fig. 25.17—cont’d (G, H) Axial CT without and with contrast of hyperdense content in the basal cisterns. The content in the patient (G) enhances after administration of intravenous contrast material (H).
Fig. 25.18 CT – complications of TB meningitis: hydrocephalus, infarction. (A–C) Axial CT with contrast of patients with basal enhancement complicated by hydrocephalus. The tips of the frontal horns are rounded, the temporal horns are visible and the biventricular to calvarial ratio is increased. It is not possible to distinguish communicating from non-communicating hydrocephalus on CT features alone. (Continued)
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Fig. 25.18—cont’d In patient (C) an air-encephalogram has been performed via LP at the time of CSF collection. Air injected via the LP is seen in the frontal horn here, indicating communicating hydrocephalus. In non-communicating hydrocephalus the air would concentrate at the basal cisterns but not enter the ventricles. (D–F) Axial CT with contrast of three children demonstrating abnormal enhancement in the Sylvian fissures and quadrigeminal plate cisterns consistent with TB meningitis. The disease is complicated by unilateral or bilateral basal ganglia and internal capsule infarcts as a result of vasculitis. There is also moderate hydrocephalus in all the patients. (Continued)
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Fig. 25.18—cont’d (G) Axial CT with contrast of a patient demonstrating enhancement of bilateral basal ganglia infarcts as well as enhancement of the cortical mantle consistent with cortical laminar necrosis; the results of TB meningitis. Depending on the age of the infarct there may be enhancement or calcification.
Fig. 25.19 MRI – tuberculomas, abscesses, focal disease. (A) T1 axial with contrast shows that, in addition to the abnormal meningeal enhancement, there is a right cerebellar tuberculoma. The centre is isodense to parenchyma and there is ring enhancement. Smaller discoid-enhancing tuberculomas are present in the right temporal lobe. (B–D) Left cerebellar tuberculoma. (B) T1 axial without contrast. (Continued)
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Fig. 25.19—cont’d (C) T1 axial with contrast and (D) T2 axial of the left cerebellar tuberculoma, which is predominantly isodense to cortex on T1 and ring enhanced with contrast. The diagnostic MRI feature of a tuberculoma is the low signal intensity on T2 (D). The centre of the lesion is showing the converse with low signal on T1 and high signal on T2, which indicates evolution to caseous necrosis. (E) T2 axial of three aggregated tuberculomas associated with the tentorial hiatus showing the characteristic low signal intensity on T2 MRI. (F–H) Tuberculous abscess. (F) T1 axial without contrast. (Continued)
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Fig. 25.19—cont’d (G) T1 axial with contrast and (H) T2 axial of a tuberculous abscess demonstrating caseating necrosis: an unusual presenting lesion of intracranial TB demonstrating a low signal centre on T1 (with ring enhancement after contrast) and high signal centre on T2 (H). (I) T1 coronal and (J) axial with contrast of tentorial and basal meningeal-based tuberculomas demonstrate ring and discoid enhancement, respectively. (Continued)
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Fig. 25.19—cont’d (K) T1 axial and (L) coronal with contrast demonstrating contrast filling the suprasellar cistern (K) and double lines (L) as well as asymmetrical enhancement of the left middle cerebral artery cistern, confirming the objective criteria described for CT.
Fig. 25.20 Advantage of MRI over CT. (A) Axial CT with contrast and (B) corresponding T1 axial with contrast. The CT demonstrates none of the objective or any subjective features of basal enhancement but the MRI in the same patient demonstrates double lines, Y-on-the-side and linear enhancement over successive slices coating the lobes and brainstem. (Continued)
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Fig. 25.20—cont’d (C) On CT with contrast the basal ganglia appear normal. (D) FLAIR imaging. (E) The confirmation of infarction is by demonstrating the high signal on DWI with corresponding black areas on (F) ADC map indicating restricted diffusion of water.
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SPINAL TUBERCULOSIS Half of skeletal TB cases involve the spine. Three different patterns of involvement are described: (1) osteitis, (2) osteitis with an abscess and (3) osteitis with discitis with or without an abscess.16 The anterior portion of the vertebral body is most commonly involved. As the disease progresses, the cortex is disrupted and the infection spreads to involve the adjacent discs, the subligamentous region and soft tissue. The intervertebral disc is believed to be involved late in the disease and preservation of disc space is often considered a diagnostic feature of spinal TB. It has been shown that discs may be involved more often in children than in adults either because of the nature of the disc in childhood or because children present late (Fig. 25.21).16 Subligamentous spread may result in multiple levels of contiguous or ‘skip’ vertebral body
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involvement.15 Posterior element involvement is rare but diagnostic of TB. Extensive disease results in multilevel vertebral body destruction and gibbus formation with kyphosis. Paravertebral abscesses can vary in size and may produce significant soft-tissue opacity when large, and cord compression is a significant complication of this. MRI best demonstrates all these features. When TB presents early it is difficult to distinguish from pyogenic spondylitis. On CT TB demonstrates large erosions, whereas in pyogenic spondylitis they are small, multiple and well defined.17 Calcification seen in the erosions or surrounding soft tissue are diagnostic of TB. The rim enhancement of the soft-tissue mass is reported to be smooth compared with irregular enhancement in pyogenic spondylitis.16
Fig. 25.21 Radiographs, CT and MRI – spinal TB. (A) Lateral radiograph of disc space narrowing between L1 and L2 vertebral bodies. There is endplate irregularity and some height loss of the vertebral bodies. These features are consistent with an infective spondylitis but it is difficult to distinguish TB from a pyogenic cause. (B–D) Axial CT (bone window) demonstrating different stages of vertebral body destruction in TB spondylitis. (B) The initial destruction is in the form of oval lytic lesions. These can be likened to the holes in Swiss cheese as compared with the smaller pepper pot holes of pyogenic spondylitis. (Continued)
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Fig. 25.21—cont’d (C) As more of the vertebra is destroyed it collapses and ‘explodes’ outwards, resulting in a rim of bone beyond the expected margins. With further destruction and collapse small fragments are displaced anteriorly and posteriorly into the spinal canal. (D) With advanced destruction, kyphosis results in visualization of components of more than one vertebral body in one axial plane. A large soft-tissue mass in this case is seen to displace and compress the trachea. (Continued)
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Fig. 25.21—cont’d (E–H) T1 sagittal without and with contrast, T2 sagittal and T1 axial with contrast of multiple consecutive vertebral bodies showing abnormal signal (low on T1 and high on T2). Discs appear to be floating between some of the involved vertebrae which is a well-known phenomenon of adult TB spondylitis (i.e. sparing of discs till late). In children, however, discs are destroyed quite early on or patients present late. There are three destroyed vertebral bodies (as seen by three spinous processes without visible matching bodies). The two intervening discs are also destroyed. A softtissue mass is seen predominantly anterior to the bony involvement and extends above and below the vertebral area of bone destruction with even further subligamentous extension. The mass shows relatively smooth peripheral enhancement. The involved vertebral bodies also show abnormal enhancement with contrast. The mass posteriorly, as well as the kyphosis, cause compression of the spinal cord. Note the ‘horseshoe’ shape of the anterior soft-tissue abscess as seen on the axial image with contrast (H), which displaces the airway anteriorly.
JOINT TUBERCULOSIS (TUBERCULOUS ARTHRITIS) Tuberculosis of the joints is the second most common site of involvement in skeletal TB.15 Spread into the joint occurs as a result of metaphyseal osteomyelitis crossing the physis and epiphysis into the joint (Fig. 25.22) or as, in older children and adults, deposition of the organism directly into the joint.15 Tuberculosis of the joint is predominantly a synovial disease. Common findings include periarticular osteopenia, effusions, synovitis with pannus, subchondral erosions, cortical irregularity and joint space narrowing. Children often develop one or two round or oval lytic lesions adjacent to the joint.18 Joint effusion with soft-tissue oedema may be the earliest sign. Usually a single large joint is involved, but multiple joint involvement has been described.19 The commonest joints involved are the hip and knee.15 Differential diagnosis includes pyogenic and juvenile idiopathic arthritis
and imaging features are non-specific; thus biopsy is required to make the diagnosis.
BONE TUBERCULOSIS (TUBERCULOUS OSTEITIS) There are no pathognomonic features of TB osteomyelitis radiologically (Fig. 25.23). Common sites include the hands, feet, skull and ribs and the metaphyses of especially the lower limbs.15,20 The lesions are generally solitary and isolated. Four types have been described: cystic, infiltrative, focal erosions and spina ventosa.20 The cystic form is the most common and may cross the physis to involve the metaphysis.15 Osteopenia, soft-tissue swelling and minimal periosteal reaction are recognized features. Differential diagnosis includes pyogenic osteomyelitis, fungal infections, and benign and malignant bone tumours.
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Fig. 25.22 Radiograph and MRI – TB arthritis. (A) Frontal radiograph of the pelvis showing a lytic lesion predominantly involving the metaphysis but also spreading into the epiphysis across the growth plate which has relatively well-defined margins (right hip). There is also associated unilateral osteopenia. The joint space is widened consistently with an effusion or synovitis (allowing for rotation). (B) T1 with contrast coronal. (C) Axial shows not only enhancement of the metaphyseal lesion but visible cortical breakthrough into the joint space. The joint capsule and synovial lining is thickened and shows enhancing pannus with a moderate effusion. These features are consistent with TB arthritis and osteitis.
CONCLUSION Tuberculosis can involve any part of the body and can have many varied appearances which may be inseparable from other causes. Imagers must use all available modalities while consistently weighing up the radiation dose imparted, as well as the expense and availability of the examination against the diagnostic value. Researchers are constantly trying to find new ways that imaging can help to make the
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diagnosis, especially for when other tests fail or when they are time-consuming. In addition, imaging has been useful in demonstrating complications that may require surgical or more detailed medical management. Even though imaging has extended far beyond the plain radiograph for diagnosing TB in children, we are still heavily reliant on this examination in communities where TB is most prevalent. Human immunodeficiency virus will change not only the frequency but also the ‘face’ of TB in children. This is therefore an open-ended chapter that requires constant revision.
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Fig. 25.23 Radiographs – TB osteitis. (A) Frontal and (B) lateral radiographs of the right elbow. The proximal ulnar metaphysis is expanded by a lucent lesion which shows sclerosis around it in the form of a thick periosteal reaction. A soft-tissue mass is also present. The appearances are consistent with a chronic osteitis and TB forms part of the differential diagnosis. (C) Frontal radiograph of the right shoulder. There is a lucent lesion of the proximal humeral epiphysis which was confirmed to be due to TB. Supporting the diagnosis on this radiograph is the calcified lymphadenopathy at the right hilum. (D) The typical ‘spina ventosa’ appearance of an expanded, cystic tuberculous lesion, with soft tissue swelling, involving the proximal phalanx of the ring finger.
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REFERENCES 1. Andronikou S, Wieselthaler N. Modern imaging of tuberculosis in children: thoracic, central nervous system and abdominal tuberculosis. Pediatr Radiol 2004;34:861–875. 2. Andronikou S, Smith B, Hatherill M, et al. Definitive neuroradiological diagnostic features of TBM in children. Pediatr Radiol 2004;34:876–885. 3. Andronikou S, Wilmshurst J, Hatherill M, et al. Distribution of brain infarction in children with tuberculous meningitis and correlation with outcome score at 6 months. Pediatr Radiol 2006;36:1289–1294. 4. Andronikou S, Wieselthaler N, Smith B, et al. Value of early follow-up CT in paediatric tuberculous meningitis. Pediatr Radiol 2005;35:1092–1099. 5. de Villiers RVP, Andronikou S, van de Westhuizen S. Specificity and sensitivity of chest radiographs in the diagnosis of paediatric pulmonary tuberculosis and the value of additional high-kilovolt radiographs. Australas Radiol 2004;48:148–153. 6. Andronikou S, Brauer B, Galpin J, et al. Interobserver variability in the detection of mediastinal and hilar lymph nodes on CT in children with suspected
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14. Przybojewski S, Andronikou S, Wilmshurst J. Objective CT criteria to determine the presence of abnormal basal enhancement in children with suspected tuberculous meningitis. Pediatr Radiol 2006;36:687–696. 15. Harvey E, Wilfred C. Skeletal tuberculosis in children. Pediatr Radiol 2004;34:853–860. 16. Andronikou S, Jadwat S, Douis H. Patterns of disease on MRI in 53 children with tuberculous spondylitis and the role of gadolinium. Pediatr Radiol 2002; 32:798–805. 17. Magnus K, Hoffman E. Pyogenic spondylitis and early tuberculous spondylitis in children: differential diagnosis with standard radiographs and computed tomography. J Pediatr Orthop 2000;20:539–543. 18. Haygood T, Williamson S. Radiographic findings of extremity tuberculosis in childhood: back to the future? Radiographics 1994;14:561–570. 19. Sawlani V, Chandra T, Mishra R, et al. MRI features of tuberculosis of peripheral joints. Clin Radiol 2003;58:755–762. 20. Rasool M. Osseous manifestations of tuberculosis in children. J Pediatr Orthop 2001;21:749–755.
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Computed tomography, magnetic resonance imaging and PET imaging in tuberculosis Adelard I De Backer, Filip M Vanhoenacker, and Paul van den Brande
PULMONARY TUBERCULOSIS INTRODUCTION The presentation of pulmonary TB is still frequently determined by the age of the individual: neonates and children develop primary TB and adults develop postprimary TB with infiltrates in the apicoposterior segments of the lungs and formation of cavities. Because of the changing epidemiology, this strict age-related distinction is fading, resulting in possible atypical and ‘mixed’ radioclinical patterns in adults and immunocompromised patients.1 It is very difficult to draw distinct lines between primary and postprimary radiographic patterns, and there is considerable overlap in the radiological manifestations. The disease and its imaging patterns should be interpreted in light of the interaction between the patient’s immune status and Mycobacterium tuberculosis.2 This chapter will focus on the specific use of computed tomography (CT) in the diagnostic setting of pulmonary TB. It is emphasized that the different radiological patterns may present as isolated, combined or successive in the same patient; therefore, a specific subsection is dedicated to imaging patterns that can be seen in both primary and postprimary pulmonary TB.
PRIMARY PULMONARY TUBERCULOSIS Classically, four entities have been described: 1. gangliopulmonary TB; 2. tuberculous pleuritis; 3. miliary TB; and 4. tracheobronchial TB. Only gangliopulmonary TB will be discussed in this subsection. It is characterized by the presence of mediastinal and/or hilar adenopathy and less conspicuous parenchymal abnormalities (Ghon focus) (Fig. 26.1). Because of its preferential occurrence in children, it has been designated as ‘childhood’-type pulmonary TB; however, in regions with low incidence of TB, it is now a rare entity in children, except for non-indigenous children, and has been increasingly encountered in adults and elderly patients. Right paratracheal and hilar localizations are the most common sites of nodal involvement in primary pulmonary TB, although other combinations have been described. The prevalence of adenopathy decreases with age.3 On contrast-enhanced CT, tuberculous adenopathy, often measuring more than 2 cm, shows a very characteristic, but not
pathognomonic, ‘rim sign’ consisting of a low-density centre surrounded by a peripheral enhancing rim (Fig. 26.2). Associated parenchymal infiltrates are encountered on the same side as nodal enlargement in approximately two-thirds of paediatric cases of primary pulmonary TB.3 Parenchymal opacities are typically located in the periphery of the lung, especially in the subpleural areas. They are usually difficult to see on conventional radiographs, because of their small volume; therefore, CT is often necessary to detect these subtle parenchymal infiltrates.2 Generally, the disease is self-limiting and the only radiological or CT evidence is the so-called Ranke complex: the combination of a parenchymal scar (whether calcified or not) – the Ghon lesion – and calcified hilar and/or paratracheal lymph nodes. Gangliopulmonary TB may be complicated by perforation of a node in a bronchus, retro-obstructive pneumonia, and/or atelectasis (epituberculosis; Fig. 26.3). A retro-obstructive infiltrate in primary TB most commonly appears as an area of homogeneous consolidation. Obstructive atelectasis or overinflation may result from compression by an adjacent enlarged node. Distribution is typically right sided, with obstruction occurring at the level of the right lobar bronchus or bronchus intermedius.2 Retro-obstructive inflammation may resorb and evolve to a fibrotic and/or calcified lesion. Destruction and fibrosis of the lung parenchyma result in formation of traction bronchiectasis within the fibrotic region. Evolution to cavitary disease is rare in children. Primary infection in adults most frequently results in parenchymal consolidation without adenopathy. These infiltrates may excavate and lead to phtysis. Immunodeficient and elderly patients may present with the childhood type (hilar/mediastinal adenopathy and parenchymal abnormalities), frequently combined with formation of cavities (mixed type).
POSTPRIMARY PULMONARY TUBERCULOSIS OR PHTYSIS Postprimary pulmonary TB is one of the many terms (reactivation TB, secondary TB, ‘adulthood’ TB, etc.) applied to the form of TB which develops and progresses under the influence of acquired immunity. It results from the reactivation of dormant residual foci, spread at the time of the primary infection. It is usually, but not always, a disease of adults.4 Phtysis defines a form of respiratory TB characterized by: 1. liquefaction of caseous necrosis; 2. formation of cavities; and 3. progressive fibrosis and lung destruction.
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Fig. 26.1 Primary TB. Contrast-enhanced chest CT shows a well-delineated, solitary nodular lesion (Ghon focus) in the apical segment of the right upper lobe (large arrow) and right hilar lymphadenopathy (small arrow).
Fig. 26.2 Tuberculous adenopathy. Contrast-enhanced CT demonstrates enlarged tuberculous lymph node in the mediastinum characterized by peripheral enhancement and low-density centre (arrow).
Fig. 26.3 Epituberculosis. Contrast-enhanced CT shows hilar adenopathy and associated retro-obstructive consolidation in the lingula.
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Fig. 26.4 Postprimary TB with cavity formation. CT obtained with lung windowing demonstrates irregular defined cavities accompanied by mural bronchial wall thickening and endobronchial spread of tuberculous disease in both lungs.
Typically, lesions are located in the apicoposterior lung segments and to a lesser degree in the apical segments of the lower lobes.5 In the first stage of disease, regions of caseous necrosis liquefy and communicate with the tracheobronchial tree to form cavities. CT may show extensive abnormalities, such as apicoposterior infiltrates, cavities, pleural exudates, fibro-productive lesions causing distortion of lung parenchyma, elevation of fissures and hila, pleural adhesions and formation of traction bronchiectasis. Cavitation in one or multiple sites is evident in 40% of cases of postprimary disease (Fig. 26.4). The cavity walls may range from thin and smooth to thick and nodular. It can be difficult to distinguish thin-walled cavities from bullae, cysts or pneumatoceles. When multiple apical cavities are encountered, the possibility that cystic bronchiectases are present in addition to necrotic cavities must be considered.6 Air-fluid levels in the cavity may occur in 10% of cases and may represent superimposed bacterial or fungal infection of the cavity.2 High-resolution (HR) CT is the imaging technique of choice to reveal early bronchogenic spread.7 Typical findings are 2- to 4mm centrilobular nodules and sharply marginated linear branching opacities, which have been shown to represent caseous necrosis containing bacilli within and around terminal and respiratory bronchioles (‘tree-in-bud’ sign; Fig. 26.5). Cicatrization atelectasis is a common finding after postprimary TB. Up to 40% of patients with postprimary TB have a marked fibrotic response, which manifests as atelectasis of the upper lobe, retraction of hilum, compensatory lower lobe hyperinflation and mediastinal shift towards the fibrotic lung (Fig. 26.6). Apical pleural thickening associated with fibrosis may reveal proliferation of extrapleural fatty tissue and peripheral atelectasis on CT.7 Complete destruction of a whole lung or a major part of a lung is not uncommon in the end stage of TB; such damage results from a combination of parenchymal and airway involvement. Secondary pyogenic or fungal infection may supervene. Once the lung is destroyed, the activity is difficult to assess with imaging.2 Diagnosis of postprimary TB is made bacteriologically. After antituberculous therapy, radiographs show disappearance of infiltrates and fibrosis develops. Fibrosis may be stable or regress. When sputum culture is negative, but CT findings suggest bronchogenic spread, a guided fibroscopy to assess the correct diagnosis of active
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Computed tomography, magnetic resonance imaging and PET imaging in tuberculosis
Fig. 26.5 Endobronchial spread of TB (same patient as in Fig. 26.3). CT obtained with lung windowing shows severe changes of bronchiolar dilatation and impaction. Bronchiolar wall thickening (small arrow) and mucoid impaction of contiguous branching bronchioles produce a tree-in-bud appearance (large arrow).
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Exudative pleuritis Exudative pleuritis is seen most frequently in older children and adolescents as a complication of primary TB. Contrast-enhanced CT and MRI with exudative tuberculous pleuritis typically shows smooth thickening of visceral and parietal pleura (‘split-pleura’ sign; Fig. 26.7).9 Tuberculous pleurisy may become localized, causing a tuberculous empyema. This empyema may break through the parietal pleura to form a subcutaneous abscess, so-called empyema necessitatis.9 In chronic tuberculous empyema, CT shows a focal fluid collection with pleural thickening and calcification with or without extrapleural fat proliferation. Fibrothorax with diffuse pleural thickening, but without pleural effusion on CT, suggests inactivity.2 Empyema may also communicate with the bronchial tree by bronchopleural fistula. Diagnosis of bronchopleural fistula is based on an increasing amount of sputum production, air in the pleural space, a changing air-fluid level and contralateral spread of disease. CT demonstrates directly the communication between the pleural space and bronchial tree or lung parenchyma in patients with bronchopleural fistula.10 Tracheobronchial tuberculosis Tracheobronchial TB occurs in 2–4% of patients with pulmonary TB. Plain radiographs may be normal. On HRCT, acute tracheobronchial TB manifests as irregular or smooth circumferential bronchial narrowing associated with mural thickening.11 Enhancement
Fig. 26.6 Lung destruction in postprimary TB. CT demonstrates a fibrotic, shrunken left lung with compensatory overexpansion of the right lung. Bronchiectasis is noted in the left lung with areas of emphysema and atelectasis. Bilateral symmetrical interstitial nodules, typical of miliary TB, are also present.
TB may be proposed. If staining and/or culture remain negative and the imaging features remain stable, the process may be considered as ‘inactive’ TB.
IMAGING PATTERNS ENCOUNTERED IN BOTH PRIMARY AND/OR POSTPRIMARY PULMONARY TUBERCULOSIS Several imaging patterns are not seen exclusively in either primary or postprimary TB. These patterns are discussed separately.
Miliary tuberculosis Computed tomography may demonstrate miliary disease before it becomes radiographically apparent. At thin-section CT, a mixture of both sharply and poorly defined 1- to 4-mm nodules are seen in a diffuse, random distribution often associated with intra- and interlobular septal thickening (Fig. 26.6).2 The more widespread location of these micronodules, including subpleural location, excludes the diagnosis of lymphangitis carcinomatosa and bronchiolitis.8
Fig. 26.7 Exudative tuberculous pleuritis demonstrated on MRI. Contrast-enhanced T1-weighted image shows a right-sided pleural effusion with enhancement of both visceral and parietal pleura.
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and enlarged adjacent mediastinal nodes are common findings in the active stage of stenosis. After healing of this focal infection of the bronchial wall, cicatricial bronchostenosis may occur. The left main bronchus is most frequently involved in fibrotic disease. In the chronic fibrotic stage, CT findings include concentric narrowing of the lumen, uniform thickening of the wall and involvement of a long bronchial segment.
Tuberculoma Although pulmonary tuberculomas are most often the result of healed primary TB, they are seen in 3–6% of cases of postprimary TB as the main or only abnormality on chest radiographs.2 Lesions range in size from 0.4 to 5 cm in diameter and are solitary or multiple. Small lesions are more conspicuous on CT. The majority of lesions remains stable in size and may calcify. Calcification is found in 20–30% of tuberculomas and is usually nodular or diffuse. In 80% of cases, small round opacities (‘satellite lesions’) are observed in the immediate vicinity of the main lesion. COMPLICATIONS OF PULMONARY TUBERCULOSIS, DOCUMENTED BY CT A residual tuberculous cavity may be colonized by Aspergillus species and present as an ‘aspergilloma’. CT scan shows a spherical nodule or mass separated by a crescent-shaped area of decreased opacity or air from the adjacent cavity wall. On supine and prone positions, it is obvious that the nodule is often mobile. Bronchogenic carcinoma and pulmonary TB often coexist, creating a difficult diagnostic problem. Manifestations of carcinoma may mimic or may be misinterpreted as progression of TB. Tuberculosis may favour the development of bronchogenic carcinoma by local mechanisms (scar cancer), or TB and carcinoma may be coincidentally associated. In addition, carcinoma may lead to reactivation of TB, both by eroding into an encapsulated focus and by affecting the patient’s immunity; therefore, any predominant or growing nodule should be suspicious for coexisting lung cancer in patients with TB. Pulmonary arteries and veins in an area of active TB may demonstrate vasculitis and thrombosis. Bronchial arteries may be enlarged in bronchiectasis associated with TB or
in parenchymal TB itself. In patients with bronchiectasis, nodular and tubular structures therefore are suggestive for hypertrophied bronchial arteries on HRCT scan. Spiral-CT angiography may be a useful technique for confirming these hypertrophied arteries.2 A Rasmussen aneurysm is a pseudoaneurysm of a pulmonary artery caused by erosion from an adjacent tuberculous cavity.12 Broncholithiasis is an uncommon complication, caused by rupture of a calcified pulmonary peribronchial node into an adjacent bronchus. Right-sided lobar or segmental bronchi are most frequently involved.13 CT scan shows a calcified lymph node that is either endobronchial or peribronchial and is associated with findings of bronchial obstruction, such as atelectasis, obstructive pneumonitis, branching opacities in V- or W-shaped configuration (obstructive bronchoceles), focal hyperinflation or bronchiectasis. Tuberculous pericarditis may be caused by extranodal extension of tuberculous adenitis into the pericardium due to the close anatomical relationship between the lymph nodes and the posterior pericardial sac. The pericardium may also be involved in miliary spread of the disease. On CT, adenopathies and a pericardial thickening (with or without effusion) may be seen. Constrictive pericarditis with fibrous or calcified constrictive thickening of the pericardium of more than 3 mm occurs as a delayed complication (Fig. 26.8).14 Pneumothorax secondary to TB occurs in approximately 5% of patients with postprimary TB, usually in severe cavitary disease. Tuberculous fibrosing mediastinitis is an uncommon complication and progresses insidiously without significant clinical symptoms. CT findings include a mediastinal or hilar mass, calcification in the mass, tracheobronchial narrowing, pulmonary vessel encasement and sometimes a superior vena cava syndrome.15
MAGNETIC RESONANCE IMAGING (MRI) The use of MRI for the evaluation of intrathoracic tuberculous lesions is limited because of technical restrictions, as well as the limited availability in countries where TB is endemic. MRI has been used for the demonstration of intrathoracic lymphadenopathy, pericardial thickening (with or without effusion) (Fig. 26.8) and pleural effusions (Fig. 26.7).16
Fig. 26.8 CT and MRI findings in a patient with postprimary tuberculous pericarditis resulting in calcific pericarditis. (A) On CT pericardial thickening with extensive, coarse calcifications are noted. (B) Black blood MR image shows calcifications as areas with low signal intensities. A localized pericardial fluid collection along the wall of the left ventricle is noted.
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Computed tomography, magnetic resonance imaging and PET imaging in tuberculosis
EXTRAPULMONARY TUBERCULOSIS INTRODUCTION Although the predominant form of TB is pulmonary disease, infection with M. tuberculosis may be seen in any organ system. Extrapulmonary TB mainly results from haematogenous dissemination or lymphogenous spread from a primary, usually a pulmonary, focus.17 An increasing incidence has been noted both in developing countries and in developed countries since the mid-1980s,18 especially in HIV-infected patients.19 The more widespread use of cross-sectional imaging modalities may also explain why extrapulmonary TB is more commonly diagnosed. The most common sites of extrapulmonary TB consist of lymphatic, genitourinary, bone and joint, and central nervous system involvement followed by peritoneal and other abdominal organ involvement.
ABDOMEN Gastrointestinal tuberculosis Pathologically, the most active inflammation takes place in the submucosal lymphoid tissue of the intestine, resulting in wall thickening due to the formation of epithelioid tubercles, cellular infiltration and lymphatic hyperplasia.20 Within 2–4 weeks, caseous necrosis of the tubercle begins, which eventually leads to ulceration of overlying mucosa. Further extension within the bowel wall and regional lymph nodes occurs by lymphatic spread. Granuloma formation, fibrosis and scarring develop in a later stage.17 Regional lymphadenopathy may adhere to the diseased bowel wall, forming an inflammatory mass.21 The gross appearance of the intestinal tuberculous lesions has led to its traditional categorization into three forms: 1. The more common ulcerative form is characterized by the presence of multiple small ulcers, usually 3–6 mm in diameter, with an irregular margin; they usually present as transverse lesions located parallel to each other. This orientation is related to the arrangement of the submucosal lymphatic structures. 2. In the less common hypertrophic form, extensive inflammatory response and reactive tissue produce a multinodular mucosal pattern resembling a neoplastic process. 3. The ulcero-hypertrophic pattern consists of a combination of both types and may result in a cobble-stone appearance.17 The ileum and ileocaecal region are the most commonly involved sites, followed by the ascending colon, which is commonly affected in direct continuity with ileocaecal involvement.22 This is related to the abundance of lymphoid tissue and relative stasis. Other sites in which the disease occurs are, in descending order of frequency, the ascending colon, jejunum, other parts of colon, rectum, duodenum and stomach.23 Usually one segment of the colon, the ascending, transverse or descending colon, is involved. Pancolitis is rare and is difficult to differentiate from ulcerative colitis.24 On barium enema, spiculation, spasm and rigidity in the early stage, and short or long stenosis in the advanced stage, may be seen.17 On CT and MRI, associated lymphadenopathy and manifestations of tuberculous peritonitis may be demonstrated. CT has become an important imaging modality in demonstrating gross morphological changes of the tuberculous bowel wall as well as extraluminal ancillary features, such as adenopathy and
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mesenteric changes. When inflammation is mild, CT shows only slight and symmetrical wall thickening, slight haziness of the pericaecal fat and an enlarged ileocaecal valve with a few regional lymph nodes. Features may be indistinguishable from Crohn’s disease or ileocaecal lymphoma. With severe and advanced involvement, caecal wall thickening and adjacent lymph nodes form a soft-tissue mass centred at the ileocaecal valve, resulting in asymmetric wall thickening. The tuberculous mass may result in engulfment of the terminal ileum (Fig. 26.9). On CT and MRI, the inflammatory mass may have a heterogeneous appearance on contrast-enhanced images.21 On MRI, the tuberculous lesion may show intermediate signal intensity and increased, slight heterogeneous signal intensities on T1- and T2-weighted images, respectively. Associated regional lymph nodes are usually multiple, ranging between 0.5 and 3.5 cm in size. Gastric TB is exceedingly rare. The antrum is the commonest site of involvement, and findings include benign ulcer in the ulcerative form, mass lesion simulating malignancy in the hypertrophied form and gastric outlet obstruction due to the formation of fibrosis.17 CT and MRI are useful for demonstrating associated regional lymphadenopathy. Duodenal involvement is also extremely rare and occurs in only 2% of patients with gastrointestinal TB.25,26 The third and fourth part of the duodenum is usually involved. Adjacent lymphadenopathy may result in narrowing with duodenal obstruction and is sometimes complicated by fistula formation.17 Cross-sectional imaging is useful for demonstrating thickening of the duodenal wall, associated regional lymphadenopathy and a thickened mesenteric root. Jejunal or ileal involvement, except for the terminal ileum, occurs infrequently and is usually associated with peritonitis.17,26 Imaging characteristics are non-specific and include non-stenotic ulcers, girdle ulcers with strictures, and mucosal fold thickening.17
Peritoneal tuberculosis The incidence of tuberculous peritonitis is low in western countries and immunocompetent patients, although in developing countries it may account for 30% of all non-pulmonary TB and for at least 20% of all cases of ascites.25 It is commonly associated with tuberculous adenopathy and gastrointestinal TB. Tuberculous peritonitis is traditionally divided into three types according to the amount of ascitic fluid:17,27 1. The ‘wet’ type is the most common and is associated with large amounts of ascitic fluid that may be either diffusely distributed or loculated. 2. The ‘fibrotic-fixed’ type is less common and characterized by omental masses, matted loops of bowel and mesentery and occassionally loculated ascites. 3. The ‘dry-plastic’ type is uncommon and consists of caseous nodules, fibrous peritoneal reaction and dense adhesions. There is considerable overlap between the first two types,26 and this classification does not seem accurate enough to reflect all combinations of radiological features demonstrated by imaging modalities; therefore, the radiological features of the peritoneum and its reflections are better discussed separately.26
Ascites A variable amount of ascites is usually seen in tuberculous peritonitis and can be free, localized or loculated. Ultrasound is a sensitive technique for imaging very small quantities of ascites, but its value is limited in the presence of overlying bowel gas. Usually, multiple
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Fig. 26.9 Ileocaecal TB. (A) Contrast-enhanced CT shows concentric caecal wall thickening (large arrow). Some blurring in the pericaecal fat is present. Note the presence of associated regional lymphadenopathy (small arrow). Lymphadenopathy is characterized by heterogeneous and peripheral contrast enhancement. (B) Coronal and (C) axial 18F-fluoro-2-deoxyglucose–positron emission tomography (FDG-PET) image shows a marked FDG uptake in the right lower quadrant. Patient was initially suspected for intestinal malignancy. Positive mycobacterial cultures from biopsy material obtained by colonoscopy proved abnormalities corresponded to intestinal TB.
fine, complete or incomplete and mobile strands of fibrin and debris are seen within the ascites. This results in a lattice-like appearance.25,28 On CT, the fluid typically has high attenuation values (25– 45 HU), higher than that of water, which probably reflect the high
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protein and cellular content of the fluid;17,26 however, the ascitic fluid may be of similar density to that of water in some patients.29 This may be due to a transudative phase of the immune reaction.29 A fat–fluid level is rarely seen in chylous ascitic fluid, resulting from lymphatic obstruction.30
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Computed tomography, magnetic resonance imaging and PET imaging in tuberculosis
CT, unlike ultrasound, is not limited by bowel gas but fails to demonstrate the internal septa. The combination of the two imaging modalities has been advocated for obtaining the correct diagnosis of tuberculous peritonitis.28 On contrast-enhanced MRI ascites may demonstrate delayed enhancement 15–20 minutes after intravenous administration of gadolinium contrast medium.31
Peritoneum Ultrasound may demonstrate diffuse hypoechoic peritoneal thickening of 2–6 mm, or irregular nodular thickening with tiny nodules of less than 5 mm only if a considerable amount of ascites is present.17,26 CT and MRI demonstrate smooth, mild peritoneal thickening and/or pronounced enhancement (Fig. 26.10).17,26,32 Omentum and small bowel mesentery CT is the modality of choice for demonstrating tuberculous omental and small bowel mesentery involvement. Involvement of the omentum in tuberculous peritonitis has a smudged or caked appearance.33 The differential diagnosis of tuberculous peritonitis consists of disseminated peritoneal malignancy, mesothelioma, non-tuberculous peritonitis and occasionally lymphoma.17,26,34 Extension of the inflammation through the peritoneum into the extraperitoneal compartment suggests TB and can be helpful in the differential diagnosis from peritoneal carcinomatosis. In mesothelioma, the ascites is disproportionately minimal in relation to the degree of tumour dissemination. Furthermore, the presence of a smooth peritoneum with minimal thickening and pronounced enhancement supports the diagnosis of tuberculous peritonitis, whereas nodular implants and irregular peritoneal thickening rather suggest peritoneal carcinomatosis. Other features in favour of tuberculous peritonitis include the presence of mesenteric macronodules, relative regularity of infiltrated omentum and lymph nodes with low-density centre or calcification.17,26 Tuberculous lymphadenopathy Tuberculous lymphadenopathy is the most common manifestation of abdominal TB.35 It may occur as an isolated manifestation without other evidence of abdominal involvement; however, associated involvement of the gastrointestinal tract, peritoneum and solid viscera (e.g. liver and spleen) is often seen. Commonly involved lymph node groups are the upper para-aortic region, the lesser omentum, the mesentery and the anterior pararenal space.35 This preferential distribution is explained by lymphatic drainage from main areas of infection: small bowel, ileocaecum, right side of the colon, liver and spleen. The lower
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para-aortic lymph nodes may be involved through systemic haematogenous spread or from direct spread from the reproductive organs.17,26 Tuberculous lymphadenopathy is usually multiple. A wide spectrum of patterns ranging from increased number of normal-sized nodes to massive nodal conglomerates has been described.35,36 Tuberculous lymphadenopathy is usually not responsible for invasion or obstruction of the common bile duct, blood vessels and urinary or gastrointestinal tracts.35,36 The CT findings of abdominal tuberculous lymphadenopathy include circular or ovoid lesions showing peripheral enhancement with low-density centre; heterogeneous or homogeneous enhancement on contrast-enhanced CT has also been described.35 The involved lymph nodes may occasionally show calcification.37 On MRI tuberculous lymphadenopathy is mostly hyperintense on T2-weighted images (Fig. 26.11), although hypointense lymphadenopathy on T2-weighted images has been reported.35,36 Similar to the T2-weighted appearance of an intracranial tuberculoma, the signal intensity may differ, depending on the stage of evolution, with central hyperintensity on T2-weighted images corresponding to liquefaction necrosis, and central hypointensity resulting from the presence of paramagnetic free radicals secreted from active phagocytic cells.38 Obliteration of the perinodal fat, characterized by increased signal intensities on T2-weighted images, has been suggested to reflect capsular disruption.35 On T1-weighted fat-suppressed images, lymphadenopathy is iso- or hypointense and shows a variety of patterns of enhancement, even within the same nodal group, after intravenous administration of gadolinium. This finding reflects the different stages of the pathological process.35 Enhancement patterns include peripheral enhancement visible as a uniform, thin or thick, complete or incomplete rim; and conglomerate group of nodes showing peripheral and central areas of enhancement. Heterogeneous enhancement and, less frequently, homogeneous enhancement or no enhancement may also be seen.35–38 The peripheral enhancing portion has been proposed to correspond to a perinodal highly vascular inflammatory response or granulation tissue within the nodes, whereas the central non-enhancing portion corresponds to caseation or liquefaction necrosis within the nodes.38 This appearance, especially when found in young people, is highly suggestive but not pathognomonic of TB. A similar pattern may also be seen with metastatic malignancy, lymphoma after treatment, inflammatory conditions, such as Crohn’s disease, pyogenic
Fig. 26.10 Tuberculous peritonitis. (A) Contrast-enhanced CT demonstrates ascites with thickening of the peritoneum, omental thickening and lymphadenopathy in the mesentery and retroperitoneum. (B) Contrast-enhanced T1-weighted fat-suppressed MR image at another level shows diffuse infiltration of the mesentery, thickening and enhancing of the peritoneum (black arrow) and rim-enhancing retroperitoneal lymphadenopathy (white arrow).
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Fig. 26.11 Tuberculous lymphadenopathy. (A) T2-weighted MR image shows a 5-cm-large mass in the porta hepatis. The lesion is heterogeneous, and shows central areas of high signal intensity and a peripheral, irregular hypointense rim (arrow). (B) On the gadolinium-enhanced T1-weighted image, lymphadenopathy shows heterogeneous enhancement due to the presence of focal enhancing and non-enhancing intranodal areas (large arrow). A smaller lesion is demonstrated in the lesser omentum showing predominant peripheral contrast enhancement (small arrow).
infection and Whipple’s disease.27 In untreated lymphoma, the enhancement pattern of lymphadenopathy is usually homogeneous; however, after treatment the enlarged lymph nodes may show decreased density and mesenteric stranding.39 The presence of calcification within enlarged lymph nodes is not pathognomonic of TB and may rarely be seen in metastases from teratomatous testicular tumours and non-Hodgkin’s lymphoma after treatment.39 However, nodal calcification in patients from endemic areas in the absence of known primary malignancy suggests a tuberculous aetiology.
Tuberculosis of the solid organs Liver, spleen and gallbladder On imaging, two main types of hepatosplenic TB have been described: the micronodular and the macronodular form.17 The more common micronodular form manifests usually only as moderate hepatosplenomegaly. The individual lesions typically are below the resolving capability of imaging modalities, but may appear on CT as tiny low-density foci throughout the spleen. The macronodular form is rare, and may be seen as solitary or multiple rounded or oval lesions measuring between 1 and 3 cm, rarely exceeding 3 cm in size (Fig. 26.12).40 However, a few giant lesions
Fig. 26.12 Splenic TB. Contrast-enhanced CT demonstrates widespread low-attenuation nodules within the spleen.
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have been reported with a diameter up to 17 cm.41 CT findings of the macronodular form are considered variable and non-specific. Findings vary from a non-calcified low-density lesion to a calcified high-density lesion with or without rim enhancement. On MRI, a solitary tuberculoma may also show non-specific features. A tuberculoma has been described on T1-weighted images as an isointense lesion compared with adjacent splenic tissue and may become visible on T2-weighted images as a hypointense mass with hyperintense areas. On gadolinium-enhanced images, slight peripheral rim enhancement may be seen.40 On MRI, tuberculous focal hepatosplenic lesions may show variable signal intensities and enhancement patterns after intravenous administration of gadolinium (Fig. 26.13). This spectrum of variable imaging findings may represent different phases of disease progression corresponding to different degrees of fibrosis, granuloma formation, caseation and liquefaction necrosis.40 Lesion hypointensity on T2-weighted images, thought to be due to the presence of free radicals produced by macrophages during active phagocytosis, may be associated with increased fibrosis and granulomatous tissue, or may reflect the presence of calcifications.17 The finding of lesion hypointensity on T2-weighted images may be a helpful characteristic for differentiating splenic tuberculoma from other neoplastic or inflammatory lesions.42 Furthermore, a hypointense nodule with a less hypointense rim on T1-weighted images, and a hyperintense central area with a less intense rim on T2-weighted images have also been reported.42 These findings may reflect caseating granuloma with a liquid centre and peripheral reactive fibrosis.43 Finally, a hyperintense mass without rim hypointensity on T2-weighted images may also be noted. The latter finding may reflect extensive central liquefaction necrosis with only minimal peripheral granuloma formation and/or fibrosis. Dynamic contrast-enhanced MRI most often shows a central unenhancing lesion with peripheral enhancement. This finding probably represents central caseation or liquefaction necrosis with peripheral granulation tissue. Recently, a less common pattern consisting of a peripheral enhancing lesion with, on delayed images, complete fill-in has been described. The latter finding probably represents a granuloma with minimal or absent caseation necrosis.44 The differential diagnosis of the miliary form includes metastases, lymphoma, sarcoidosis and fungal infection. The macronodular form mimics metastases, primary malignant tumour or pyogenic abscess.17
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Computed tomography, magnetic resonance imaging and PET imaging in tuberculosis
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Fig. 26.13 Macronodular hepatic TB. (A) T2-weighted MR image shows a heterogeneous lesion within the left lobe of the liver (arrow). (B) On the gadolinium-enhanced T1-weighted MR image, heterogeneous enhancement due to the presence of non-enhancing intralesional areas is noted (arrow).
Because of the non-specific and wide spectrum of imaging appearances, ultrasound- or CT-guided biopsy with subsequent staining for acid-fast bacilli, culture and histology will be mandatory for obtaining a definitive diagnosis. The value of the histological and microbiological examination depends on a very careful technique, with multiple passes through the periphery and the centre of the lesion; the periphery of the lesions contains caseating granulomas and aspiration of material from the necrotic centre is more likely to yield viable tubercle bacilli.17 Fine needle aspiration biopsy of the spleen has recently been reported to be of diagnostic value with a low complication rate.45 The gallbladder is a very rare site of infection, because the normal mucosa and gallbladder wall are resistant to M. tuberculosis.46 It is usually associated with severe abdominal TB affecting the peritoneum, mesentery and lymph nodes. Extension from adjacent foci is the usual route of infection. Imaging is non-specific and reveals an enlarged, thick-walled gallbladder and/or an internal soft-tissue mass. The differential diagnosis from gallbladder carcinoma or adenomyomatosis must be made.17
Fig. 26.14 Tuberculous involvement of head of pancreas and tuberculous spondylitis. Gadolinium-enhanced T1-weighted MR image with fat suppression shows a sharply delineated heterogeneous mass with multiloculated appearance (arrow).
Pancreas Pancreatic TB is extremely rare and is usually due to miliary spread.47 Focal tuberculous involvement of the pancreas occurs most frequently in the pancreatic head.48 Diffuse pancreatic involvement is exceedingly rare.48 On contrast-enhanced CT and MRI, focal involvement is characterized by a well-defined mass showing irregular margins and peripheral enhancement. Areas of central enhancement may result in a multiloculated appearance (Fig. 26.14). On MRI, the lesion is hypointense and mixed (hypo- and hyperintense) on T1-weighted, fat-suppressed images and T2-weighted images, respectively. The common bile duct and main pancreatic duct are normal. These features are nonspecific and may resemble inflammatory or neoplastic cystic lesions of the pancreas.47 Rarely, diffuse enlargement of the pancreas along with hypodense areas may be seen.49 On MRI, diffuse involvement is characterized by pancreatic enlargement with narrowing of the main pancreatic duct and heterogeneous enhancement. Signal intensity abnormalities include hypointensity and hyperintensity on T1-weighted, fat-suppressed images and T2-weighted images, respectively.47 The latter morphological abnormalities are also non-specific and may be seen with pancreatitis and lymphoma. Diffuse enlargement of the gland with pancreatic duct narrowing may also be seen in patients with autoimmune pancreatitis.17
Genitourinary tuberculosis Renal Renal TB typically occurs secondary to haematogenous spread from the lungs when bacilli lodge in periglomerular capillaries. When host immunity prevails, cortical granulomata form and remain stable for many years. Renal TB usually does not manifest before 10–15 years later when reinfection/reactivation of bacilli results in spread of organisms into the collecting system. The end result is destruction, loss of function and calcification of the entire kidney (autonephrectomy). Spread beyond the kidney to involve perinephric and retroperitoneal tissues may occur and fistulae may form with the gastrointestinal tract or skin.50 CT accurately detects calcifications, and may demonstrate perinephric extension. Coalescence of granulomas to form a tuberculoma may mimic tumour. In advanced disease CT may show cavities communicating with the collecting system, large caseating granulomas, focal or diffuse cortical scarring, non-function and dystrophic amorphous calcifications. In end-stage disease a nonfunctioning small calcified renal remnant may be seen. Collecting system involvement leads to ulceration, wall thickening and fibrosis with stricturing involving the infundibulum, renal pelvis and ureter; various patterns of hydronephrosis, including hydrocalyx, are
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demonstrated, depending on the site of stricture. Bladder involvement is seen in one-third of genitourinary TB. Tuberculous cystitis appears as a shrunken bladder with wall thickening, and occasionally granulomas present as filling defects in the bladder and mimic carcinoma. Bladder wall calcification is rare and should raise the possibility of other diseases such as schistosomiasis in appropriate clinical settings.50
Adrenal tuberculosis Adrenal gland TB is rare. It is usually bilateral, but unilateral disease may occur.17 Imaging is non-specific and reveals enlargement of the adrenal glands with areas of central necrosis. The gland may undergo atrophy and calcification in the end stage of the disease.34 Male genital tuberculosis Tuberculosis of the prostate is characterized by non-specific imaging findings.17 On contrast-enhanced CT, foci of caseous necrosis and inflammation present as non-specific hypoattenuating areas. On contrast-enhanced T1-weighted MR images peripheral enhancement is seen in areas of caseous necrosis, whereas T2weighted images reveal diffuse, radiating, streaky areas of low signal intensity in the periphery of the prostate (‘watermelon skin’ sign).51 Healing results in prostate calcification. Unilateral or bilateral tuberculous epididymal involvement may occur. In the more advanced stages, testicular involvement caused by direct extension of a tuberculous abscess in the epididymis may be seen.52 Tuberculous epididymo-orchitis manifests on ultrasound as focal or diffuse areas of decreased echogenicity.17 If calcification or central necrosis is present, the lesion may have a more heterogeneous echotexture.52
Female genital tuberculosis Female genital TB is an uncommon disease in developed countries but is not infrequently reported in patients from developing countries.32 Female genital TB may be primary, but is usually secondary to haematogenous dissemination during the time of active extragenital disease.53 The initial infection in female genital TB probably begins in the fallopian tubes and subsequently involves, with decreasing frequency, the endometrium, the cervix, the myometrium and the ovaries.32 With tuberculous involvement, the fallopian tubes may become enlarged and distended with multiple constrictions and a beaded appearance. The fimbriae, in contrast to other forms of salpingitis, may be patent. With further disease progression, a more pronounced enlargement of the tubes and occasionally pyosalpinges and even tubo-ovarian abscesses may be seen. Peritubal adhesions are common findings and may, especially in the presence of ascites, attach the adjacent viscera and pelvic walls to the anterior abdominal wall. When uterine involvement occurs, the endometrial cavity may become filled. In some cases dilatation as a consequence of obstruction of the cervix may be seen. In the presence of tuberculous peritonitis, the serosal surfaces of the fallopian tubes may become covered with miliary tubercles. Contrast-enhanced CT and MRI may demonstrate heterogeneous tubo-ovarian masses, dilatation of the fallopian tubes with wall thickening and marked enhancement (Fig. 26.15).32 Extrapelvic spread with involvement of the peritoneum, omentum, mesentery and bowel may be seen.17 Tuberculous tubo-ovarian abscesses may calcify.25 Imaging findings of female genital TB are non-specific and differential diagnosis includes pelvic inflammatory disease, chlamydial
Fig. 26.15 Tuberculous salpingitis. (A) On a left parasagittal gadolinium-enhanced, T1-weighted MR image, a hypointense dilatated tubular structure with peripheral enhancement, representing the left salpinx, is seen (arrow). There is associated infiltration of the mesentery. (B) Axial gadoliniumenhanced, T1-weighted MR image demonstrates fluid within the pouch of Douglas with nodular thickened and enhancing peritoneum, a diffuse mass-like appearance of the mesentery and a dilated left and right tube with peripheral enhancement (arrows). Note rim-enhancing iliac lymph nodes.
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salpingitis, sarcoidosis, fungal infections, tertiary syphilis, lymphogranuloma venerium, brucellosis, lymphoma and primary tumour and metastatic disease of the fallopian tubes.54
TUBERCULOSIS OF THE AORTA AND ITS BRANCHES Tuberculous involvement of blood vessels is a rare phenomenon.55 Of the vascular structures that may be involved, aortic involvement is the rarest.56 Aortic involvement may take the form of stenosing arteritis or an aneurysm. Most tuberculous aneurysms are pseudoaneurysms (87%) and rarely true (9%) or dissecting (4%). They are usually saccular in shape.56 They result from haematogenous dissemination or from direct extension of a contiguous tuberculous focus, usually lymphadenitis. One should consider the possibility of tuberculous aetiology of an aneurysm in cases of known disseminated TB or the presence of an aneurysm with an adjacent focus with suspicion of TB. Unlike atherosclerotic aneurysms, calcification is conspicuously absent in tuberculous aneurysms.56
TUBERCULOSIS OF THE SPINE Tuberculosis of the spine results from haematogenous dissemination of tubercle bacilli from a primary or reactivated focus. Rarely, vertebral TB may result by extension from a paraspinal infection or from lymphatic drainage from an adjacent affected area.57 Once in the vertebra, a granulomatous lesion develops. The inflammatory reaction, with the formation of granulation tissue, may cause bone expansion with gradually trabecular destruction, progressive demineralization, bone destruction and, eventually, cartilage destruction with involvement of the adjacent disc space. The margins of the bony, lytic lesions are distinct and usually there is no bone regeneration or periosteal reaction. Fibrosis, bone sclerosis and a resulting ankylosis occur when the disease has chronically faded out. Paraosseous abscesses (so-called ‘cold abscesses’), erosion and sinus tract formation may develop.58
Radiological features Vertebral TB is most often found in the lower thoracic and upper lumbar regions. Cervical and sacral involvement is uncommon. Two distinct patterns of vertebral osteomyelitis may be seen. The classic finding of spondylodiscitis is characterized by destruction of two or more contiguous vertebrae and opposed end plates, disc infection and commonly a paraspinal mass or collection; the increasingly more common atypical form of spondylitis without disc involvement is the second pattern.59 The infection typically commences at the superior or inferior anterior vertebral body corner adjacent to the discovertebral junction, and spreads by subligamentous extension and penetration of the subchondral plate. With further disease progression, the lateral and anterior cortices of the vertebral body may become destroyed, leading to collapse, kyphosis and vertebral instability. Because the disc is avascular, disc infection is seen late, and results in disc interval narrowing secondary to herniation of the disc into the undermined, collapsed vertebral body. Collapse and wedging of multiple vertebral bodies because of intraosseus cavitation result in the characteristic gibbus deformity. Paravertebral and/or epidural soft-tissue infection with subsequent abscess formation may track for considerable distances beneath the anterior or posterior longitudinal ligament, and may discharge by sinus tracts in unusual locations, such as groin, buttock or chest. Advanced disease may
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demonstrate abscesses tracking along fascial planes. Paraspinal infection may involve the iliopsoas muscle, resulting in psoas abscess and may extend into the groin and thigh. The paravertebral collection in a high cervical infection may be seen as a retropharyngeal collection. Calcification within the abscess is virtually pathognomonic of TB.39 CT is of great importance in demonstrating small, early foci of bone infection and the extension of the bone and soft-tissue involvement. End plate destruction, fragmentation of the vertebrae and paravertebral calcifications are adequately demonstrated. After administration of intravenous iodinated contrast paravertebral and/or epidural abscesses may show thick, nodular wall enhancement and a sinus tract may adequately be delineated.60 However, beam hardening may impair detection of more subtle epidural involvement. CT-guided fine needle aspiration has become widely accepted for both culture and histological diagnosis. Multiplanar capability and superior tissue contrast make MRI the modality of choice in the evaluation and follow-up of spondylodiscitis. A major advantage of MRI, compared with CT, is the higher sensitivity for detection of early inflammatory bone marrow changes and infiltrative end plate changes in the vertebra. MRI is mostly useful in delineating paravertebral, epidural and intraosseous abscesses and in evaluating the extent of cord compression and the presence of intramedullary lesions (Fig. 26.16).60 MRI findings in tuberculous osteomyelitis may be non-specific and consist of low signal intensity on T1-weighted images and heterogeneous increased signal intensity on T2-weighted images. With intraosseous abscess, low signal intensity on T1-weighted images and very high signal intensity on T2-weighted images may be seen located centrally in the vertebral body.57 However, characteristic findings of MRI in vertebral TB include decreased signal intensity on T1-weighted images of both vertebral bodies and disc spaces, but a signal intensity that is increased in the vertebral disc and markedly decreased in the vertebral bodies on T2weighted images.60 With late chronic vertebral TB, signal intensity is variable; T1-weighted images may show decreased or increased signal intensity. Hyperintense signal intensity on T1-weighted images in the setting of chronic infection may be specific to TB and shows normalization with treatment.61 The intravenous administration of gadolinium chelates allows better delineation of epidural abscesses and masses, and cord and nerve root compromise. Peripheral enhancement is seen in abscesses and represents granulomatous infectious tissue while central low signal intensity on T1-weighted contrast-enhanced images represents central necrosis. With tuberculous spondylodiscitis, the disc shows signal characteristics seen with pyogenic discitis in at least 75% of cases: bright signal on T2-weighted images, decreased signal on T1-weighted images and enhancement after contrast administration.57 Disc space preservation, normal signal intensity and lack of enhancement may also been seen.60
Differential diagnosis of vertebral tuberculosis Many infectious processes may have imaging findings similar to those of vertebral spondylodiscitis. These include low-grade pyogenic infections, such as brucellosis, and other bacterial and fungal infections. Granulomatous diseases (sarcoidosis), traumatic and osteoporotic fractures, and primary and metastatic neoplasms may have features comparable to those of vertebral TB. The diagnosis of TB is favoured if a calcified paravertebral mass and absence of sclerosis or new bone formation are noted. Conversely, a reduced height of an intervertebral disc is only rarely seen
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Fig. 26.16 Tuberculous spondylodiscitis of the thoracic spine. (A) Sagittal T2-weighted MR image shows extensive spondylodiscitis of T8–T10 characterized by destruction of vertebral bodies and disc spaces. Large paravertebral and epidural abscesses of high signal intensity are noted. (B) Sagittal gadolinium-enhanced T1-weighted MR image shows peripheral enhancement of paravertebral abscess and marked enhancement of epidural involvement. Epidural involvement results in displacement and compression of spinal cord.
in neoplastic forms, and a rapid loss of height in the disc with destruction, along with extensive sclerosis, the absence of gibbus deformities and the absence of calcified paravertebral masses are in favour of a pyogenic spondylodiscitis. Characteristic features of brucellar spondylitis include gas within the disc, a minimal associated paraspinal mass, absence of kyphosis and a predilection for the lower lumbar spine.34,58
EXTRASPINAL MUSCULOSKELETAL TUBERCULOSIS Musculoskeletal tuberculous lesions mainly result from haematogenous dissemination or lymphogenous spread from a primary or reactivated infected focus. Rarely, mycobacterial disease may be the result of direct inoculation. Injuries may result in reactivation of pre-existing tuberculous foci.62 Tuberculous involvement of the joint space may result from haematogenous dissemination through the subsynovial vessels, or indirectly from epiphyseal (more common in adults) or metaphyseal (more common in children) lesions, which erode into the joint space. A granulomatous lesion develops within the bone at the site of deposition of the mycobacterium. This lesion becomes a caseating focus which expands, causing trabecular destruction. Cortical destruction may then occur with subsequent development of a periosteal reaction and a soft-tissue mass.63
Tuberculous arthritis As in most infectious joint diseases, tuberculous arthritis is usually monoarticular. In approximately 10% of patients multiple joints may be involved.62 Most commonly involved joints are the hip
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and knee, followed by, in order of frequency, the sacroiliac joint, shoulder, elbow and ankle. Radiographic features include joint effusion, cortical irregularity, lytic lesions, joint space narrowing and periosteal new bone formation.63 Peripherally located osseous erosions are characteristic features of TB in ‘tight’ or weight-bearing articulations, such as the hip, knee and ankle. A triad of radiological abnormalities (Phemister triad) consisting of periarticular osteoporosis, peripherally located osseous erosion and gradual diminution of the joint space suggests the diagnosis of TB.62,63 Occasionally, wedge-shaped areas of necrosis (kissing sequestra) may be present on both sides of the affected joint. Bone sclerosis and periostitis occur late in the disease, except for children, in whom a layered periosteal reaction may be seen. The end stage of tuberculous arthritis is characterized by severe joint destruction and eventually sclerosis and fibrous ankylosis when the active infectious stage has slowly extinguished. In contradiction to pyogenic arthritis, the development of bone ankylosis is an uncommon finding. Ultrasonography may demonstrate the presence of joint effusions. It may also be helpful for aspiration of these effusions for microbiological and histopathological examination. CT is useful for evaluating the degree of bone destruction, sequestrum and surrounding soft-tissue extension.62 Although conventional radiography is the appropriate initial imaging test for the evaluation of musculoskeletal TB, plain films may be negative early in the disease. Therefore, in case of a high index of suspicion of tuberculous arthritis, MRI should be considered. On MRI, focal areas of cartilaginous destruction interspersed with areas of relatively normal-appearing chondral elements may be
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demonstrated. Chondral and subchondral bone erosions may be visible at a stage when the joint space is well preserved. Bone marrow changes may reflect either osteomyelitis or bone marrow oedema. Hypertrophied synovial lining and joint effusion with mixed high and intermediate signal intensity on T2-weighted images rather than pure signal intensity is seen.40 Therefore, it is often difficult to clearly differentiate between the synovial abnormalities and joint effusion on unenhanced images. On contrast-enhanced images, acute synovitis often produces moderate-to-marked enhancement, whereas chronic synovitis may show no enhancement.63 Suh et al.64 reported invariably intermediate signal intensity in synovial abnormalities on T2weighted images corresponding to haemorrhage, inflammatory debris, fibrosis and caseation necrosis. Associated soft-tissue abnormalities, such as para-articular collections, myositis, tenosynovitis, bursitis and sinus tract formation, may be seen. Sinus tracts are characterized by a linear, high signal intensity on T2-weighted images with marginal ‘tram-track enhancement’ on gadoliniumenhanced images.62 Para-articular abscesses mostly show a thin and smooth enhancing wall.62 The differential diagnosis of tuberculous arthritis includes pyogenic and fungal arthritis, subacute or chronic pyogenic arthritis, traumatic arthritis and even pauci-articular rheumatoid arthritis and juvenile idiopathic arthritis.
Extra-axial tuberculous osteomyelitis Tuberculous osteomyelitis is less common than tuberculous arthritis. Previously, tuberculous osteomyelitis was more often multifocal and disseminated.62 However, recent reports indicate that solitary lesions are now more commonly seen.63 Tuberculous osteomyelitis occurs most commonly in bones of the extremities, including the small bones of the hands and feet, although virtually any bone may be affected. The bacillus implants in the medulla of the metaphysis with subsequent formation of a granulomatous lesion. As the infected focus enlarges, caseation and liquefaction necrosis occurs with resorption of bone trabeculae. Further disease progression may result in macroscopic visible bone destruction, transphyseal spread of disease and joint involvement.62 Rarely, lesions involve the diaphysis. Tuberculous infection may erode through the cortex to form a paraosseous mass or collection. Findings of tuberculous osteomyelitis include soft-tissue swelling, minimal periosteal reaction, osteolysis with little or no reactive change, periarticular osteoporosis and erosions. Sclerosis is less frequently seen. Tuberculous sequestration is uncommon and less extensive than with pyogenic osteomyelitis.63 Multifocal tuberculous osteomyelitis is also known as osteitis cystica tuberculosa multiplex. The lesions are found at different stages of development owing to the haematogenous spread by which bacilli are seeded at different times to the flat and long bones. Multiple sites of involvement are usually seen in children; in adults involvement is more often confined to a single bone. The radiographic appearance may be somewhat different in children compared with adults. In children, the lesions usually are lytic and well defined, are without sclerosis and may show a variable size. Lesion growth may cause metaphyseal expansion. In adults, the lesions are smaller, are located in the long axis of bone and may show well-defined sclerotic margins.62,64,65 MRI may demonstrate intraosseous involvement earlier than with other imaging modalities. Marrow changes are demonstrated as areas of low and high signal intensity on T1- and T2-weighted images, respectively, and show enhancement after the intravenous administration of gadolinium chelates. Areas of necrosis appear hyperintense
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on T2-weighted images. Deep soft-tissue fistulae, sinus tracts and abscesses are better delineated on gadolinium-enhanced images (Fig. 26.17).62 The differential diagnosis of a monostotic tuberculous lesion includes pyogenic and fungal osteomyelitis, Brodie’s abscess and rarely neoplasm such as bone cyst, non-ossifying fibroma, enchondroma and even sarcoma. In an epiphyseal-located lesion, a chondroblastoma may be considered. Involvement of the metatarsophalangeal joint of the great toe may be misdiagnosed as gout. The differential diagnosis of multifocal tuberculous osteomyelitis includes eosinophilic granulomas, sarcoidosis, multiple myeloma, cystic angiomatosis, lymphoma and even metastases.
Soft-tissue tuberculosis Tuberculous tenosynovitis and bursitis Primary tuberculous tenosynovitis, a rare condition, most commonly involves the flexor tendon sheaths of the dominant hand.66 It may result from haematogenous spread or from periarticular extension of tuberculous arthritis. Either tendon or synovium, or both, may be infiltrated and thickened. Tubercle formation may result in caseation necrosis and secondary effusion within the tendon sheath. Disease progression may lead to thinning of the tendon and tendon rupture. As in other forms of chronic tenosynovitis, tendon and synovial thickening predominate with relatively little synovial sheath fluid as opposed to acute suppurative tenosynovitis where synovial sheath fluid is the predominant feature. Ultrasound is an ideal first-line investigation of tenosynovitis to confirm the diagnosis and reveal the degree and extent of tendon and tendon sheath involvement. In more advanced cases, MRI may be helpful to delineate the precise extent of soft-tissue involvement and associated osseous or joint involvement. Three forms of tuberculous tenosynovitis are described: the hygromatous, serofibrinous and fungoid stage.67 The hygromatous stage is characterized by the presence of fluid inside the tendon sheath without associated sheath thickening. The serofibrinous stage is characterized by thickening of flexor tendons and synovium with multiple tiny hypointense nodules within the hyperintense synovial fluid on T2-weighted images. These tiny nodules correspond to the rice bodies previously reported in the literature. Finally, a soft-tissue mass involving the tendon and tendon sheath is a characteristic feature in the fungoid stage. Secondary tuberculous involvement of synovial bursa membranes is a well-known condition, but primary bursitis is rarely reported.62,66 The trochanteric bursa, subacromial, subgluteal and radioulnar wrist bursae are most commonly affected. Two patterns of involvement have been reported on MRI: a uniform distended bursa and a bursa containing multiple small abscesses.68 Low signal intensity material on T2-weighted images within the fluid-filled bursa corresponds to caseous necrosis and fibrotic material.69 The wall of the distended bursa may contain calcifications. Long-standing bursitis is usually complicated by local osteopenia due to hyperaemia. Local pressure of the enlarged bursa may result in focal lytic bone destruction (e.g. greater trochanter, humeral head). The differential diagnosis of tuberculous tenosynovitis and bursitis includes pyogenic and fungal infection and post-traumatic lesions. Imaging does not reliably differentiate tuberculous and non-tuberculous bursitis. TUBERCULOSIS OF THE CENTRAL NERVOUS SYSTEM Central nervous system TB is the most hazardous type of systemic TB.43,67 A central nervous system infection with M. tuberculosis may
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Fig. 26.17 Tuberculous osteomyelitis of second metatarsal bone, tenosynovitis and tuberculous abscess. (A, B) Axial and coronal T1-weighted image shows bone marrow oedema, endosteal erosion, periosteal thickening, soft-tissue oedema and tenosynovitis. (C) Coronal T2-weighted image with fat suppression shows bone marrow oedema, cortical destruction and soft-tissue involvement characterized by increased signal intensities. A tuberculous abscess is noted at the dorsal aspect of metatarsal bone (arrow). (D) Contrast-enhanced, T1-weighted image with fat suppression shows marked enhancement of tuberculous changes. Soft-tissue swelling and thickening of the tendon sheath of the second toe and central necrosis in metatarsal bone is noted. Peripheral enhancement of tuberculous abscess is noted (arrow).
present either as a diffuse form (e.g. basal exudative leptomeningitis) or as a localized form (e.g. tuberculoma, abscess or cerebritis). Coexistence of extraneural TB is reported amongst 50% of cases of neuro-TB,70 which may be a clue to the diagnosis of central nervous system TB. Contrast-enhanced MRI is considered to be superior to CT in the detection and assessment of central nervous system TB. Neuroimaging procedures should include both the brain and spine, as concomitant intracranial and intraspinal involvement is common.43
Meningeal tuberculosis Tuberculous leptomeningitis Tuberculous meningitis is the most common presentation of neuro-TB and occurs predominantly in young children and
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adolescents.43 The common triad of neuroradiological findings in tuberculous meningitis is: (1) basal meningeal enhancement, (2) hydrocephalus and (3) infarctions in the supratentorial brain parenchyma and brainstem. Basal meningeal enhancement is the most consistent feature, caused by the ‘leaky’ inflammatory neovessels.67 On non-contrast CT, obliteration of the basal cisterns is observed. After contrast administration, there is typically diffuse enhancement of the basal subarachnoid cisterns and occasionally meningeal enhancement is seen over the cerebral convexities, the Sylvian fissures and the tentorium.67 In the early stages, MRI without the use of a paramagnetic contrast agent may show little or no abnormalities. In a later stage, distension of the affected subarachnoid spaces occurs with associated
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mild shortening of T1 and T2 relaxation times compared with normal cerebrospinal fluid. Gadolinium-enhanced T1-weighted imaging demonstrates abnormal meningeal enhancement and is generally considered to be more sensitive than CT.67 Some authors have reported minimal or absent meningeal enhancement on CT or MR images in patients with acquired immunodeficiency syndrome-related neuro-TB, supposedly due with an impaired immunological response resulting in the absence of basal meningeal exudates;71 however, other reports have not shown major imaging differences compared with immunocompetent patients.72 Extension of the inflammatory response to the ventricular system through the cerebrospinal fluid pathways resulting in ependymitis or choroid plexitis can cause ependymal or choroid plexus enhancement.43 Hydrocephalus is the most frequent complication of tuberculous meningitis and is usually more prominent in children. In addition to the dilatation of lateral ventricles, an increased periventricular signal may be seen on T2-weighted images as a sign of interstitial oedema due to increased intraventricular pressure with transependymal migration of cerebrospinal fluid.43 Cerebral infarction is another common complication of basal meningitis.73 The inflammatory exudate involves the adventitia and progresses to affect the entire vessel wall, leading to panarteritis with secondary thrombosis and occlusion.67 The majority of the infarcts are seen in the basal ganglia and internal capsule related to the encasement of the basal perforating arteries by the extensive basal meningeal exudates that characterize tuberculous meningitis. The large vascular distribution territories of the anterior and middle cerebral arteries are less commonly involved.43 A high proportion of these infarctions are haemorrhagic and this may lead to cavitation. Following infarction, CT shows ill-defined hypodense areas with mass effect and variable peripheral, sometimes diffuse, intravenous contrast enhancement. These lesions progress to circumscribed hypodensities. MRI is more accurate than CT in depicting basal ganglia infarctions. A hyperintense lesion on T2weighted images with mass effect and variable enhancement pattern after intravenous administration of gadolinium of a recent infarct will progress to a cavitated infarct, which is typically hypointense on T1-weighted images and hyperintense on T2weighted images.43 Fluid-attenuated inversion-recovery (FLAIR) imaging may even be more useful for defining the exact extent of the lesion and for differentiating old cerebral infarctions with cystic appearance from the surrounding tuberculous border zone encephalitis. On FLAIR imaging the old infarcts are characterized by a central area of low signal intensity (cavity due to tissue loss), surrounded by a hyperintense rim (presumably reflecting gliotic scar tissue). Conversely, T2-weighted images demonstrate both areas as equally hyperintense. MR angiography has also been reported to be a useful and non-invasive technique for assessment of vascular involvement in tuberculous meningitis.43,73 Involvement of cranial nerves is common with tuberculous meningitis. Cranial nerves II, III, IV, VI and VII are most frequently affected. Cranial nerve impairment can be due to vascular compromise resulting in ischaemia of the nerve or entrapment of the nerve in the basal exudates.67,73 Cranial nerve involvement may also be due to direct mass effect of a tuberculoma within the subarachnoid course of the cranial nerves or by direct involvement of the cranial nerve nuclei in the brain.67 Late-stage fibrotic changes can cause permanent loss of function in these nerves.43 The proximal portion of the nerve at the root entry zone is most vulnerable, and on contrast-enhanced MRI this portion of the nerve may be thickened and enhancing.67
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The brain tissue immediately underlying the tuberculous exudate shows various degrees of oedema, perivascular infiltration and microglial reaction, a process called ‘border zone encephalitis’.43,67 Recognition of border zone encephalitis is difficult, as the bright signal on MR T2-weighted images in these border zones merges with the high signal of the leptomeningeal exudate.43 Meningeal, parenchymal and ependymal tuberculoma formation is common during the course of tuberculous meningitis.43 Potential sequelae of tuberculous meningitis include meningeal or ependymal calcifications, focal areas of atrophy secondary to infarcts and hydrocephaly, encephalomalacia in the areas of cerebral infarction and occasionally syringomyelia or syringobulbia.67
Pachymeningeal tuberculosis Pachymeningeal TB consists of either isolated dural involvement or a predominantly dural-based lesion with secondary pial or parenchymal involvement. Focal and diffuse patterns of tubercular pachymeningitis exist. Most focal lesions of pachymeningeal TB are seen as en plaque, homogeneous, uniformly enhancing, duralbased masses; lesions appear hyperdense on plain CT scans, isointense to brain parenchyma on T1-weighted MR images and isointense to hypointense on T2-weighted MR images. Parenchymal tuberculosis Parenchymal TB is more common in HIV-infected patients and can occur with or without meningitis.74 The most common parenchymal form of central nervous system TB is tuberculous granuloma (tuberculoma). Other presentations of parenchymal diseases are tuberculous abscesses, focal cerebritis and ‘allergic’ tuberculous encephalopathy. Parenchymal tuberculomas Parenchymal tuberculomas may occur at any age. They are commonly found in patients with miliary pulmonary TB who are neurologically asymptomatic.43 Tuberculomas may involve the brain, spinal cord, subarachnoid, and subdural or epidural space, and may be solitary or multiple. The frontal and parietal lobes are the most commonly affected regions.70 Occasionally, tuberculomas have been described in the intrasellar region, brainstem, thalami, basal ganglia, cerebellopontine angle, optic pathways, pineal region and ventricles.43 Most tuberculomas occur at the corticomedullary junction. This supports the hypothesis of haematogenous spread in their pathogenesis, for there is a dramatic narrowing of the arterioles supplying the cortex as they enter the white matter.74 A small number of tuberculomas develop from extension of cerebrospinal fluid infection into the adjacent parenchyma via cortical veins or perivascular Virchow–Robin spaces around small penetrating arteries.74 These lesions originate as a conglomerate of microgranulomata in an area of tuberculous cerebritis that join to form a mature non-caseating tuberculoma. In most cases subsequent solid central caseous necrosis will develop, which may eventually liquefy.67 The radiological presentation depends on whether the granuloma is non-caseating (homogeneous enhancement), caseating with a solid centre (heterogeneous enhancement centrally and ring enhancement of the capsule) or caseating with a liquid centre (rim enhancement).67,74 The degree of surrounding oedema is variable and is thought to be inversely proportional to the maturity of the lesion. The non-caseating granuloma is usually slightly hypodense or isodense to the surrounding brain tissue on CT studies. On contrast-enhanced CT, these solid lesions are characteristically round, oval or lobular, and they enhance homogeneously. On MRI, these lesions are hypointense relative to brain tissue on T1-weighted images and hyperintense on T2-weighted acquisitions. On
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contrast-enhanced MR studies, homogeneous enhancement is seen. In the early stage of these lesions, they are frequently surrounded by a halo of contiguous vasogenic white matter oedema, which can be demonstrated by CT and MRI.67,74 In the solid, caseating granuloma the central portion enhances heterogeneously, whereas the capsule presents a ring-enhancing pattern. This ring enhancement tends to be unbroken and is usually of uniform thickness. This type of lesion appears relatively hypointense or isointense on T1-weighted images and isointense to
hypointense on T2-weighted images. The rim of a caseating tuberculoma is often strikingly hypointense on T2-weighted images and enhances on T1-weighted gadolinium-enhanced MRI. The reason for shortening of the T2 signal in some tuberculomas is not clear but may be the result of the presence of paramagnetic free radicals in the enclosed macrophages.43 In the next stage, central liquefaction of the tuberculoma develops. This granuloma with central liquefaction of caseous material (Fig. 26.18) is seen as a hypodense core surrounded by a dense ring
Fig. 26.18 Cerebral tuberculoma. (A) Axial T2-weighted MR image shows a subcortical lesion within the right lobe, with surrounding vasogenic oedema. (B, C) Axial and coronal gadolinium-enhanced, T1-weighted MR image shows strong enhancement of the lesion. Areas of ring-like enhancement are seen within the lesion with central areas of absence of enhancement, and correspond to caseating granuloma with central liquefaction of caseous material.
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of enhancement on contrast-enhanced CT. The central signal is hypointense on T1-weighted images and hyperintense on T2weighted images. T1-weighted gadolinium demonstrates intense rim enhancement of the lesion. In this stage, lesions may be indistinguishable on MRI from true tuberculous or pyogenic abscess formation.42,74 According to McGuinness,74 the target sign, defined as a central nidus of calcification or central enhancement surrounded by a ring of enhancement, is a pathognomonic finding of central nervous system TB; however, recent studies have suggested that only the target sign with central calcifications is pathognomonic of tuberculoma, whereas the target sign with a central enhancing dot does not necessarily correspond to tuberculoma.75 Such cases may represent reactivation of chronic calcified parenchymal lesions.43 Miliary central nervous system tuberculomas usually are associated with tuberculous meningitis and many of these patients have a primary pulmonary focus of TB.67,74 The contrast-enhanced CT and T1-weighted images after gadolinium administration may show numerous enhancing foci which are hyperintense on T2-weighted images.43,74 The activity of a tuberculoma may be judged by the degree of contrast enhancement on follow-up CT or MRI studies.74 Occasionally, newly developing or enlarging intracranial tuberculomas may be observed despite appropriate anti-TB therapy.43,74 Therefore, patients on anti-TB therapy who develop signs of raised intracranial pressure or new neurological signs should have urgent neuroimaging to exclude the development of new lesions or the enlargement of existing granulomas located in close proximity to strategic points of possible cerebrospinal fluid obstruction.76 Late changes include calcifications and regional atrophy, although many lesions leave no radiological traces following successful medical treatment.74
Tuberculous abscess Tuberculous abscess formation is a rare complication of central nervous system TB.43 A tuberculous abscess develops from parenchymal tuberculous granulomas or the spread of tuberculous foci in the meninges to the brain substance in patients with tuberculous meningitis.74 In contrast to a tuberculoma, which contain few bacilli, a tuberculous abscess is formed by semiliquid pus teeming with tubercle bacilli. Tuberculous abscesses may be indistinguishable from caseating granulomas with a liquid centre. They are usually larger (often > 3 cm in diameter), multiloculated and solitary, with thin walls.43 Spinal tuberculosis Spinal TB may take a variety of forms, including tuberculous radiculomyelitis, myelitic tuberculoma, epidural phlegmon and abscess. MRI should be the primary imaging modality in the screening of patients with suspected intraspinal TB, since MRI better delineates the extent of leptomeningeal disease than CT myelography and allows direct evaluation of intramedullary lesions and associated epidural or osseous pathology of the spine.77,78 Tuberculous radiculomyelitis Tuberculous leptomeningitis in the spinal canal frequently involves the spinal cord and nerve roots. This condition is known as tuberculous radiculomyelitis. It frequently accompanies intracranial disease. The thoracic cord is most commonly affected, followed by the lumbar and the cervical regions.43 Although the contents of the spinal canal may be difficult to see on CT, some CT findings have been reported in tuberculous
26
radiculomyelitis, such as gross volume changes of the myelum, pear-shaped cross-section in the lower thoracic region, related extra-axial mass lesions and associated spinal tuberculous osteomyelitis. Administration of intravenous contrast may be of value in enhancing epidural tuberculous granulation tissue or any paravertebral abscess.43 The MRI features of spinal tuberculous meningitis include cerebrospinal fluid loculations, obliteration of the spinal subarachnoid space with loss of outline of the spinal cord in the cervicothoracic spine and thickened, clumped nerve roots in the lumbar region. The spinal cord can be directly or indirectly affected, with diffuse high signal intensity changes on T2-weighted images representing oedema, cord infarction or myelitis. Contrastenhanced MRI reveals a linear or nodular enhancement coating the nerve roots and spinal cord or a thick intradural enhancement completely filling the subarachnoid space. Contrast-enhanced MRI is helpful in differentiating active tuberculous granulomatous disease from chronic fibrotic adhesions and in separating tuberculoma from surrounding oedema, as areas of both fibrotic tissue and oedema fail to enhance.43,67 Syringomyelia is a well-known complication of tuberculous radiculomyelitis. Inflammatory oedema and spinal cord ischaemia appear to be the underlying mechanisms in the early cases, whereas chronic arachnoiditis underlies late-onset cases.43 Indeed, focal scarring in the subarachnoid spaces impedes free circulation of cerebrospinal fluid, thus forcing cerebrospinal fluid into the central canal of the spinal cord via Virchow–Robin spaces. Focal cystic dilatations in the cord eventually coalesce to form a syrinx. On MRI syringomyelia presents as a central cavity that is isointense to cerebrospinal fluid on both pulse sequences and does not enhance.43
Myelitic tuberculomas Myelitic tuberculomas are very rare. They arise from haematogenous dissemination. The MRI findings are similar to the characteristic appearance of intracranial tuberculomas.43 Infrequent cases of intramedullary tuberculous abscesses have been reported.79 Extrinsic tuberculous involvement Extrinsic tuberculous involvement of the spinal cord is usually secondary to epidural abscess formation. They often extend directly from infections of the spinal column (Fig. 26.16).
POSITRON EMISSION TOMOGRAPHY IN PULMONARY AND EXTRAPULMONARY TUBERCULOSIS Metabolic imaging with positron emission tomography (PET) has become an important new technique in the diagnosis and differential diagnosis of malignant lesions. PET is also used in the prognosis, management and follow-up of malignant diseases.80 The most frequently used tracer in PET is 18F-fluoro-2-deoxyglucose (FDG). Its effect is based on a higher rate of glucose metabolism of cancer cells, but also on other pathological non-tumoral conditions, such as infectious diseases, radiation pneumonitis, postoperative surgical conditions and inflammatory diseases. Furthermore, FDG accumulates in various organs with high glucose metabolism, such as brain, muscles, myocardium, thyroid gland, gonadal tissue, gastrointestinal and urogenital tract, and the brown adipose tissue in the neck.80,81 The mechanism by which FDG uptake takes place is due to the promotion of glycolysis by an increased expression of glucose transport proteins and an upregulation of the intracellular
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hexokinase and phosphofructokinase activity in tumour cells. This results in accumulation of FDG in the neoplastic cells, a process called ‘metabolic trapping’, since structural changes prevent FDG from being catabolized and transported back into the extracellular space once FDG is phosphorylated.82 The distribution of the tracer, using positron-emitting isotopes such as 18fluorine, can be measured in vivo using a PET camera, resulting in whole-body imaging; FDG-PET also provides semiquantitative data in the form of standardized uptake value (SUV) or standardize uptake ratio (SUR). A SUV of 2.5 or more has generally been used as the cut-off value indicative for malignancy. However, FDG uptake is not specific for malignancy; positive findings may also be found in infectious diseases (mycobacterial, fungal, bacterial) and in inflammatory conditions (sarcoidosis). With infectious lesions, the increase of FDG uptake is attributed to an increase in granulocytic and/or macrophage activity (Fig. 26.9).80
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Tuberculosis is one of the examples of granulomatous disease together with sarcoidosis, histoplasmosis, Wegener’s disease and coal miner’s lung. A large number of case reports have been published with positive FDG-PET in pulmonary and extrapulmonary TB.83,84 However, in tuberculous disease, FDG-PET shows a low specificity, and, as a consequence, makes investigation not appropriate for its diagnosis. 11 C-choline is another tracer that can be used for imaging malignancies. An increased activity of choline transporter and choline kinase corresponds to an increased cell membrane synthesis and tumour cell proliferation. Unlike the macrophages in malignancy, the macrophages in the chronic phase of TB do not proliferate and do not need 11C-choline, resulting in low 11 C-choline uptake. Therefore, the combination of a high FDG and low 11C-choline SUV may be useful in directing the diagnosis towards TB.82
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37. De Backer AI, Mortele´ KJ, Van Den Heuvel E, et al. Tuberculous adenitis: comparison of CT and MRI findings with histopathological features. Eur Radiol 2007;17:1111–1117. 38. De Backer AI, Mortele´ KJ, De Roeck J, et al. Tuberculous epididymitis associated with abdominal lymphadenopathy. Eur Radiol 2004;14:748–751. 39. Yang ZG, Min PQ, Sone S, et al. Tuberculosis versus lymphomas in the abdominal lymph nodes: evaluation with contrast-enhanced CT. Am J Roentgenol 1999;172:619–623. 40. Fan ZM, Zeng QY, Huo JW, et al. Macronodular multi-organs tuberculoma: CT and MR appearances. J Gastroenterol 1998;33:285–288. 41. Buxi TB, Vohra RB, Sujatha Y, et al. CT appearances in macronodular hepatosplenic tuberculosis : a review with five additional new cases. Comput Med Imaging Graph 1992;16:381–387. 42. Murata Y, Yamada I, Sumiya Y, et al. Abdominal macronodular tuberculomas: MR findings. J Comput Assist Tomogr 1996;20:643–646. 43. Bernaerts A, Vanhoenacker FM, Parizel PM, et al. Tuberculosis of the central nervous system: overview of neuroradiological findings. Eur Radiol 2003; 13:1876–1890. 44. De Backer AI, Vanhoenacker FM, Mortele´ KJ, et al. MRI features of focal splenic lesions in patients with disseminated tuberculosis. Am J Roentgenol 2006; 186:1097–1102. 45. Rajwanshi A, Gupta D, Kapoor S, et al. Fine needle aspiration biopsy of the spleen in pyrexia of unknown origin. Cytopathology 1999;10:195–200. 46. Jain R, Sawhney S, Bhargava D, et al. Gallbladder tuberculosis: sonographic appearance. J Clin Ultrasound 1995;23:327–329. 47. De Backer AI, Mortele´ KJ, Bomans P, et al. Tuberculosis of the pancreas: MRI features. Am J Roentgenol 2005;184:50–54. 48. Ladas SD, Vaidakis E, Lariou C, et al. Pancreatic tuberculosis in non-immunocompromised patients: reports of two cases, and a literature review. Eur J Gastroenterol Hepatol 1998;10:973–976. 49. Desai SR, Bhanthunmavin K, Hollands M. Primary pancreatic tuberculosis: presentation and diagnosis. Aust N Z Surg 2000;70:141–143. 50. Browne RF, Zwirewich C, Torreggiani WC. Imaging of urinary tract infection in the adult. Eur Radiol 2004;14(Suppl 3):E168–183. 51. Wang JH, Sheu MH, Lee RC. Tuberculosis of the prostate: MR appearance. J Comput Assist Tomogr 1997;21:639–640. 52. De Backer AI, Mortele´ KJ, De Roeck J, et al. Tuberculous epididymitis associated with abdominal lymphadenopathy. Eur Radiol 2004;14:748–751. 53. Figueroa-Damian R, Martinez-Velazco I, VillagranaZesati R, et al. Tuberculosis of the female reproductive tract: effect on function. Int J Fertil Menopausal Stud 1996;41:430–436.
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65. Morris BS, Varma R, Garg A, et al. Multifocal musculoskeletal tuberculosis in children: appearances on computed tomography. Skeletal Radiol 2002; 31:1–8. 66. Jaovisidha S, Chen C, Ryu KN, et al. Tuberculous tenosynovitis and bursitis: imaging findings in 21 cases. Radiology 1996;201:507–513. 67. Jinkins JR, Gupta R, Chang KH, et al. MR imaging of central nervous system tuberculosis. Radiol Clin North Am 1995;33:771–786. 68. Babhulkar S, Pande S. Tuberculosis of the hip. Clin Orthop 2002;398:93–99. 69. Soler R, Rodriguez E, Rumuinan C, et al. MRI of musculoskeletal extraspinal tuberculosis. J Comput Assist Tomogr 2001;25:177–183. 70. Kumar R, Jain R, Kaur A, et al. Brain stem tuberculosis in children. Br J Neurosurg 2000; 14: 356–361. 71. Katrak SM, Shembalkar PK, Bijwe SR, et al. The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 2000;181:118–126. 72. Villoria MF, Torre J de la, Fortea F, et al. Intracranial tuberculosis in AIDS: CT and MRI findings. Neuroradiology 1991;34:11–14. 73. Gupta RK, Gupta S, Singh D, et al. MR imaging and angiography in tuberculous meningitis. Neuroradiology 1994;36:87–92. 74. McGuinness FE. Intracranial tuberculosis. In: Clinical Imaging in Nonpulmonary Tuberculosis. Berlin: Springer, 2000: 5–25.
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Management algorithms for tuberculosis where there are few or no diagnostic facilities Jan van den Hombergh
BACKGROUND An algorithm is a finite set of well-defined instructions for accomplishing a task or solving a particular problem which, given an initial state, will terminate in a defined end-state. An algorithm must be specified exactly, so there can be no doubt about what to do next and it has a finite number of steps that iterate and require decisions. The concept of an algorithm is often illustrated by the example of a recipe or a flow chart, although many algorithms are more complex. This definition implies that many procedures related to TB control could be referred to as algorithms, such as standard operating procedures (SOPs), guidelines, score charts, decision trees, and flow charts. This chapter will be confined to a limited number of diagnostic algorithms frequently used (and often modified) in guidelines, manuals, and education tools for TB control in resource-limited settings. The absence of adequate diagnostic facilities in areas where TB is most prevalent reflects a sobering reality. In most countries where TB incidence is high and often accompanied by a human immunodeficiency virus (HIV) epidemic, sputum smear microscopy and chest radiography remain the most important and widely available diagnostic methods. Both methods are neither fully sensitive nor specific, a shortcoming further compounded by concomitant HIV infection. In situations where there are no diagnostic tests available at all, the diagnosis of TB rests purely on clinical judgement, possibly with support of a practical tool, such as clinical guidelines, criteria, score charts, or other algorithms. Being developed with the aim to assist health workers to arrive at the diagnosis of TB with an acceptable level of accuracy, most of these tools have never been adequately validated. In order to increase specificity, complex algorithms have been developed, with often the consequence that substantial periods of time are required to reach the definitive outcome. In high-burden, low-resource settings, this unfortunately provides opportunities for drop-out of suspect patients (due to, for example, financial or logistic constraints, but also because of premature death in the case of HIV coinfection). Diagnostic algorithms are not meant to be technical instruments to replace sound clinical judgement and rational thinking in the management of TB, but rather provide useful support in a decision process, thus maximizing identification of true TB cases. As a consequence the number of TB cases missed in the process could be minimized, whereas non-TB cases will not be misclassified as TB and subjected to long treatment, unnecessarily straining human and financial resources.
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Most algorithms for TB are based on the TB case definitions developed by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD) that are presented in the International Standards for Tuberculosis Care.1 In a situation of a patient with symptoms suggestive of pulmonary TB and the availability of sputum microscopy, any diagnostic algorithm is short and conclusive when the sputum smear for acid-fast bacilli (AFB) is positive. However, the accuracy and validity is decreasing in those patients who present with an atypical clinical picture and negative AFB smear (e.g. TB–HIV coinfected patients). Since the sensitivity of sputum smear ranges from 30% to 70%,2 many pulmonary TB patients will have a negative sputum smear. In particular TB–HIV coinfected patients are more frequently sputum microscopy smear-negative and in children less than 5 years of age a positive sputum smear is rare. For extrapulmonary TB there are no generic algorithms developed, with the exception for lymph node TB, the most frequent manifestation of extrapulmonary TB. Hence the diagnosis of extrapulmonary TB rests on case definitions and clinical judgement. The typical starting point for any algorithm in TB is a patient with symptoms suggestive of TB, mostly referred to as a ‘TB suspect’. However, the symptoms and signs may as well be part of the algorithm itself. The most commonly used definition of a (pulmonary) TB suspect is any person with a cough for 2–3 weeks or longer and any constitutional symptoms such as fever, weight loss, or night sweats. There is no definition of a TB suspect that has both high sensitivity and specificity. Depending on the purpose and the consequent algorithm for which the TB suspect needs to be defined, a combination of symptoms, clinical signs, and investigations such as sputum smear and chest radiograph may be used, with a large range of predictive values. The definition therefore differs, e.g. for TB diagnosis in patients, detection of TB in prevalence surveys, and exclusion of TB in persons eligible for isoniazid preventive treatment (IPT), as well as other active casefinding activities.3,4
PULMONARY TUBERCULOSIS IN ADULTS A standardized schematic algorithm for the diagnosis of pulmonary TB is presented in Fig. 27.1. This was originally developed by the WHO and the IUATLD,5 and is now the recommended management approach for TB and is included in the International Standards for Tuberculosis Care. A national adaptation of this algorithm from National TB Control Guidelines in Ethiopia is presented as an example in Fig. 27.2.6 It includes both smear-negative and -positive
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Management algorithms for tuberculosis where there are few or no diagnostic facilities All patients suspected of having pulmonary TB
Patient with symptoms suggestive for TB
Sputum microscopy for AFB
2 or 3 positive
Only 1 positive
Three negative smears
1 or 2 positive
Examine 2 additional sputum specimens
Broad-spectrum antimicrobials (excluding anti-TB drugs and fluoroquinolones) No improvement
Improvement
Unchanged or worse
Repeat sputum microscopy 1 or more positive smears
Repeat sputum smear (three specimens)
All smears negative
13 positive*
Chest radiograph and physicians judgement TB
Yes No TB
AFB = acid-fast bacilli; TB = tuberculosis
Fig. 27.1 An illustrative approach to the diagnosis of sputum smearnegative pulmonary TB.5
TB and does not differentiate between settings with a differing prevalence of HIV infection. In order to appropriately apply this algorithm, sputum smear microscopy and chest radiography are assumed to be available. For resource-constrained settings, e.g. many of the high-burden countries, this implies a number of potential obstacles for patients with symptoms suggestive of TB who present at health facilities where these diagnostics are not available. Sputum can be transported to the nearest health facilities with microscopy available but in practice this does not happen. Rather the patient will be referred as is the case when a chest radiograph is required. This will result in delay and additional costs for the patient. Waiting for better diagnostic tools, wide distribution, and decentralization of sputum microscopy services is still the standing recommendation in settings where this algorithm is used. The diagnostic algorithm is combined with management algorithms for the follow-up of TB patients under treatment, with cure, death, or failure as an outcome. These are presented in Figs. 27.3 and 27.4. In case of treatment interruption for more than 2 months or when follow-up sputum smears are not carried out according to the recommended schedule (second to third month, fifth and sixth to eighth month), outcome can be default, transfer out, or completion of treatment, respectively. In case of recurrence of TB (after treatment completion) or return after treatment interruption, different algorithms apply and can be derived from current WHO guidelines.
EXTRAPULMONARY TUBERCULOSIS Definitive and rapid diagnosis of extrapulmonary TB remains a challenge in the absence of appropriate diagnostic tools. Even less sophisticated conventional techniques such as fine needle aspiration
Treat as smear-positive pulmonary TB* *
All negative
Sputum smear (three specimens)
Both negative
Treat with non-specific broad-spectrum antibiotics for 710 days (not a fluoroquinolone) Review after 2 4 weeks
All negative
Chest radiograph and physicians judgement: suggestive for TB?
Treat as smear-negative pulmonary TB
Cured or improved No
Treatment based on clinical evaluation
Discharge
* If initially all three smears are negative but after antibiotics only one repeat smear appears positive, it is advised to carry out two additional smears. If one or both are positive, proceed with TB treatment. If both are negative proceed with a chest radiograph and evaluation for conditions other than TB. ** If the patient was never treated before, register and treat as a new pulmonary TB smear-positive patient. If the patient has been treated before, register for re-treatment regimen. If possible, send a sputum specimen for culture and drug susceptibility testing.
Fig. 27.2 Standard algorithm for the diagnosis of pulmonary TB as adapted for the National TB Control Programme in Ethiopia.6
and cytology (FNAC), biopsy, pathology examination, and/or culture have limitations and are often not available in resource-limited settings. Among extrapulmonary TB cases, lymph node TB and pleuritic TB are by far the most common presentations. In practice the diagnosis of extrapulmonary TB will often be based on clinical judgement only. The algorithm in Fig. 27.5 can be of support in the diagnosis of lymph node TB. It is strongly recommended to offer an HIV test to the patient, since extrapulmonary TB is a frequent manifestation of an underlying HIV infection. It is noted that this algorithm includes always a sputum examination to exclude concomitant pulmonary involvement.
TUBERCULOSIS AND HIV COINFECTION The diagnosis of TB being straightforward for patients who are sputum smear-positive, the basic algorithms leave many questions for those patients who turn out to be smear-negative. In the past decades specific algorithms for detecting sputum smear-negative TB have been developed to address the diagnostic dilemmas and to avoid the risk of overdiagnosis. Initially these tools included as many as two courses of antibiotics,7,8 repeated sputum smears, and chest radiographs.9 Robust validation has never been achieved and increasing reports of early mortality in HIV-coinfected TB
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patients have prompted adaptation of the approach towards the diagnosis of smear-negative TB, in particular in areas with high HIV prevalence and consequently high TB–HIV coinfection rates. The specific characteristics of TB in HIV-infected patients have necessitated revisiting earlier versions of the pulmonary smear-negative diagnostic approach. With the aim to minimize delay in TB treatment and the associated mortality, new algorithms to be used in high TB and HIV prevalence settings have been proposed by the WHO.10,11 Figures 27.6 and 27.7 present algorithms for ambulatory and seriously ill patients who have a positive HIV test result or are clinically likely to be HIV-infected (adapted from the WHO recommendations for HIV-prevalent and resource-constrained settings). These guidelines are applicable in countries with an HIV prevalence of 1% in pregnant women and 5% in TB patients.11 The essential difference with earlier guidelines is that one (instead of two) positive smear for AFB can prompt the definite diagnosis and initiation of treatment for TB. Antibiotics have become part of the management of the HIV-infected patient, rather than a criterion on which TB is defined or refuted. An alternative approach to the diagnosis of smear-negative TB, specifically for HIV-infected adults, has been recently proposed and is based on a case definition algorithm and includes the diagnosis of common forms of extrapulmonary TB, such as lymph node TB. This algorithm includes a standardized response to treatment to increase the specificity of the case definitions.3
New smear-positive PTB Category I treatment
1 follow-up sputum specimen for AFB at 2 months AFB-negative
Start continuous phase 1 sputum smear follow-up at 5 months of treatment. Same procedure as at 2 months AFB-positive
AFB-negative
Failure: start re-treatment
Continue treatment
AFB-positive
Repeat 2 smears Add 4 weeks of intensive drug phase
AFBpositive
Start the continuous phase after this extra month (no sputum)
1 sputum smear follow-up at 7 months of treatment. Follow same procedure as at 2 months
1 sputum follow-up after 3 months of continuation phase. Same procedure as at 2 months
AFB-negative
2 smears AFB-positive
AFB-negative
Outcome: Cured
Failure: start re-treatment
Continue treatment
Continue treatment for 4 weeks, discharge
AFB-positive Cured
AFB-negative
1 sputum follow-up at 8 months. Same procedure as at 2 months
PTB: Pulmonary tuberculosis; AFB: Acid-fast bacilli
Fig. 27.3 Algorithm for the follow-up of a new smear-positive pulmonary TB patient.5
318
Smear-negative pulmonary TB patient, Category III treatment Good response to treatment
No response to treatment or worsening
Continue and complete treatment
At 2 months of treatment
Continue treatment and refer to physician to be re-assessed: Initial diagnosis may have been wrong Paradoxical worsening of TB or (usually in the first 6 weeks of treatment) Other complicating disease or OI may have occurred
Check 3 sputum smears for AFB
AFB-negative
If only 1 AFBpositive, repeat
Further AFBs are negative
If a 2nd AFB is also positive
At 3 months after start continuation phase
Prolong intensive phase drugs 4 weeks and then start continuous phase
Check 3 sputum smears for AFB
AFB-negative
If only 1 AFB-positive, repeat A 2nd AFB is positive
Other AFBs are negative
Treatment failure
Continue and complete TB treatment, unless there is certainty that patient has no TB but confirmed other condition Cured Start re-treatment (Category II)
AFB: Acid-fast bacilli; OI: Opportunistic infection
Fig. 27.4 Algorithm for the follow-up of a smear-negative pulmonary TB
patient.5
Any HIV-infected person without TB (sputum smear-negative/ chest radiograph negative), jaundice or known liver problems, or heavy alcohol use and willing to take 6 months of anti-TB prophylaxis is eligible for starting the isoniazid preventive treatment.
ALGORITHMS FOR THE MANAGEMENT OF TUBERCULOSIS IN HIV-INFECTED PATIENTS UNDER CARE In the context of increasing availability of antiretroviral therapy (ART) in low-resource settings, a number of practical algorithms for the comanagement of TB and HIV are presented in Tables 27.1–27.6. These describe the different scenarios and options for co-treatment when the people living with HIV/AIDS (PLWHA) and developing active TB are already receiving ART or are not yet on ART. Table 27.1 describes the steps to be followed to reassess a PLWHA already on ART, who develops active TB disease. If an episode of TB occurs during the first 6 months following the initiation of ART, this should not be considered a treatment failure event and the ART regimen should be adjusted for co-administration with a rifampicin-containing regimen. If an episode of TB develops more than 6 months after the initiation of ART and data on the CD4 cell count and viral load are
Patient with enlarged lymph nodes
Lymph nodes are hard and fixed to underlying tissue Physician to rule out inflammatory disease or malignancies
HIV-infected(a) patient with cough for 2 3 weeks and no danger signs(b) Sputum smear microscopy for AFB
Lymph nodes are mobile, firm or soft and /or fluctuant
Extra-inguinal site Medical history for symptoms and examination for clinical signs of TB
FNA cytology and /or excision biopsy services available
1 or more smears AFB-positive
2 smears AFB-negative
TB treatment and CPT(c) HIV assessment(d)
Clinical assessment and CXR Sputum culture
TB likely or culture-positive
TB unlikely
Inguinal site only Physician to rule out inflammatory disease in legs, STI or inguinal hernia
Treat for PCP HIV assessment
FNA cytology and /or excision biopsy services not available
PCP(e) signs
HIV assessment and CPT Treat for bacterial infection(f )
No or partial response FNA for examination & AFB, sputum AFB 3¥, CXR and offer HIV test
Sputum AFB 3¥, CXR and offer HIV test
No signs of PCP
Complete treatment
Reassess for TB
Response
(a)
No lymph node tuberculosis
Lymph node tuberculosis confirmed
Antibiotics and review
Full TB treatment
Lymph node tuberculosis inconclusive
Lymph node tuberculosis likely or AFB-positive or CXR changes
Broad-spectrum antibiotics or review after 4 8 weeks
Full TB treatment No improvement
No improvement
Improvement
Discharge
In the absence of HIV testing, classifying a patient as HIV-infected depends on clinical assessment in line with national and/or local policy. (b) The danger signs include any one of: respiratory rate >30/minute, fever >39°C, pulse rate >120/min and unable to walk unaided. (c) Co-trimoxazole Preventive Therapy. (d) Assessment includes HIV clinical staging, determination of CD4 count if available and referral for HIV care. (e) Pneumocystis jiroveci pneumonia, Signs include: 1. chest radiograph: bilateral interstitial infiltrate. 2. exertional dyspnoea (onset <3 months). 3. hypoxia. (f) Antibiotics (except fluoroquinolones) to cover both typical and atypical bacteria should be considered.
Fig. 27.6 Algorithm for the diagnosis of TB in an ambulatory HIV-infected patient.
Refer to specialist AFB: Acid-fast bacilli; STI: Sexually transmitted infection; FNA: Fine-needle aspirate; CXR: Chest radiography
HIV-infected(a) patient with cough for 2 - 3 weeks and danger signs(b)
Fig. 27.5 Algorithm for the diagnosis of lymph node TB.13
Referral to higher level facility
Immediate referral not possible
Parenteral antobiotic treatment(c) Sputum for AFB and culture Chest radiograph
Parenteral antibiotic treatment(c) Sputum for AFB and culture Consider treatment for PCP(d)
available, the decision about whether the TB diagnosis represents ART failure is based on the CD4 cell count and, if available, the viral load. If a CD4 cell count is not available the decision on whether the TB diagnosis constitutes ART failure depends on whether the TB is pulmonary or extrapulmonary and whether there are other non-TB WHO stage 3 or 4 HIV disease events. However, in general the development of an episode of pulmonary TB after 6 months of ART, without other clinical and immunological evidence of disease progression, should not be regarded as representing ART failure. Extrapulmonary TB should be considered as indicating ART failure, although simple lymph node TB or uncomplicated pleural disease may be less significant than disseminated TB. If there is a good response to TB therapy the decision to switch to a second-line regimen can be delayed until short-course TB therapy has been completed. Table 27.2 describes the specific therapeutic options if the PLWHA develop TB within 6 months of starting ART. If the patient develops TB after 6 months of starting ART and there is evidence of clinical/immunological failure, the possibility of ART failure must be considered and the ART regimen should be switched to second-line drugs (two nucleoside reverse transcriptase inhibitors + protease inhibitors as lopinavir–ritonavir or saquinavir– ritonavir-based regimen). Whenever the HIV-infected patient develops active TB but is not yet on ART, it is important to choose carefully the moment for concomitant ART/TB treatment.
1 or 2 smears AFB-positive
2 smears AFB-negative
TB unlikely
TB likely or culture positive
Assess for other HIVrelated disease
Start TB treatment & CPT(e) Complete antibiotics HIV and tuberculosis care(f)
Does not improve in 3 - 5 days
Improved after 3 - 5 days
TB unlikely
TB likely
Reassess for TB
Complete antibiotics
(a)
In the absence of HIV testing, classifying a patient as HIV-infected depends on clinical assessment in line with national and/or local policy. The danger signs include any one of: respiratory rate >30/minute, fever >39⬚C, pulse rate >120/min and unable to walk unaided. (c) Antibiotics (except fluoroquinolones) to cover both typical and atypical bacteria should be considered. (d) Pneumocystis jiroveci pneumonia. (e) Co-trimoxazole Preventive Therapy. (f) Assessment includes HIV clinical staging, determination of CD4 count if available and referral for HIV care. (b)
Fig. 27.7 Algorithm for the diagnosis of TB in a seriously ill HIV-infected patient.
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Table 27.1 HIV-infected patient on ART suspected to have developed active tuberculosis Signs/symptoms
Step A
Step B
Unremitting cough > 2 weeks and/or Persistent fever Unexplained weight loss Severe undernutrition Suspicious nodes Night sweats
Fill out laboratory sputum request form and send to laboratory for morning/spot sputum examination Or Refer to higher facility level, if not producing sputum or if symptoms and signs suggest extrapulmonary TB
If one sputum specimen is AFB positive, treat as smearpositive TB and If on first-line ART < 6 months or > 6 months but without clinical and immunological evidence of disease progressiona: Continue the same ART regimenb Clinical monitoring and laboratory monitoring If all specimens are negative, do a CXR If it is suggestive for TB treat as smear-negative pulmonary TB, otherwise treat as other disease If CXR not suspect, treat with non-specific broad spectrum antibiotics, review after 2–4 weeks, then: If unchanged or worse, repeat 3 sputum smears If all the specimens are negative, repeat CXR If 1 specimen is positive, treat as smear-positive pulmonary TB If improved, discharge If patient develops lymph node TB or uncomplicated pleural TB, treat as extrapulmonary TB and If already on first-line ART < 6 months or > 6 months but without clinical and immunological evidence of disease progressiona Continue the same ART regimenb Clinical monitoring and laboratory monitoring If patient develops extrapulmonary TB other than lymph node or pleural: Consider treatment failure after ruling out other causes (e.g. nonadherence) Switch to second-line ART regimen
AFB, acid-fast bacilli; CXR, chest radiograph; ART, antiretroviral therapy. If ART > 6 months with clinical (e.g. other non-TB stage 3 or 4 events) and immunological evidence of disease progression, regardless of the type of TB (pulmonary or extrapulmonary), it may represent ART failure and it requires switching to a second-line ARV regimen (refer to Table 27.2). Non-adherence must be excluded. b If already second-line ART, refer to Table 27.2. a
Table 27.2 ART recommendations for patients who develop tuberculosis within 6 months of starting ART First-line or second-line ART
ART regimen at the time TB occurs
Options
First-line ART
2 NRTIs + EFV 2 NRTIs + NVP
Alternative first-line ART Second-line ART
Continue with 2 NRTIs + EFV Substitute NVP to EFV or Substitute to triple NRTI or Continue 2 NRTIs +NVP but do liver function tests monthly Continue triple NRTI
Triple NRTI
2 NRTIs + boosted PI
Substitute to or continue (if already taken) LPV-r or SQV-r containing regimen-adjusting dose of RTVa
NRTI, nucleoside reverse transcriptase inhibitor; EFV, efavirenz; NVP, nevirapine; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RTV, ritonavir; LPV-r, lopinavir–ritonavir; SQV-r, saquinavir–ritonavir; ART, antiretroviral therapy. a In a setting where boosted PIs are not available and patients are on unboosted PIs, switch PI to an NNRTI (EFV).
320
Co-treatment raises adherence issues emanating from an increased pill burden and could produce immune reconstitution inflammatory syndrome (IRIS, also referred to as paradoxical reactions). In patients with HIV-related TB the priority is to treat the TB and ideally ARV treatment should be postponed. However, severely immunosuppressed patients with HIV-related TB can have ART and TB treatment at the same time if managed carefully. People living with HIV/AIDS already diagnosed with TB and on TB treatment should be assessed about the ART eligibility on every visit, and the proper timing for starting the ART has to be decided (Tables 27.3 and 27.4). In general treatment can be deferred at least until the initial phase is completed if the patient is clinically stable; in contrast, ART is recommended to be started as soon as possible if the TB patient has extrapulmonary TB, is clinically unstable, or is immunologically seriously compromised (CD4 count < 200 cells/mm3). Table 27.5 summarizes common ART regimens to be used in TB–HIV coinfected patients; the listed regimens must be used according to the different scenarios described earlier.12 In pregnant women living with HIV and who have TB, the first priority is to treat the TB (Table 27.6). If a pregnant woman receiving ART develops TB, such therapy should be continued, although drug–drug interactions may necessitate the use of other ARV drugs. If a woman is in the second or third trimester of
CHAPTER
Management algorithms for tuberculosis where there are few or no diagnostic facilities
27
Table 27.3 Evaluation of TB/HIV coinfected adult patient not on ART and CD4 not available
Table 27.6 Choose the appropriate TB-ART co-treatment regimen for pregnant women
Patient clinical status
How to manage
Options
Comments
Smear-positive pulmonary TB only (no other signs of clinical WHO stage 3 or 4 HIV disease) and patient is gaining weight on treatment Smear-negative pulmonary TB only (no other signs of clinical WHO stage 3 or 4 HIV disease) and patient is gaining weight on treatment Any pulmonary TB and patient has or develops signs of clinical WHO stage 4 disease or thrush, pyomyositis, recurrent pneumonia, persistent diarrhoea, new prolonged fever, or losing weight on treatment or if no clinical improvement Extrapulmonary TB (only isolated pleural or lymph node TB can be considered as uncomplicated TB, and ART can be deferred until after the intensive phase).
Defer ART until TB treatment is completed Start ART after the intensive phase of TB treatment
Defer ART until the end of first trimester Defer ART until the start of the continuation phase of TB treatment if isoniazid and ethambutol is used Use triple NRTI regimen Use NVP-based regimen
EFV can be used in the second and third trimester Many countries use isoniazid and ethambutol in the continuation phase as the standard first-line TB treatment regimen AZT + 3TC + ABC May be the only option in resource-poor settings
Start ART as soon as TB treatment is tolerated (2–8 weeks) Start ART as soon as TB treatment is tolerated (2–8 weeks)
See Table 27.5 for definitions of abbreviations.
Client or patient for HIV counselling and testing Pre-testing counselling including description of services available Screening for TB disease Psychosocial support STI syndromic evaluation Condom provision ART CPT and IPT
Table 27.4 Evaluation of TB/HIV coinfected adult patient not on ART and CD4 available
At CT room, TB clinic, ward or OPD : HIV testing
CD4 cell count 3 (cells/mm )
ART Timing of ART in relation to recommendations the start date of TB treatment
History of cough of 32 weeks duration
< 200 200–350 > 350
Recommend ART Recommend ART Defer ART
Between 2 and 8 weeks After 8 weeks intensive phase Re-evaluate patient at 8 weeks and the end of TB treatment
Table 27.5 Recommended ART regimens in TB/HIV coinfected patients receiving rifampicin in a antituberculosis regimen First line
Alternative first line Second line
TDF + 3TC (or FTC) + EFV or AZT + 3TC (or FTC) + EFV or d4T + 3TC (or FTC) + EFV AZT + 3TC + ABC or AZT + 3TC + TDF LPV-r or SQV-r-based regimen
TDF, tenofovir; 3TC, lamivudine; FTC, emtricitabine; d4T, stavudine; AZT, zidovudine; EFV, efavirenz; ABC, abacavir; LPV, lopinavir; SQV, saquinavir. Adapted from WHO.13 a The table is based on current practice in 2006. However, new antiretroviral drugs may be introduced and commonly used regimens may be adapted accordingly.
NO
HIV-negative
HIV-negative
HIV-positive
Preventive counselling and condom provision
CT room : Post-test counselling
CT room : Preventive counselling and condom provision
AFB lab: Screen for active TB according to NTP guidelines, treat STIs
Screen for active TB according to NTP guidelines and refer to CT room to evaluate the test results
General OPD: treatment of any STIs
YES
No TB
TB yes
Discharge
TB clinic: TB treatment according to NTP guidelines
No TB
Co-trimoxazole preventive therapy for HIV positive TB patients. Treat any STIs. ART to commence after TB treatment intensive phase or after 2 3 weeks if patient is criticalyl ill DOTS care and support for other OIs
Investigate for other OIs and treat STIs OI no
OI yes
CT room : Offer TB preventive therapy
Care and support
HIV-care clinic : ART and CPT if CD4 is <200 Becomes sick
pregnancy, an EFV-based ART regimen can be considered. Changing from an EFV-based to an NVP-based ART regimen could be considered once the TB treatment is completed. NVPbased regimens can be started during the continuation phase of TB treatment if these do not include rifampicin. An alternative for women with TB is zidovudine + lamivudine + abacavir. Figure 27.8 presents an algorithm for TB/HIV collaborative activities. Box 27.1 lists the clinical stages of HIV in adults as defined by the WHO.
Home-based care and psychosocial support
Remains healthy Monthly control visit
The services for the TB-HIV co-infected patient provided by the TB-clinic can as well be carried out by the TB-HIV clinic or HIV-care clinic (where one is operational).
Fig. 27.8 Generic algorithm for TB/HIV collaborative service. ART, antiretroviral therapy; CPT, cotrimoxazole preventive therapy; CT, counseling and testing; DOTS, directly observed therapy, short course; IPT, isoniazid preventive therapy; OI, opportunistic infection; OPD, outpatient department; STI, sexually transmitted infection.
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14
Box 27.1 WHO HIV clinical staging (adults)
Stage I Asymptomatic. Persistent generalized lymphadenopathy. Performance scale: asymptomatic; normal activity. Stage II Weight loss < 10% of body weight. Minor mucocutaneous manifestation (seborrhoeic dermatitis, prurigo, fungal nail infection, recurrent oral ulceration, angular chelitis). Herpes zoster within the past 5 years. Recurrent upper respiratory tract infections. Performance scale: symptomatic; normal activity. Stage III Weight loss > 10% body weight. Unexplained chronic diarrhoea > 1 month. Unexplained prolonged fever (intermittent or constant). Oral candidiasis. Oral hairy leucoplakia. Pulmonary TB within the past year. Severe bacterial infection (pneumonia, pyomyositis).
REFERENCES 6. 1. International Standards for Tuberculosis Care (ISTC) 2006. The Hague: Tuberculosis Coalition for Technical Assistance, 2006. 2. Laserson KF, Yen NTN, Thornton CG, et al. Improved sensitivity of sputum smear microscopy after processing specimens with C18-carboxypropylbetaine to detect acid-fast bacilli: a study of United States-bound immigrants from Vietnam. J Clin Microbiol 2005;43:3460–3462. 3. Wilson D, Nachega J, Morroni C, et al. Diagnosing smear-negative tuberculosis using case definitions and treatment response in HIV-infected adults. Int J Tuberc Lung Dis 2006;10:31–38. 4. Day JH, Charalambous S, Fielding KL, et al. Screening for tuberculosis prior to isoniazid preventive therapy among HIV-infected gold miners in South Africa. Int J Tuberc Lung Dis 2006;10:523–529. 5. Adapted from Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. WHO/CDS/TB/ 2003.313, Geneva: World Health Organization,
322
7.
8.
9.
10.
Performance scale: bed-ridden < 50% of the day during the past month. Stage IV Wasting syndrome. Pneumocystis jiroveci pneumonia. Toxoplasmosis of the brain. Cryptosporidiosis with diarrhoea > 1 month. Cryptococcus extrapulmonary. Cytomegalovirus disease of any organs other than liver, spleen, and lymph nodes. Herpes simplex virus infection, mucocutaneous for > 1 month or visceral any duration. Candida of the oesophagus, trachea, bronchi or lungs. Atypical mycobacteriosis, disseminated. Extrapulmonary TB. Kaposi’s sarcoma. HIV encephalopathy. Performance scale: bed-ridden > 50% of the day during last month.
2003; and modified for settings where culture (+ susceptibility testing) and second-line TB drugs are not available. Manual 2005. National TB and Leprosy Control Programme, Ministry of Health, Ethiopia. Iwnetu R, van den Hombergh J, Aseffa A. Fineneedle aspiration of enlarged lymph nodes increases the specificity of a clinical algorithm to detect lymph node tuberculosis in Ethiopia. Int J Tuberc Lung Dis 2006;10 S–80. Wilkinson D, Newman W, Reid A, et al. Trial of antibiotic algorithm for the diagnosis of tuberculosis in a district hospital in a developing country with high HIV prevalence. Int J Tuberc Lung Dis 2000;4(6): 513–518. Fourie B, Weyer K. Trials of anti-tuberculosis treatment as a diagnostic tool in smear-negative tuberculosis are of questionable benefit. Int J Tuberc Lung Dis 2000;4(11):997–1001. Mello FC, Bastos LG, Soares SL, et al. Predicting smear negative pulmonary tuberculosis with classification trees and logistic regression: a crosssectional study. BMC Public Health 2006;6:43.
11. World Health Organization. Improving the Diagnosis and Treatment of Smear-Negative Pulmonary and Extrapulmonary Tuberculosis among Adults and Adolescents. Recommendations for HIV-Prevalent and Resource-Constrained Settings. Geneva: World Health Organization, 2006. 12. Getahun H, Harrington M, O’Brien R, et al. Diagnosis of smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resourceconstrained settings: informing urgent policy changes. Lancet 2007;369:2042–2049. 13. World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in ResourceLimited Settings: Towards Universal Access. Recommendations for a Public Health Approach, rev edn. Geneva: World Health Organization, 2006. 14. World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults and Children. Strengthening Health Services to Fight HIV/AIDS. Geneva: World Health Organization, 2006.
CHAPTER
28
Management algorithms for paediatric tuberculosis Ben J Marais, H Simon Schaaf, and Peter R Donald
BACKGROUND Tuberculosis control programmes previously placed an almost exclusive emphasis on the diagnosis and management of adults with sputum smear-positive TB, as they are the most infectious and therefore responsible for sustaining the TB epidemic. However, it has been recognized that this ‘exclusive approach’ reduces treatment access for people with sputum smear-negative disease, especially in settings where TB and human immunodeficiency (HIV) virus coinfection is common. HIV-infected individuals are more likely to develop sputum smear-negative pulmonary TB. These patients experience considerable TB-related morbidity and mortality, despite posing less of an infection risk to the community than sputum smear-positive patients. Because of the underlying moral imperative, TB control programmes now recognize the need to provide sputum smear-negative patients with a reliable diagnosis and access to effective treatment. Childhood TB benefited indirectly from this broadened perspective that recognizes the need to treat individuals with sputum-smear negative TB. Childhood TB has long been neglected as children usually develop sputum smear-negative disease and rarely contribute to disease transmission within the community;1 this is not true for adolescent children who frequently develop adulttype cavitary disease and pose a huge transmission risk.2 Although children contribute little to the maintenance of the TB epidemic, they do contribute a significant proportion of the global TB caseload and experience considerable TB-related morbidity and mortality, particularly in TB-endemic areas.3,4 Previously few children in TB-endemic areas had access to reliable diagnostics and/or anti-TB treatment, but this is changing. Recently the World Health Organization (WHO) published guidelines for national TB programmes on the management of TB in children,5 and the Global Drug Facility made child-friendly anti-TB drugs available to deserving countries for the first time. Since the moral obligation to treat children with TB is now widely acknowledged and child-friendly treatment formulations are more readily available, the tenacious problem of establishing a definitive TB diagnosis and the absence of standard diagnostic algorithms applicable in resource-limited settings has become more pronounced. This chapter aims to develop a clear and consistent rationale and to suggest practical diagnostic approaches that can be stratified according to the resources available in a particular setting.
THE CONCEPT OF RISK Robert Koch (1843–1910) described Mycobacterium tuberculosis as the organism that causes TB, but it was soon recognized that infection with this organism, as indicated by a positive tuberculin skin test (TST), is not at all uncommon.4 It remains an intriguing and largely unexplained observation that only a small minority of people infected with M. tuberculosis ever progress to active TB. It also explains why the diagnostic challenge in TB-endemic countries is more pronounced. Tuberculosis infection is exceedingly common in these areas, even among children, which increases the need to differentiate latent infection from active disease. The natural history of disease documented in the pre-chemotherapy literature identifies the most important variables that determine a child’s risk to progress through the main disease transitions:6,7 1. exposure to infection; and 2. infection to active disease. It is important to consider these risk variables as they provide the rationale for the suggested management algorithms and public health intervention strategies. (See Chapter 14 for a more detailed description of the natural history of disease in children.)
EXPOSURE TO INFECTION Tuberculosis is spread via tiny aerosol droplets predominantly produced by adults with sputum smear-positive TB, but children with cavitary disease and adults with sputum smear-negative pulmonary disease also contribute to transmission. The risk of infection after TB exposure depends on the infectiousness of the index case, as well as the proximity and duration of contact with the index case.8 In TB-endemic areas the majority of transmission occurs outside the household,9,10 which reduces the sensitivity of documented household exposure as a diagnostic criterion. However, this observation does not reduce the importance of household exposure when it is reported; it remains particularly relevant in young and vulnerable children where the risk of exposure outside the household is reduced,9 and in non-endemic areas household exposure remains the most likely source of infection. Documented household exposure also presents an important opportunity for health education and the provision of preventive chemotherapy when indicated.
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Infection to disease Table 28.1 summarizes the age-specific risk to progress to active disease following primary infection with M. tuberculosis in HIVuninfected children, as documented in the prechemotherapy literature.6 It demonstrates that the highest risk to develop active TB following infection occurs in very young (immune immature) children. From more recent observations it is clear that immunocompromised (e.g. HIV-infected) children of any age experience an increased risk, similar to the risk of immune immature children less than 2–3 years of age. Because the risk of disease is mainly determined by the age and immune status of the child, these variables are of primary importance for identifying priority groups for preventive therapy intervention. Following documented exposure and/or infection, careful risk assessment should guide clinical management. In any particular setting, the optimal risk/benefit/cost trade-off will depend on the level of epidemic control achieved, as this determines the prevalence of TB infection within the community, and is inversely correlated with resources available for diagnosis and treatment. Apart from the importance of accurate risk assessment to guide the management following TB exposure and/or infection, the diagnosis is further complicated by the diversity of disease manifestations seen in children.11,12 Table 28.2 reflects the disease diversity recorded in a prospective community-based study, conducted in a highly endemic setting.13 This indicates that in TB-endemic areas children frequently present with advanced disease and that extrathoracic disease manifestations are not uncommon. Figure 28.1 reflects the relative frequency with which specific disease entities occur in different age groups, demonstrating the strong influence of age and immune maturity.12 Immunocompromised (e.g. HIVinfected) children are prone to poor disease containment just like very young (immune immature) children, and they share a similar disease profile.13 Because both the risk to develop disease and the disease profile is influenced by the HIV status of the child, Table 28.1 Age-specific risk to progress to disease following primary infection with M. tuberculosis in a immune competent children Age at primary infection (years)
Risk to progress to disease
<1
No disease 50% Intrathoracic disease 30–40% Disseminated (miliary) disease No disease 75–80% Intrathoracic disease 10–20% Disseminated (miliary) disease No disease 95% Intrathoracic disease 5% Disseminated (miliary) disease No disease 98% Intrathoracic disease 2% Disseminated (miliary) disease No disease 80–90% Intrathoracic disease 10–20% Disseminated (miliary) disease
1–2
2–5
5–10
> 10
TBM, tuberculous meningitis. a Adapted from Marais et al.6
324
Table 28.2 Disease spectrum documented in a prospective community-based survey of all children < 13 years of age, a treated for TB in a highly endemic area TB manifestation
Total (%) n = 439
Not TB Intrathoracic TB Ghon focus Uncomplicated (with/without hilar adenopathy) Complicated Lymph node disease Uncomplicated Complicated Compression Consolidation Pleurisy Pericarditis Disseminated (miliary) disease Adult-type disease Extrathoracic TB Peripheral lymphadenitis Cervical Other Central nervous system TB Meningitis Tuberculoma Abdominal TB Osteoarticular TB Vertebral spondylitis Other Skin [Intraþextrathoracic TB]
85 (19.4) 307 (69.9) 16/307 (5.2) 3/307 (1.0) 147/307 (47.9) 25/307 (8.1) 62/307 (20.6) 24/307 (7.8) 1/307 (0.3) 15/307 (4.9) 14/307 (4.6) 72 (16.4) 35/72 (48.6) 1/72 (1.4) 14/72 (19.4) 2/72 (2.8) 1/72 (1.4) 4/72 (5.6) 7/72 (9.7) 8/72 (11.1) 25 (5.7)
Not TB, chest radiograph not suggestive of TB (confirmed by two independent child TB experts), no bacteriological or histological proof and no extrathoracic TB recorded. [Intraþextrathoracic TB], children with intra- and extrathoracic TB were included in both groups and therefore this number should be deducted to add up to a total of 439 or 100%. a Adapted from Marais et al.13
determination of the child’s HIV status is essential for facilitating optimal management, especially in settings where HIV infection is highly prevalent.
DIAGNOSIS or TBM 10–20%
or TBM 2–5%
or TBM 0.5%
or TBM < 0.5% or TBM < 0.5%
SCREENING FOR DISEASE The WHO guidelines advise that all children < 5 years of age in close contact with a sputum smear-positive index case should be actively traced, screened for TB, and provided preventive chemotherapy once active TB has been excluded.5 Performing a TST and chest radiograph (CXR) are no longer regarded as prerequisite screening tests in settings where these tests are not readily available (Fig. 28.2), as the non-availability of these tests should not serve as a barrier to the provision of preventive therapy to high-risk asymptomatic children. In resource-limited settings, symptombased screening may have considerable value in improving access to preventive therapy.14 The guidelines acknowledge the fact that any close contact with a sputum smear-positive source case is important, even if it occurs
CHAPTER
Management algorithms for paediatric tuberculosis
Frequency of disease manifestation
outside the household, and that HIV-infected (immunocompromised) children should be regarded as high-risk contacts, irrespective of their age. Some of the issues that the guidelines fail to address include the following:
(1)
0 (1) (2) (3) (4)
1
(2)
2
(3)
4
6
(4)
8 10 Age in years
12
14
16
Complicated Ghon focus and/or disseminated disease Uncomplicated Ghon focus and/or lymph node disease. Complicated lymph node disease Pleural effusion Adult-type disease
Fig. 28.1 Age-related manifestations of intrathoracic TB in children, documented during the prechemotherapy era.
Child in close contact with source case of sputum smear-positive TB <5 years Well 6H #
> 5 years -
Symptomatic
$
Symptomatic
Evaluate for TB
If becomes symptomatic #
28
Well$ 6H #
If becomes symptomatic
Isoniazid 5/mg/kg daily for 6 months Unless the child is HIV-infected (in which case isoniazid 5/mg/kg daily for 6 months is indicated)
Fig. 28.2 Suggested approach (WHO 2006) to contact management when chest radiograph and tuberculin skin testing are not readily available.
1. the frequency with which children in settings where TB/HIV coinfection is common among adults are exposed to adults with sputum smear-negative TB, and the transmission risk that this exposure poses, particularly within HIV-affected households; and 2. in most TB-endemic areas the reluctance and/or inability of health systems, already overburdened with the provision of curative treatment, to take on board as well the screening of child contacts and the provision of preventive therapy to large numbers of children. In these resource-limited settings, it is of particular importance to focus preventive therapy interventions on those children who are at highest risk of progressing to active disease following documented TB exposure and/or infection; these are children < 3 years of age and immunocompromised children of all ages. A simple screening approach that takes these considerations into account is presented in Fig. 28.3. The rationale is completely different in low-burden countries where TB eradication is an achievable goal and the risk of reinfection is low; preventive chemotherapy may be provided to everyone with documented TB infection in an attempt to eradicate the pool of latent TB infection from which future reactivation disease may result. In settings where the TST is used for screening purposes it is important to remember that TST conversion may be delayed for up to 3 months. In fact, the contribution made by the TST in routine TB contact screening is limited, as infection can only be reliably excluded in non-anergic children 3 months after exposure has occurred. Therefore, current practice is that all high-risk children should receive preventive therapy irrespective of the TST result. Novel T-cell assays are regarded as more sensitive and specific measures of M. tuberculosis infection than the TST, but they are bound by similar limitations and the advantages of their use for routine screening purposes have not been well established.
Documented exposure Any close contact with a sputum smear-positive index case Also household contact with a sputum smear-negative case with pulmonary TB Symptom-based screening Any current symptom suspicious of possible TB: cough, fever, lethary, fatigue, weight loss or palpable neck mass Asymptomatic High risk (< 5 years or immune compromised) Provide preventive chemotherapy
Symptomatic
Low risk (>-3 years and immune competent) Observe main risk period 1st year following exposure/infection
All symptomatic children (Irrespective of age or immune status) Perform chest radiography if available See algorithm for symptomatic presentation (Figure 28.4)
Fig. 28.3 Proposed algorithm to screen children in resource-limited settings with documented exposure to an infectious TB index case.
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DIAGNOSING ACTIVE DISEASE Establishing a definitive diagnosis of childhood TB remains a challenge. Sputum smear microscopy is positive in less than 10–15% of children with intrathoracic TB, and culture yields are generally low (30–40%),15,16 although they may be considerably higher in children with advanced disease.17 In low-burden countries the triad of (1) known contact with an infectious source case, (2) a positive TST and (3) a suggestive CXR is frequently used to establish a diagnosis of childhood TB.18 This provides a reasonably accurate diagnosis in non-endemic settings where exposure to M. tuberculosis is rare and usually well documented. However, it has limited value in endemic areas where exposure to and/or infection with M. tuberculosis is common. Consequently, the diagnosis of TB in endemic areas depends predominantly on the subjective interpretation of the CXR.19 Despite its many limitations, the CXR remains a very helpful test and usually provides an accurate diagnosis in HIV-uninfected children with suspicious symptoms, if evaluated by an experienced clinician.
Bacteriology-based diagnosis A positive culture is regarded as the ‘gold standard test’ to establish a definitive diagnosis of TB in a symptomatic child. However, it is limited by the fact that organisms may be isolated from non-diseased (asymptomatic) children shortly after primary infection, and, in addition, traditional culture methods are limited by suboptimal sensitivity, slow turnaround times, excessive cost (automated liquid broth systems), and the difficulty of sample collection. In contrast adolescent children frequently develop sputum smearpositive disease that is easy to diagnose using traditional methods.2 Novel culture-based approaches include TK Medium; a simple colorimetric system with reduced turnaround times, but its accuracy and robustness in field conditions have not been reported.20 The microscopic observation drug susceptibility (MODS) assay uses an inverted light microscope to rapidly detect mycobacterial growth in liquid growth media. It is an inexpensive method that has demonstrated excellent performance under field conditions (both in adults and in children),21,22 being more sensitive than standard liquid broth or solid culture media systems. However, the test is not widely available at present and some biosafety concerns have been raised, although this is currently being addressed. The phage amplification assay utilizes bacteriophages to infect live M. tuberculosis and is commercially available as FASTPlaqueTB; a variant (FASTPlaque-TB Response) was designed for the rapid detection of rifampicin (RMP) resistance. The test has a turnaround time of only 2–3 days, but is less sensitive than traditional culture methods and no information exists on its utility in children.20 Polymerase chain reaction (PCR)-based tests amplify nucleic acid regions specific to the M. tuberculosis complex; these tests have shown highly variable results and limited utility in children to date.20 The detection of antigens offers another innovative organism-based approach and preliminary results from novelantigen-capture assays that detect lipoarabinomannan (LAM) in sputum and/or urine samples look promising.23 Table 28.3 summarizes the traditional and novel diagnostic approaches, their potential application, and the perceived problems and/or benefits of each. The various diagnostic tests are discussed in greater detail in Chapter 22. Sample collection Collecting an adequate sample presents a significant challenge, particularly in small children who cannot produce a good sputum specimen. In young children (< 7–8 years of age), the routine specimens collected are two or three fasting gastric aspirates. The
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collection of two or three fasting early morning gastric aspirate specimens are cumbersome and usually require hospitalization. The collection of a single hypertonic saline-induced sputum specimen seems to provide the same yield as three gastric aspirate specimens,23 but the value/risk of the technique has not been tested outside the hospital setting and sputum induction may pose a nosocomial transmission risk if adequate infection control measures are not in place.24 The string test is another non-invasive collection method that has been used with great success to retrieve M. tuberculosis from sputum smear-negative HIV-infected adults, demonstrating superior sensitivity to induced sputum.25 The test is also well tolerated by children as young as 4 years of age.26 Fine needle aspiration (FNA) is a robust and simple technique that provides a rapid and definitive diagnosis in children with superficial TB lymphadenitis; the use of a small 23-gauge needle is well-tolerated and associated with minimal sideeffects.27 Table 28.4 provides a summary of various specimen collection methods and the perceived problems and/or benefits of each.
Immune-based diagnosis Although commercial kits for antibody detection are marketed widely in the developing world, no serological assay is currently accurate enough to replace microscopy and culture.20 Immune-based diagnosis is complicated by the wide clinical disease spectrum (ranging from subclinical latent infection to various manifestations of active disease) and other factors that influence the immune response such as Bacillus Calmette Gue´rin (BCG) vaccination, exposure to environmental mycobacteria, and HIV coinfection; all of which are particularly prevalent in TB-endemic areas.20 Novel T-cell assays measure interferongamma (IFN-g) released after stimulation by M. tuberculosis-specific antigens. Two assays are currently available as commercial kits: the T-SPOT.TB and the QuantiFERON-TB Gold assay. In general these tests are regarded as more specific and potentially more sensitive than the traditional TST.20 However, like the TST, these novel T-cell assays fail to differentiate M. tuberculosis infection from active disease and identifying the correct application of these novel T-cell-based assays in TB-endemic areas remains a priority for future research. Symptom-based diagnosis Intrathoracic TB Because of the diagnostic limitations mentioned and the difficulty of obtaining a CXR in TB-endemic areas with limited resources, a variety of clinical scoring systems have been developed to diagnose active TB. A critical review of these scoring systems concluded that they are severely limited by the absence of standard symptom definitions and inadequate validation.28 Accurate symptom definition is important to differentiate TB from other common conditions, as poorly defined symptoms (such as a cough of > 3 weeks’ duration) have poor discriminatory power.29 However, the diagnostic use of well-defined symptoms with a persistent, non-remitting character holds definite promise in low-risk children (immunocompetent children > 3 years) in whom TB is usually a slowly progressive disease.30,31 The most helpful symptoms include: 1. persistent, non-remittent coughing or wheezing; 2. documented failure to thrive despite food supplementation (if food security is a concern); and 3. fatigue or reduced playfulness. Clinical follow-up is also a valuable diagnostic tool, particularly in children who are at low risk of rapid disease progression.31
Extrathoracic TB The most common extrathoracic manifestation of TB in children is cervical lymphadenitis (Table 28.2). A simple clinical algorithm that
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28
Management algorithms for paediatric tuberculosis
Table 28.3 Traditional and novel diagnostic approaches; potential application and perceived problems and/or benefits Diagnostic approaches
a
Application
Problems/benefits
Validation
TB culture using solid or liquid broth media Chest radiography
Bacteriological confirmation of active TB Diagnosis of probable active TB
Slow turnaround time; too expensive for most poor countries; poor sensitivity in children Rarely available in endemic areas with limited resources; accurate disease classification important
Accepted gold standard
Symptom-based approaches Tuberculin skin test (TST)
Diagnosis of probable active TB Diagnosis of M. tuberculosis infection
Poor symptom definition Rarely available in endemic areas with limited resources; does not differentiate latent TB infection (LTBI) from active disease; not sensitive in immunocompromised children; simple to use and less expensive than blood-based tests
Various cut-offs advised in different settings
Bacteriological confirmation of active TB Diagnosis of probable active TB, and detection of rifampicin resistance Diagnosis of probable active TB, and detection of drug resistance Diagnosis of probable active TB, and detection of rifampicin resistance
Simple and feasible, limited resources required; potential for contamination in field conditions Requires laboratory infrastructure; performs relatively poorly when used on clinical specimens
Not well validated in children
Simple and feasible, limited resources required
Not well validated in children
Traditional
Marked inter- and intraobserver variability; reliable in expert hands and in presence of suspicious symptoms Not well validated
Novel Bacteriology-based Colorimetric culture systems (e.g. TK-Medium) Phage-based tests (e.g. FASTPlaque-TB) Microscopic observation drug susceptibility assay PCR-based tests
Rarely available in endemic areas Sensitivity tends to be poor in paucibacillary TB Specificity a concern in endemic areas, where LTBI is common Requires adequate quality control systems
Not well validated in children
Extensively evaluated, but evidence not in favour of widespread use
Antigen-based LAM detection assay
Diagnosis of probable active TB
Simple, point of care testing; limited clinical data on accuracy
Not well validated
Diagnosis of probable active TB Diagnosis of LTBI
Simple, point of care testing, variable accuracy and difficulty in distinguishing LTBI from active TB Limited data in children, inability to differentiate LTBI from active TB; blood volume required (3–5 mL); expensive; may have particular relevance in high-risk children, where LTBI treatment is warranted
Not validated
Symptom-based screening
Screening child contacts of adult TB cases
Refined symptom-based diagnosis
Diagnosis of probable active TB
Limited resources required; should improve access to preventive chemotherapy for asymptomatic high-risk contacts in endemic areas Limited resources required; should improve access to chemotherapy in resource-limited settings; poor performance in HIV-infected children
Immune-based Antibody-based assays T-cell assays
Not well validated in children
Symptom-based Additional validation preferable
Additional validation preferable
Abbreviations: LAM, lipoarabinomannan; LTBI, latent TB infection. a Adapted from Marais and Pai. 20
identified children with a persistent (> 4 weeks) cervical mass of 2 2 cm, without a visible local cause or response to first-line antibiotics, showed excellent diagnostic accuracy in a TB-endemic area.27 However, this approach would be less accurate in non-endemic areas and in areas where alternative diagnoses, such as Burkitt’s lymphoma, occur more commonly.27 In non-endemic settings a positive TST is generally more specific for active TB than in TB-endemic areas where TB infection is common among the general population;
however, a positive TST may fail to differentiate TB lymphadenitis from disease caused by non-tuberculous mycobacteria (NTM). In fact, NTM is the most common cause of cervical lymphadenitis in nonendemic areas; in these settings and in the absence of known TB exposure, a positive TST is generally more indicative of disease caused by NTM than by M. tuberculosis.32 Establishing a definitive tissue and/or culture diagnosis is always preferable and this can be done in a minimally invasive fashion using FNA.27
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Table 28.4 Specimen collection methods, problems and/or benefits and potential clinical application
a
Specimen collection method
Problems/benefits
Potential clinical application
Sputum
Routine sample to be collected in children > 7 years of age (all children who can produce a good quality specimen) To be considered in the hospital setting on an in- or outpatient basis
Bronchoalveolar lavage
Not feasible in very young children; assistance and supervision may improve the quality of the specimen Increased yield compared with gastric aspirate; no age restriction; specialized technique, which requires nebulization and suction facilities; use outside hospital setting not studied; potential transmission risk Difficult and invasive procedure; not easily performed on an outpatient basis; requires prolonged fasting; sample collection advised on 3 consecutive days Less invasive than gastric aspirate; no fasting required; comparable yield to gastric aspirate Less invasive than gastric aspirate; tolerated well in children > 4 years; bacteriological yield and feasibility requires further investigation Extremely invasive
Urine/stool
Not invasive; excretion of M. tuberculosis well documented
Blood/bone marrow
Good sample sources to consider in the case of probable disseminated TB Fairly invasive; bacteriological yield low Minimally invasive using a fine 23-G needle; excellent bacteriological yield, minimal side-effects
Induced sputum
Gastric aspirate
Nasopharyngeal aspiration String test
Cerebrospinal fluid (CSF) Fine needle aspiration (FNA) a
Routine sample to be collected in hospitalized who cannot produce a good quality sputum specimen To be considered in primary healthcare clinics or on an outpatient basis Potential to become the routine sample collected in children who can swallow the capsule, but cannot produce a good quality sputum specimen Only for use in patients who are intubated or who require diagnostic bronchoscopy To be considered with novel sensitive bacteriological or antigen-based tests To be considered for the confirmation of probable disseminated TB in hospitalized patients To be considered if signs of tuberculous meningitis Procedure of choice in children with superficial lymphadenopathy
Adapted from Marais and Pai.24
Severe forms of TB (miliary disease and TBM) are not uncommon among very young and/or immunocompromised children in TBendemic areas,13 despite the limited protection provided by universal BCG vaccination.8,33 The initial signs of disease may be difficult to detect or differentiate from other common diseases, but persistent or intermittent unexplained fever (> 7 days) and/or lethargy are of great importance, as well as any sign indicative of central nervous system involvement (e.g. meningism or convulsions); especially in very young (< 3 years) children who are at greatest risk of developing disseminated (miliary) disease and/or TBM. History of contact with an adult index case in the preceding 3–6 months provides another important diagnostic clue, although its absence does not rule out TB. Tuberculosis can affect nearly every organ system, mostly as a result of disease progression at sites where the TB bacillus was deposited during the initial phase of occult haematogenous dissemination. In addition, newborn babies may acquire congenital TB if the mother experienced occult or overt disease dissemination during pregnancy. As the route of organism entry is via the placenta, the primary (Ghon) focus is usually located within the liver. It is expected that cases of congenital TB may rise in countries where TB/HIV coinfection rates among pregnant mothers are high. The diagnosis should be considered in an infant if the mother is diagnosed with TB and/or if the baby fails to thrive or has abdominal distension with hepatomegaly and/or ascites.
HIV infection HIV-related immune compromise is one of the main risk factors that increases the vulnerability of adults to develop active TB following infection, which explains why sub-Saharan Africa, the region worst affected by HIV, reports the highest TB incidence rates in the world.34 It is often forgotten that, unlike the adult
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epidemic where TB/HIV coinfection dominates in these areas, the majority of children with TB remain HIV-uninfected.18 However, the diagnostic challenge is most pronounced in HIVinfected children.35
HIV-infected children who live with HIV-infected adults are more likely to be exposed to an adult TB source case at home. HIV-infected adults often have sputum smear-negative pulmonary TB and although they may be regarded as less infectious they do pose a significant transmission risk (about 20–40% of the risk posed by a sputum smear-positive patient). In addition, adult patients with sputum smear-negative TB often experience prolonged diagnostic delay, which increases the transmission risk posed to children within the household; this risk is often not appreciated by healthcare workers. The TST has low sensitivity in HIV-infected children. Although the sensitivity is influenced by the degree of immune compromise present, it is positive in the minority of HIVinfected children with bacteriologically confirmed TB despite using a reduced induration size cut-off of 5 mm.36 Chronic pulmonary symptoms from other HIV-related conditions such as gastro-oesophageal reflux and bronchiectasis are not uncommon and failure to thrive is a typical feature of both TB and HIV, which greatly reduces the specificity of symptombased diagnostic approaches.31 Rapid disease progression may also occur, thereby reducing the sensitivity of diagnostic approaches that focus on persistent, non-remitting symptoms.31 CXR interpretation is complicated by HIV-related comorbidity such as bacterial pneumonia, lymphocytic interstitial pneumonitis (LIP), bronchiectasis, pulmonary Kaposi’s sarcoma, and the atypical presentation of TB in immunocompromised children.37
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Management algorithms for paediatric tuberculosis
Immune reconstitution inflammatory syndrome (IRIS) has emerged as an important complication to consider after the introduction of highly active antiretroviral therapy (HAART) in HIVinfected, immunocompromised patients.18,31 This temporary exacerbation of TB-associated symptoms and signs is mainly ascribed to the effects of improved immune function, although a ‘hypersensitivity’ reaction to antigens released by killed TB bacilli may also contribute. It does not indicate treatment failure and should subside spontaneously, although severe cases may require treatment with corticosteroids.31
Proposed diagnostic algorithm Figure 28.4 proposes a diagnostic algorithm that is sufficiently comprehensive to permit diagnosis of the vast majority of children who present with active TB to healthcare facilities, yet is simple enough to implement in everyday practice even in resource-limited settings. The diagnostic rationale applied is consistent, but the approach may be adapted according to the resources available in a particular setting. A simplified approach always represents a compromise, as not all the complicating factors and rare disease manifestations can be taken into consideration, but the approach suggested should enable fairly accurate diagnosis of the majority of children who may benefit from anti-TB therapy.
Fever, fatigue, sleepiness/lethargy, and/or recent weight loss Consider TBM Usually children <3 years Tests to consider: TST, T-cell assay CXR LP, air encephalogram CT scan with contrast Culture CSF/GA
In absence of further tests Persistent symptoms > 7 days and confirmed TB contact in past 3 6 months with/without neck stiffness Treat as TBM Monitor treatment response
#
TREATMENT The two principles of anti-TB treatment are: 1. to reduce the organism load as rapidly as possible; and 2. to ensure effective eradication of all persistent bacilli.18 This provides the rationale behind the intensive and continuation phases of current anti-TB treatment regimens. Rapid reduction of the organism load is important to reduce clinical symptoms, limit disease progression, terminate transmission, and reduce the risk of acquired drug resistance. Eradication of persistent (dormant or intermittently metabolizing) bacilli is essential to prevent future disease relapse.18 Treatment-related issues are discussed in greater detail in Chapter 61 and the management of drug-resistant disease in Chapter 52. A flow diagram has been developed (Fig. 28.5) to guide individual patient diagnosis, classification and management.18 It is based on answering five simple questions. 1. Is the child exposed to or infected with M. tuberculosis? 2. Does the child have active TB? 3. If the child is exposed or infected, but does not have active TB, is preventive chemotherapy indicated?
Present with suspicious symptoms Persistent cough, wheeze, chest pain, fever, fatigue, lethargy, weight loss or neck mass Perform a HIV screening test*
Not acutely ill, localized chest pain with associated dullness, fever Consider TB pleural effusion Usually children >5years
In absence of further tests Persistent symptoms > 7 days Treat as TB pleural effusion Monitor treatment response
Persistent neck mass palpable, >1 ¥ 1 cm Consider TB cervical adenitis
Persistent cough not responding to first line antibiotics, fatigue and/or recent weight loss Consider pulmonary TB All ages
Tests to consider: TST (usually very reactive) CXR (decubitus position) Fluid aspiration (cell count, chemistry) Culture pleural fluid / GA
28
Tests to consider: CXR (AP and lateral), Culture GA / induced sputum CT scan rarely indicated TST not very valuable
HIV-uninfected In absence of further tests Persistent cough, fatigue and recent weight loss OR Persistent, non remitting cough after >2 weeks of FU Treat as PTB Monitor treatment response
Tests to consider: TST, CXR FNA for cytology and /or culture
In absence of further tests Persistent neck mass >2¥ 2 cm Treat as TB adenitis Monitor treatment response
HIV-infected In absence of further tests Persistent cough, fatigue and recent weight loss WITH confirmed TB contact in the past and/or a positive TST (novel T-cell assays may offer improved value) Treat as PTB Monitor treatment response
Rare disease manifestations are not included in this algorithm; it aims to identify the vast majority of children with TB as accurately as possible, given limited resources
in a TB endemic setting.
*It is essential to know the HIV status of a child with symptoms suspicious of TB, especially in settings where TB/HIV co-infection is not uncommon (e.g. HIV prevalence >1-5%). Abbreviations used: TB tuberculosis GA gastric aspirate HIV human immunodeficiency virus CXR chest radiograph TBM tuberculous meningitis AP anterio-posterior TST tuberculin skin test FNA fine needle aspiration LP lumbar puncture PTB pulmonary TB/intra-thoracic TB, excluding TB pleural effusion CSF cerebro-spinal fluid
Fig. 28.4 Proposed algorithm to evaluate children who present with symptoms, suspicious of active TB#.
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(1) INFECTION? Recent exposure with a high likelihood of infection or immunologic proof of infection No
Yes
(2) DISEASE? Symptom-based screening and/or diagnosis and/or Radiological signs indicative of disease No
Yes (4) DISEASE GROUP?
(3) RISK OF PROGRESSION TO DISEASE? if infected and/or exposed <3 years of age and/or immunocompromised No Low
Sputum smear-negative disease Treatment 3 drugs
Yes risk#
Sputum smear-positive disease Treatment 4 drugs
Disseminated (miliary) disease Treatment 4 drugs*
High risk (5) COMPLICATING FACTORS TO CONSIDER?
#
In non-endemic areas where the risk of re-infection is low and where TB eradication is an achievable goal, it would be desirable to provide preventive treatment to all individuals with documented TB infection.
4. If the child has active TB, what is the appropriate treatment regimen? 5. Are there any special circumstances such as HIV infection, retreatment, or exposure to a drug-resistant source case to consider?
PREVENTIVE CHEMOTHERAPY Isonaizid (INH) monotherapy for 6–9 months is the best-studied prophylactic regimen, but poor adherence with unsupervised preventive treatment and the transmission of drug-resistant organisms remain a serious concern and alternative prophylactic regimens with improved adherence require consideration.18,38
Fig. 28.5 Flow diagram to guide the diagnosis and appropriate management of children with suspected pulmonary TB.
STANDARD TREATMENT The main variables that influence the success of chemotherapy, apart from primary drug resistance, are the bacterial load and the anatomical distribution of bacilli.13 This provides the rationale for the three disease categories used in Fig. 28.5: (1) sputum smearnegative disease, (2) sputum smear-positive (often cavitary) disease, and (3) disseminated (miliary) disease. Table 28.5 reflects the various TB disease categories identified and provides a summary of current treatment guidelines. Sputum smear-negative disease is usually paucibacillary and therefore the risk of acquired drug resistance is low. Drug penetration into the anatomical sites involved is good and the success of three drugs
Table 28.5 Treatment rationale and current treatment guidelines applicable to each of the childhood tuberculosis disease a groups identified TB disease group
Treatment rationale
ATS treatment b guideline
WHO treatment b guideline
Exposure/latent TB infection (LTBI) All children < 5 yrs of age (children < 3 yrs at highest risk) All HIV-infected children, irrespective of age (unless documented normal CD4 count) Active disease Sputum smear-negative TB
Preventive chemotherapy High risk of disease progression following exposure/infection Low organism load
9H
6H
2 HRZ/4HR
2 HRZ/4 HR
2 HRZE/4 HR
2 HRZE/4 HR
2 HRZE/7–10 HR
Miliary: 2 HRZE/4 HR TBM: 2 HRZS/4 HR
Sputum smear-positive TB Disseminated (miliary) TB And/or TBM
Curative treatment Low organism load Drug penetration good High organism load Drug penetration good High organism load CNS penetration variable
H, isoniazid; R, rifampin; Z, pyrazinamide; E, ethambutol; S, streptomycin; CNS, central nervous system; ATS, American Thoracic Society. Adapted from Marais et al.18 b Treatment forms part of the DOTS strategy and all curative treatment should be given as directly observed therapy.5,40 a
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(INH, RMP, PZA) during the 2-month intensive phase and two drugs (INH, RMP) during the 4-month continuation phase is well established.18 In the presence of extensive radiographic disease with/without cavitation, and/or suspicion of INH resistance, the use of ethambutol (EMB) in addition to the three drugs during the intensive phase should be contemplated. After completion of the intensive phase, successful organism eradication may be achieved with intermittent (2–3/week) therapy during the continuation phase.18 Sputum smear-positive disease implies a high organism load and an increased risk for random drug resistance.18 Selecting drug-resistant mutants is a particular concern where INH mono-resistance is prevalent, as this increases the likelihood of selecting multidrug-resistant (MDR) organisms. The use of four drugs (INH, RMP, PZA, EMB) during the 2-month intensive phase should reduce this risk. Once the organism load is sufficiently reduced, intermittent (2–3/week) therapy with INH and RMP during the 4-month continuation phase is sufficient to ensure organism eradication. However, caution should be exercised when initial treatment response has not been optimal and in HIV-infected patients.18 Disseminated (miliary) disease is frequently associated with central nervous system (CNS) involvement.18 It is therefore essential to consider the cerebrospinal fluid (CSF) penetration of drugs used in the
REFERENCES 15. 1. Donald PR. Childhood tuberculosis: out of control? Curr Opin Pulm Med 2002;8:178–182. 2. Marais BJ, Gie RP, Hesseling AC, et al. Adult-type pulmonary tuberculosis in children 10-14 years of age. Pediatr Infect Dis J 2005;24:743–744. 3. Marais BJ, Hesseling AC, Gie RP, et al. The burden of childhood tuberculosis and the accuracy of community-based surveillance data. Int J Tuberc Lung Dis 2006;10:259–263. 4. Chintu C, Mudenda V, Lucas S, et al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet 2002;360:985–990. 5. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children, WHO/HTM/TB/2006.371. WHO: Geneva, 2006. 6. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis—a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402. 7. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis— a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:278–285. 8. Marais BJ, Obihara CC, Warren RM, et al. The burden of childhood tuberculosis—a public health perspective. Int J Tuberc Lung Dis 2005;9:1305–1313. 9. Schaaf HS, Michaelis IA, Richardson M, et al. Adultto-child transmission of tuberculosis: household or community contact? Int J Tuberc Lung Dis 2003; 7:426–431. 10. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004; 363:212–214. 11. Marais BJ, Gie RP, Starke JR, et al. A proposed radiological classification of childhood intra-thoracic tuberculosis. Pediatr Radiol 2004;33:886–894. 12. Marais BJ, Donald PR, Gie RP, et al. Diversity of disease in childhood pulmonary tuberculosis. Ann Trop Paediatr 2005;25:79–86. 13. Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of disease in children treated for tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006; 10:732–738. 14. Marais BJ, Gie RP, Hesseling AC, et al. Radiographic signs and symptoms in children treated for
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treatment of disseminated (miliary) disease. INH and PZA penetrate the CSF well.39 RMP and streptomycin (SM) penetrate the CSF poorly, but may achieve therapeutic levels in the presence of meningeal inflammation.39 The value of streptomycin is limited by poor CSF penetration and intramuscular administration. EMB hardly penetrates the CSF, even in the presence of meningeal inflammation and has no demonstrated efficacy in the treatment of TBM.18
CONCLUSION Improving the access of (1) high-risk exposed and/or infected children to preventive therapy and (2) all children with active disease to anti-TB treatment will reduce the severe TB-related morbidity and mortality suffered by children in TB-endemic areas. A consistent rationale is applied in the management algorithms suggested, but screening, diagnostic, and treatment guidelines should be stratified according to the resources available in a particular setting. Childhood TB has been a neglected orphan disease for a long time,1,15 but luckily the tide is turning. The challenge is to provide practical management guidelines that are applicable in resourcelimited settings where TB is endemic.
tuberculosis: possible implications for symptom-based screening in resource-limited settings. Pediatr Infect Dis J 2006;25:237–240. Starke JR. Pediatric tuberculosis: time for a new approach. Tuberculosis 2003;83:208–212. Eamranond P, Jaramillo E. Tuberculosis in children: reassessing the need for improved diagnosis in global control strategies. Int J Tuberc Lung Dis 2001;5:594– 603. Marais BJ, Hesseling AC, Gie RP, et al. The bacteriologic yield in children with intrathoracic tuberculosis. Clin Infect Dis 2006;42:e69–71. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuberculosis—old wisdom and new challenges. Am J Respir Crit Care Med 2006;173: 1078–1090. Theart AC, Marais BJ, Gie RP, et al. Criteria used for the diagnosis of childhood tuberculosis at primary health care level in a high-burden, urban setting. Int J Tuberc Lung Dis 2005;9:1210–1214. Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007;92: 446–452. Moore DAJ, Evans CAW, Gilman RH, et al. Microscopic-observation drug-susceptibility-assay for the diagnosis of TB. N Engl J Med 2006;355: 1539–1550. Oberhelman RA, Soto-Castellares G, Caviedes L, et al. Improved recovery of Mycobacterium tuberculosis from children using the microscopic observation and drug susceptibility method. Pediatrics 2006;118: e100–e106. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005;365:130–134. Marais BJ, Pai M. Specimen collection methods in the diagnosis of childhood tuberculosis. Indian J Med Microbiol 2006;24:249–251. Vargas D, Garcia L, Gilman RH, et al. Diagnosis of sputum-scarce HIV-associated pulmonary tuberculosis in Lima, Peru. Lancet 2005;365:150–152. Chow F, Espiritu N, Gilman RH, et al. La cuerde dulce—a tolerability and acceptability study of a novel approach to specimen collection for diagnosis of paediatric pulmonary tuberculosis. BMC Infect Dis 2006;6:67. Marais BJ, Wright C, Gie RP, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area. Pediatr Inf Dis J 2006; 25:142–146.
28. Hesseling AC, Schaaf HS, Gie RP, et al. A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. Int J Tuberc Lung Dis 2002;6:1038–1045. 29. Marais BJ, Obihara CC, Gie RP, et al. The prevalence of symptoms associated with pulmonary tuberculosis in randomly selected children from a high-burden community. Arch Dis Child 2005; 90:1166–1170. 30. Marais BJ, Gie RP, Obihara CC, et al. Well-defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis. Arch Dis Child 2005;90: 1162–1165. 31. Marais BJ, Gie RP, Schaaf HS, et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics 2006;118: e1350–1359. 32. Lindeboom JA, Kuijper EJ, Prins JM, et al. Tuberculin skin testing is useful in the screening for nontuberculous mycobacterial cervicofacial lymphadenitis in children. Clin Infect Dis 2006;43:1547–1551. 33. Coldits GA, Brewer TF, Berkey CS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. JAMA 1994;271:698–702. 34. Corbett EL. The growing burden of tuberculosis. Global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–1021. 35. Marais BJ, Graham SM, Cotton MF, et al. Diagnostic and management challenges of childhood TB in the era of HIV. J Infect Dis 2007;196(Suppl 1):S76–S85. 36. Madhi S, Gray G, Huebner RE, et al. Correlation between CD4þ lymphocyte counts, concurrent antigen skin test and tuberculin skin test reactivity in human immunodeficiency virus type 1-infected and uninfected children with tuberculosis. Pediatr Infect Dis J 1999;18:800–805. 37. Graham SM, Coulter JBS, Gilks CF. Pulmonary disease in HIV-infected children. Int J Tuberc Lung Dis 2001;5:12–23. 38. Marais BJ, van Zyl S, Schaaf HS, et al. Adherence to isoniazid preventive chemotherapy: a prospective community based study. Arch Dis Child 2006;91: 762–765. 39. Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis 1993; 148:650–655. 40. ATS/CDC/IDSA. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662. 41. Marais BJ, Pai M. New approaches and emerging technologies in the diagnosis of tuberculosis. Paediatr Respir Rev 2007;8:124–133.
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Pulmonary tuberculosis in adults Christopher J Hoffmann and Gavin J Churchyard
BACKGROUND The World Health Organization (WHO) defines pulmonary tuberculosis (TB) as tuberculous disease that involves the lung parenchyma. Tuberculosis involving the trachea is often also included in the definition. Extrapulmonary TB is disease involving any part of the body other than lung parenchyma including other structures within the thorax such as the pleura, pericardium and perihilar lymph nodes. This distinction is most important from a public health perspective because patients with untreated pulmonary TB pose an infectious risk to the rest of the community, whereas the risk to the community from extrapulmonary TB is minimal. Thus patients with pulmonary TB who also have extrapulmonary involvement are classified as cases of pulmonary TB by the WHO. In addition to classification by location, TB has traditionally been classified as primary or postprimary disease. Primary infection includes the symptoms and complications arising from the first contact between host and the bacillus and is most clearly defined by conversion from a negative to a positive tuberculin skin test (TST). In the minority, the primary complex results in local progression or distant disease; in the majority, the complex resolves. Postprimary TB disease usually follows the primary infection by years, occurring through reactivation or reinfection. Other nearly synonymous terms with postprimary TB include reactivation TB, recrudescent TB, endogenous reinfection and adult-type progressive TB. In years past, primary TB was considered a disease of children and postprimary TB a disease of adults. In the era of human immunodeficiency virus (HIV) distinctions between primary and postprimary TB have become increasingly blurred as primary TB is often seen in HIV-infected adults. This chapter focuses on the clinical presentation of pulmonary TB and its complications. The classic presentation of primary and postprimary pulmonary TB among HIV-uninfected adults and the atypical presentations of pulmonary TB associated with HIV and other immunosuppressive diseases and drugs are described along with the differential diagnoses. The impact of active TB case-finding on clinical presentation and its public health importance is also included.
EPIDEMIOLOGY A basic understanding of the epidemiology of pulmonary TB is useful for estimating a patient’s or a population’s risk for pulmonary
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TB. This is especially important when determining the most likely aetiologies in building a differential diagnosis. In 2004, an estimated 9 million people had new TB diseases and 2 million deaths were attributable to TB (see Chapter 3). Most new diseases and deaths occurred in Asia and Africa, where 80% of all cases of TB occur.1 Of the 9 million new cases, three-quarters were pulmonary TB.2 Multiple factors have contributed to the surge in TB that began during the late 1980s and 1990s; immunosuppression from HIV is the most dramatic. However, the impact of HIV on pulmonary TB epidemiology is complex. HIV contributes to pulmonary TB epidemiology in four important ways. Firstly, HIV-associated immunosuppression increases the risk of tuberculous disease, either from reactivation or from progression of primary infection. Approximately 3–5% of adults with intact immune systems develop TB disease within a year of initial infection; subsequent lifetime risk of reactivation is 3–5%.3 Among HIV-infected individuals, nearly two-thirds develop symptomatic TB disease within the first few months of infection.4 As a result, a disproportionate number of HIV-infected individuals are diagnosed with pulmonary TB.1 Secondly, individuals with HIV are at higher risk than HIVuninfected individuals for recurrence of pulmonary TB from exogenous infection.5 Thus, regions with both high HIV prevalence and pulmonary TB incidence have a high proportion of the population highly susceptible to recurrence. Thirdly, HIV coinfection accelerates progression of pulmonary TB. As a result, HIV-infected individuals typically progress to death or diagnosis in a shorter time after developing pulmonary TB than HIV-uninfected individuals. Several recent studies have estimated time to diagnosis by comparing incident pulmonary TB cases identified in clinics with prevalent pulmonary TB identified through community-wide symptom and sputum screens. The estimated duration of pulmonary TB before development of significant symptoms ranges from 6 to 51 weeks among HIV-infected individuals and from 38 to 60 weeks among HIV-uninfected individuals.6–8 Fourthly, HIV coinfection diminishes the infectiousness of pulmonary TB. Although HIV leads to more rapid progression of pulmonary TB, the burden of TB bacilli in the lungs is lower among HIV-infected individuals, leading to a lower rate of sputum smear positivity.9,10 Among acquired immunodeficiency syndrome (AIDS) patients with pulmonary TB, approximately 30–40% have smear-negative disease compared with 20% smearnegative pulmonary TB among those uninfected with HIV.11 Smear-negative pulmonary TB is 10-fold less transmissible than
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smear-positive disease. Possibly as a result, contacts of HIVinfected people with pulmonary TB are slightly less likely to become infected with TB.12–16 Understanding these differences is important from clinical and public health standpoints. The implication of a much longer period of contagiousness of an HIV-uninfected person with pulmonary TB than an HIV-infected individual is increased opportunity for the HIV-uninfected individual to transmit infection. Other conditions that increase the risk of pulmonary TB include silicosis, diabetes, haemodialysis, malnutrition, smoking, underlying lung disease, diseases affecting the immune system and immunosuppressive medications.17,18 Silicosis increases pulmonary TB risk three- to fivefold.19 Diabetes mellitus, especially insulin-dependent diabetes, increases the risk of TB approximately two- to threefold.20 Immunosuppression increases risk based on the therapy and the dose. Tumour necrosis factor-alpha (TNF-a) antagonists such as infliximab and etanercept are most strongly associated with TB disease. The principal mechanism of active disease among patients receiving these medications is believed to be from reactivation of latent foci. Because of this risk, TST is recommended prior to initiation of anti-TNF-a therapy. Crowded conditions such as those found in dormitories, nursing homes, prisons, naval vessels and healthcare centres also increase transmission risk.21
PATHOPHYSIOLOGY In order to understand the differences in clinical presentation of primary and postprimary TB a brief outline of the pathophysiology of TB infection and disease is required. Tuberculosis bacilli are aerosolized during coughing, sneezing and singing. Once bacilliladen nuclei are aerosolized they can remain suspended for hours, presenting an infection risk long after a person with TB has left an indoor space. Bacilli degrade rapidly in outdoor environments because ultraviolet light from sunlight destroys the bacilli. When inhaled, small droplet nuclei, ranging from 1 to 5 mm in diameter and containing 1–10 bacilli, enter the lung, avoid being trapped in the lining of the upper respiratory tract and travel to distal alveoli. The well-aerated regions close to the pleura in the lower lung fields are the most common place for the bacilli-containing droplets to settle.22 After lodging in the alveoli, non-activated alveolar macrophages ingest the bacilli in an attempt to destroy them. It is believed that at least 5–200 bacilli are necessary to overcome the macrophage response and cause infection. These bacilli then multiply within macrophages and establish a focus of primary TB. This occurs in approximately one-third of individuals with robust immune systems. As the quantity of bacilli increases, inflammation develops, forming a collection of bacilli, macrophages, lymphocytes and debris known as the Ghon focus. During early mycobacterial replication, the burden of bacilli in the Ghon focus is insufficient to trigger a systemic immune response. As the burden of bacilli grows, additional activated alveolar macrophages and T-lymphocytes are recruited to this site and a systemic response is activated. Bacilli are also trafficked from the Ghon focus to the mediastinal and perihilar lymph nodes either within macrophages or along lymphatic channels and may become haematogenously distributed, developing foci of replication in regions with high oxygen tension: the meninges, epiphyses of long bones, kidneys, vertebral bones, lymph nodes and apicoposterior areas of the lungs. At the time that activated macrophages and lymphocytes are recruited, symptoms may become pronounced and conversion to
29
a positive TST occurs. For most individuals the systemic immune response is sufficient to control further growth of bacilli. The original Ghon focus and associated perihilar lymph node infection (known as the Ranke complex) are often eradicated within months of infection, whereas disseminated foci become walled off by granulomatous inflammation, which occasionally harbour viable bacilli. When the disseminated focus is in the lung apex, the site is known as Simon’s focus. Simon’s focus is usually the nidus of reactivation in postprimary pulmonary TB.
SYMPTOMS AND SIGNS PRIMARY PULMONARY TUBERCULOSIS Primary TB infection may be asymptomatic, cause fevers and pleuritic pain or, rarely, progress to life-threatening disease. During the primary pulmonary infection, symptoms may occur as the burden of bacilli increases and the host mounts a systemic immune response. Fever is the most common symptom. A study conducted prior to the HIV pandemic reported fever among 70% of individuals with primary TB, often several weeks after exposure, that lasted a median of 2–3 weeks, but much longer among some patients.23 The fever onset is usually gradual and is not usually accompanied by other symptoms, although some patients develop pleuritic or retrosternal pain. Cough, arthralgias and fatigue occur rarely. While haematogenous seeding of distant sites is common, rarely does it cause symptomatic disease among individuals with intact immune systems. The most common extrapulmonary manifestations, when they occur, are lymphadenitis and meningitis. On examination, a patient with primary pulmonary TB may have erythema nodosum, bluish-red tender subcutaneous nodules several millimetres to several centimetres in diameter appearing on the legs, and phlyctenular conjunctivitis, hard raised red 1- to 3-mm nodules accompanied by a zone of hyperaemia located near the limbus on the bulbar conjunctiva of the eye. Both conditions are an immune phenomenon seen in primary TB and other infectious and non-infectious diseases and do not contain bacilli. After the initial inflammation, 90% of individuals with intact immunity control further replication of the bacilli. The remaining individuals either develop TB pneumonia with expansion of infiltrates at the site of the initial seeding or near the hilum (Fig. 29.1) and hilar lymphadenopathy or develop disease at more distant sites, most commonly cervical lymph nodes, meninges, pericardium or miliary dissemination. Among individuals with weakened immune response, including advanced age, HIV, kidney failure and poorly controlled diabetes mellitus, progression to disseminated or local disease occurs more frequently.
POSTPRIMARY PULMONARY TUBERCULOSIS Postprimary pulmonary TB refers to all pulmonary TB resulting from reactivation of controlled (latent) infection, late progression of primary infection or exogenous reinfection. The contribution of any one of these mechanisms to the total number of postprimary TB cases depends on the local prevalence and the susceptibility of the individuals in the community to TB. In the past it was believed that 90% of TB among adults was a result of reactivation.24 More recent studies have suggested large population-dependent variations in the ratio of reinfection to reactivation.25
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The most salient clinical feature of TB is the chronic nature the disease can assume. Pulmonary TB may remain undiagnosed and infectious for 2–3 years, or even longer due to its indolent nature with symptoms only developing later in the course of the disease.7 However, as symptoms correlate with extent of disease in patients with normal immune systems, symptomatic individuals are more likely to have smear-positive sputum.32 Given the potentially indolent nature of the disease, patients with persistent or recurrent respiratory complaints over months to years should be aggressively evaluated for pulmonary TB, even if they describe resolution between episodes of illness, lack classic symptoms and have an unremarkable physical examination. Even after preliminary negative evaluations, repeat investigation for pulmonary TB is warranted if no other diagnosis has been made.
PHYSICAL EXAMINATION
Fig. 29.1 Chest radiograph showing right hilar adenopathy from primary pulmonary TB. From Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005: Figure 31.16.
Classic presentation of postprimary pulmonary tuberculosis The classic presentation of postprimary pulmonary TB is characterized by weeks to months of chronic cough (chronic usually referring to either > 2 or 3 weeks), weight loss, fatigue, fevers, night sweats and haemoptysis.26 Fever in postprimary TB is classically diurnal with an afebrile period early in the morning and a gradually rising temperature throughout the day, and a fever peak in the late afternoon or evening. Nighttime defervescence is often accompanied by diaphoresis leading to drenching night sweats. Both fever and night sweats are more common among patients with advanced pulmonary TB, often with significant parenchymal disease and cavitary lesions. Interestingly, the fraction of individuals with pulmonary TB presenting for healthcare with these symptoms has remained remarkably consistent over multiple decades, continents and clinical settings: cough occurs among 70–90%, weight loss among 43–75%, haemoptysis in 21–29%, fatigue or malaise among 58% and fever among 15–52%.27–31 However, no single symptom or constellation of symptoms clearly distinguishes patients who have pulmonary TB from those who do not. Cough may be absent or subtle early in the disease course. A mild non-productive cough commonly occurs initially in the morning and may be confused with a ‘smoker’s cough’ by a clinician and ignored by the patient. The morning cough is a result of accumulation of secretions during the sleeping hours (a similar mechanism to the smoker’s cough). During disease progression, cough often becomes more continuous throughout the day and may become productive of yellow or yellow–green and occasionally blood-streaked sputum. Nocturnal coughing is associated with advanced pulmonary disease, often with cavitations. Pleuritic pain may occur with coughing. Hoarseness of voice suggests laryngeal involvement (see below). Anorexia, wasting and malaise are common features of advanced disease and may be the only presenting features in some patients, especially among patients with extrapulmonary TB.
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Physical examination of an individual with pulmonary TB is usually non-specific. Classic findings are pallor, cachexia, tachycardia and post-tussive crackles over affected lung. Because of the latter examination finding, it is useful to ask the patient to cough before auscultation of the lung fields. An additional pulmonary finding in advanced cases is a cavernous or ‘amphoric’ sound on lung auscultation, so named because of a resemblance to the sound made when blowing across a Greek jug.
ATYPICAL PRESENTATIONS Culture-negative pulmonary tuberculosis Some patients present with classic symptoms of pulmonary TB with chronic and progressive fever, cough and weight loss along with radiographic findings but do not have Mycobacterium tuberculosis identified by sputum direct microscopy or culture. This may be a result of low mycobacterial burden, suboptimal sputum quality or improper sputum processing. Among a percentage of such patients, after extensive evaluation, often including fibreoptic bronchoscopy with lavage and biopsy and computed tomography of the chest and abdomen, no aetiology is identified. In some TB treatment programmes over 10% of patients fit this category.33 These patients often are preliminarily diagnosed with culture-negative TB and started on standard four-drug TB treatment. Failure to respond clinically after 2 months of treatment places the diagnosis in question and should prompt a re-evaluation of diagnosis and management; improvement in symptoms helps to confirm the diagnosis of culture-negative TB. Patients with improvement in symptoms should have treatment completion per local TB guidelines. HIV Immunosuppression with advancing AIDS alters the presenting symptoms of pulmonary TB. Patients with advanced HIV are more likely to have progression of primary infection to persistent and often disseminated (miliary) disease and less likely to have typical symptoms. Fever may be more common among HIV coinfected patients while cough is less common.34 Along with a lower proportion with cough, more HIV-infected individuals are sputum smear-negative. In addition to fever, other non-specific symptoms such as wasting and malaise are more common among individuals coinfected with HIV and pulmonary TB. AIDS patients with pulmonary TB are more likely to also have extrapulmonary infection: 60% have extrapulmonary sites of infection compared with 28% of pulmonary TB patients without AIDS.35
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29
Advanced age The presentation of infectious diseases is often atypical in older individuals, pulmonary TB included. Most notably older individuals (> 65 years old) are less likely to present with fevers, night sweats or haemoptysis and are more likely to present with the nonspecific findings of dyspnoea and fatigue. Because chronic lung disease is common in older populations, the diagnosis of pulmonary TB can easily be overlooked in a patient with chronic obstructive pulmonary disease (COPD) presenting with worsening dyspnoea and malaise. Furthermore, cavitary disease is less common and multilobar and lower lobe involvement more common.36 Thus the presentation of pulmonary TB in the elderly can be similar to that of COPD or pyogenic bacterial pneumonia. However, the incidence of pulmonary TB is two to three times higher among the elderly, especially those in institutions such as old age homes, and the risk of death considerably higher.37
recurrence depends on local disease prevalence and the effectiveness of local TB treatment programmes.25,39,40 HIV, other immunodeficiency states and cavitary pulmonary disease further increase the risk of recurrent pulmonary TB, commonly due to reinfection.25,41 Recurrent pulmonary TB may present with classic pulmonary TB symptoms of fever, night sweats, weight loss, malaise and worsening chronic cough or atypical symptoms. However, the proportion of patients with recurrent pulmonary TB presenting with classic versus atypical symptoms has not been well described. Diagnosis is often complicated because pulmonary fibrosis and cavitary lesions from previous disease can obscure new infiltrates and complicate interpretation of chest radiographs.
Laryngeal tuberculosis Before the advent of effective chemotherapy for TB, laryngeal TB was considered a terminal event during the progression of pulmonary TB, developing soon before death, and possibly occurring in over 50% of patients. In the era of effective chemotherapy, laryngeal TB has become rare (< 1% of TB cases). It can occur in isolation or in association with pulmonary TB or extrapulmonary TB. The true vocal cords, epiglottis and false vocal cords are the most common sites of involvement. Symptoms almost always include dysphonia, which is often accompanied by cough, dysphagia, odynophagia, stridor and haemoptysis.38 Findings on laryngoscopy may be areas of hyperaemia, nodules, ulcerations or exophytic masses.
Differential diagnoses for pulmonary TB are listed in Table 29.1.
Recurrent pulmonary tuberculosis Pulmonary TB should be more strongly suspected among patients who have been previously treated for TB disease as both relapse and new infection are more frequent. The specific frequency of
DIFFERENTIAL DIAGNOSIS
INVESTIGATIONS A major reason for misdiagnosis of pulmonary TB is the absence of typical symptoms or radiographic features.42,43 Many patients with pulmonary TB lack fever, night sweats, chronic cough and wasting or have only one of these symptoms. Thus, in the right clinical and epidemiological setting, the absence of classic symptoms should not diminish the vigilance and aggressiveness of evaluation for pulmonary TB. This problem is illustrated by a community-wide cross-sectional pulmonary TB prevalence study using sputum culture and clinical interviews, conducted in an area with very high TB prevalence.44 Two or more of cough, night sweats, weight loss and anorexia were present among only 25% of previously
Table 29.1 Differential diagnoses of tuberculosis Disease
Characteristics
Mycobacterium kansasii
Mycobacterium kansasii disease may have a presentation similar to that of TB, especially among individuals with advanced AIDS (CD4 < 100 mm3). A distinction is that M. kansasii is more likely to cause cavitary pulmonary disease when the CD4 count is very low. M. kansasii disease is uncommon with higher CD4 counts. Chest radiography may be similar and culture is often needed to distinguish between the two conditions.75 Upper lobe tumours and pulmonary TB both can be associated with chronic cough, malaise and weight loss and can be radiographically indistinguishable. Biopsy may be needed to confirm a diagnosis. Opportunistic infection, which is very common among HIV-infected individuals with CD4 count < 200 mm3. Usually presents with hazy bilateral infiltrates, more rarely with nodules or small cavities. Opportunistic infection of compromised hosts including people with AIDS, immunosuppressive therapy and pulmonary alveolar proteinosis. Can present with chronic cough, fevers and night sweats. May be associated with central nervous system abscesses. Opportunistic infection seen in advanced AIDS. May present with infiltrates, hilar lymphadenopathy or cavitary lesions or chest radiography. Patients most likely to acquire Rhodococcus infection have CD4 counts < 50 mm3. Common malignancy with advanced AIDS. Cutaneous lesions are often present when pulmonary disease develops. Radiographic findings are usually bilateral infiltrates spreading from hilum. In advanced AIDS (CD4 < 100 mm3) this is a common cause of meningitis. It can cause pulmonary infiltrates, nodules or cavitary disease, especially with advanced AIDS or immunosuppression from glucocorticoids or cancer chemotherapy. The serum cryptococcal antigen may be negative with localized pulmonary disease.76 Non-typhi species of Salmonella are common causes of bacteraemia with advanced AIDS (CD4 < 100 mm3). In rare cases salmonella pneumonia develops, presenting with infiltrates or cavitary lung lesions.77 Bacterial pneumonia can appear on chest radiography similar to pulmonary TB, especially if perihilar infiltrates or apical cavities are present. Evolution of disease over hours to days is more suggestive of a bacterial pneumonia caused by Streptococcus pneumoniae, Panton–Valentine leucocidin-producing Staphylococcus aureus, Pseudomonas aeruginosa or Klebsiella pneumoniae.
Lung tumour Pneumocystis jiroveci pneumonia (PCP) Nocardia spp.
Rhodococcus equi Kaposi’s sarcoma Cryptococcus
Salmonella Bacterial pneumonia
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undiagnosed pulmonary TB (prevalence cases). However, two or more of these symptoms were present among 22% of the population without pulmonary TB. Thus, in that study population, classic symptoms for pulmonary TB lacked both sensitivity and specificity. Another African study reported similar findings: 20% of individuals with pulmonary TB detected on a community survey were asymptomatic.45
SPUTUM SMEAR AND CULTURE The diagnosis of pulmonary TB (especially postprimary disease) is usually based on sputum examination and, optimally, culture. Thus quality assurance of collection, handling and processing of sputum is essential. The first sputum sample should be collected at the time of evaluation when the diagnosis of TB is considered with, ideally, at least one more specimen collected early in the morning on subsequent days. See Chapter 18 for details on sputum smear and culture.
LABORATORY INVESTIGATIONS
Fig. 29.2 Chest radiograph showing a Ghon focus with hilar adenopathy and bilateral infiltrates. From Marx J, Hockberger R, Walls R (eds). Rosen’s Emergency Medicine: Concepts and Clinical Practice, 6th edn. St Louis: Mosby, 2006: Figure 133.3.
Some patients with pulmonary TB are anaemic and have leucocytosis. Normochromic, normocytic anaemia occurs most commonly. Tuberculosis also can cause a leukaemoid reaction with markedly elevated leucocyte counts (>50,000 cells/mm3). However, normal or low leucocyte counts are also consistent with the diagnosis of pulmonary TB. Mild monocytosis or eosinophilia may also be observed. The erythrocyte sedimentation rate may be normal or increased. The platelet count, alkaline phosphatase, lactate dehydrogenase and ferritin may also be increased; however, these findings are not sensitive or specific for the diagnosis of pulmonary TB.28
TUBERCULIN SKIN TESTING The TST is a test of delayed-type, cell-mediated hypersensitivity to purified protein derivative. TST has substantial limitations that diminish its value in diagnosing pulmonary TB. The TST lacks sensitivity and specificity. Prior to the emergence of HIV, falsenegative TSTs among patients with pulmonary TB were well recognized and reported to occur in over 2% of patients.46 Among patients with immunosuppression (HIV, renal dialysis, malignancy, immunosuppressive medications), false-negative TSTs are much more common.47 A positive TST may represent latent TB infection unrelated to illness being evaluated. In addition, exposure to environmental Mycobacteria spp. and Bacillus Calmette–Gue´rin vaccination can result in a false-positive TST.
CHEST RADIOGRAPHY In primary pulmonary TB, chest radiography is often normal. When present, typical pathological findings of primary pulmonary TB are hilar enlargement with or without perihilar infiltrate and pleural effusions (Figs 29.2 and 29.3).48 In primary pulmonary TB 85% of infiltrates are in the mid- to lower lung fields. In postprimary pulmonary TB most patients have abnormalities on chest radiography, even in the absence of respiratory symptoms.27,49 Conversely the chest radiograph may be normal in a small fraction of symptomatic individuals, especially in the setting of HIV coinfection. Classic findings in postprimary pulmonary TB are alveolar infiltrates, interstitial infiltrates or cavitary lesions in the lung apex or upper zones of the lower lobes (Figs 29.4
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Fig. 29.3 Primary TB effusion in a 26-year-old adult. Grainger RG,
Allison DJ, Dixon AK (eds). Grainger amd Allison’s Diagnostic Radiology: A Textbook of Medical Imaging, 4th edn. Edinburgh: Churchill Livingstone, 2001: Figure 18.21.
and 29.5; Table 29.2). Effusions, lymphadenopathy, lower lung zone infiltrates and a miliary pattern (diffuse 2- to 3-mm nodules evenly distributed throughout the lung fields) are atypical (Fig. 29.6). Underlying lung diseases such as chronic obstructive pulmonary disease, silicosis and tumours of the lung can increase the risk for TB while making radiographic interpretation more difficult. Immunosuppression further complicates interpreting radiographs, especially when it is more profound. With HIV, at high CD4 counts, typical findings, including apical cavitary lesions, are common. HIV-infected patients with more advanced immunodeficiency (CD4 < 200 cells/mm3) very rarely develop cavitary lesions from pulmonary TB and are much more likely to have the atypical findings of lymphadenopathy, effusions or mid- and lower zone infiltrates.50 When a patient with profound immunodeficiency
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29
Table 29.2 Chest radiograph findings for patients with symptomatic pulmonary tuberculosis and approximate percentage of cases with a given finding based on HIV status or other immunodeficiency HIV(þ) CD4 < 3 200 mm (%)
HIV() immunocompromised (%)
>50
20
10–30
30–66
30
10
20
2–5 5–20 2–15 2–10 0
5–10 10–20 5–15
10–30 10–30 20–30 15 5–15
30 15 18
HIV() HIV(þ) (%) CD4 > 3 200 mm (%) Typical Upper lobe infiltrates Cavitation Atypical Reticulonodular Effusion Adenopathy Miliary Normal
60
From studies of symptomatic patients presenting for healthcare.31,50,51,78–80
Fig. 29.4 Left hilar infiltrate in postprimary pulmonary TB. Cohen J,
Powderly W (eds). Cohen & Powderly: Infectious Diseases, 2nd edn. St Louis: Mosby, 2003: Figure 31.16.
Fig. 29.5 Upper lobe cavitary lesion typical of postprimary pulmonary
TB. Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005: Figure 33.17.
develops a cavitary lesion, the differential diagnosis should be broadened to include additional causative pathogens such as M. kansasii and Nocardia (Table 29.1). The limited accuracy of chest radiography is illustrated in a recent study from Kenya in which sputum culture results were compared with an experienced radiologist ’s interpretation of a chest radiograph. In that study, 13% of chest radiographs with no abnormal findings and 27% with findings not considered consistent with TB were from
Fig. 29.6 Postprimary TB: miliary TB. Diffuse nodulation is present in all zones. Nodules are approximately 1 mm in diameter and well defined. Grainger RG, Allison DJ, Dixon AK (eds). Grainger and Allison’s Diagnostic Radiology: A Textbook of Medical Imaging, 4th edn. Edinburgh: Churchill Livingstone, 2001: Image 18.
subjects with positive sputum culture. Of note, approximately half of subjects in that study who were tested were HIV-infected.51
TRIAL OF ANTIBIOTICS The administration of empiric antibiotics was previously used in situations when the sputum smear is negative and a chest radiograph either is equivocal or cannot be obtained to aid in differentiating pulmonary TB from bacterial pneumonia and was widely used in resource-constrained settings. With this approach, symptomatic
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more likely to be asymptomatic or mildly symptomatic, below the threshold for seeking medical care, and more likely to have limited radiological disease and to be smear-negative. This is true for both HIV-infected and -uninfected individuals.6 Identification of these cases is also vital to controlling the spread of the disease.
PATHOLOGY Gross pathology of pulmonary TB is characterized by areas of caseation with surrounding fibrosis. As areas of caseation enlarge and empty into patent bronchi, cavities may form (Fig. 29.7). A smear of contents of a cavity is typically laden with acid-fast M. tuberculosis bacilli.
Fig. 29.7 Gross pathology showing lungs with postprimary pulmonary TB. The upper parts of both lungs are riddled with grey–white areas of caseation and multiple areas of softening and cavitation. Kumar V, Abbas AK, Fausto N (eds). Robbins and Cotran: Pathologic Basis of Disease, 7th edn. Philadelphia: WB Saunders, 2004: Figure 8.32.
patients with a negative sputum smear received a 5- to 10-day course of antibiotics for bacterial pneumonia (e.g. amoxicillin). Lack of response to antibiotics suggests a process other than pyogenic bacterial pneumonia, possibly pulmonary TB. However, response to antibiotics does not eliminate the possibility of pulmonary TB for two reasons: 1. symptoms of pulmonary TB may wax and wane; and 2. both bacterial pneumonia and pulmonary TB may be present at the same time.52 Because of the frequency of coinfection with community-acquired bacterial pathogens and M. tuberculosis, patients should be re-evaluated for pulmonary TB with repeat sputum examinations and culture even if they recover while taking empiric antibiotics. Although a clinical evaluation conducted in Guinea supported using empiric antibiotics,53 as 8% of patients who responded to amoxicillin had pulmonary TB, and 94% of patients who did not respond either had a positive culture for mycobacterium or responded to TB therapy despite a negative sputum culture. This approach is no longer advised by the WHO. Fluoroquinolones should not be used to treat presumptive bacterial pneumonia where TB is common because they have activity against M. tuberculosis and some other mycobacterial species, potentially confounding the diagnosis of pulmonary TB and promoting fluoroquinolone-resistant TB.54,55
ACTIVE CASE FINDING AND SCREENING ALGORITHMS The WHO directly observed treatment, short-course (DOTS) strategy is reliant on symptomatic individuals self-presenting for healthcare, which is how most cases of pulmonary TB are currently diagnosed. However, the new Global Plan to Stop TB recommends adding active case-finding for TB in order to find cases earlier and reduce transmission and morbidity and mortality from TB.56 Active case-finding involves symptom screens and, in some settings, chest radiography, sputum smear and culture as part of annual physical examinations, workplace screening, antenatal clinics and HIV care clinics, and at prison intake and release, school evaluations, HIV voluntary counselling and testing centres (VCT) and community TB surveillance programmes. However, pulmonary TB identified during active case-finding activities is
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MANAGEMENT CHEMOTHERAPY Three components of management need to be considered when pulmonary TB is diagnosed: 1. which anti-TB chemotherapy regimen is appropriate; 2. how to assure adherence; and 3. how to monitor treatment success. Please refer to Chapter 62 for details on chemotherapy for TB.
PROGNOSIS Patients with pulmonary TB who are adherent to therapy to which the bacilli are sensitive have an excellent chance of cure. Even patients with other underlying illnesses, such as AIDS, have equal rates of cure to HIV-uninfected individuals.57 However, such individuals cured of pulmonary TB are at higher risk for recurrence. In addition, permanent lung injury may occur, leading to decreased pulmonary function and risk for chronic lung disease.58
COMPLICATIONS HAEMOPTYSIS Haemoptysis usually only occurs with advanced cavitary pulmonary disease and is usually mild. The typical presentation is blood-streaked sputum. Massive, sometimes fatal, haemorrhage is rare. When it occurs it is a result of erosion into a bronchial artery or rupture of an aneurysm (Rasmussen aneurysm) within the TB cavity.59 Haemoptysis may also occur after completion of TB treatment due to bronchiectasis, a mycetoma invading and colonizing a healed cavity or recurrence of TB disease itself. Medical management is appropriate, even for major or massive haemoptysis, except in the cases of impending exsanguination which require immediate surgical care. Initial care includes bed rest, postural management, volume replacement, cough suppression and intravenous vasopressin. When medical management fails (25–50% of patients after 24 hours), options include surgical ligation of arteries, resection of a lung lobe, endobronchial tamponade and bronchial artery embolization. Both ligation and embolization can be complex because of the frequent presence of multiple feeder arteries often connecting systemic with bronchial circulation.60–62 Careful identification and ligation or embolization of feeder arteries is required to reduce the chance of recurrent haemoptysis.
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Pulmonary tuberculosis in adults
PNEUMOTHORAX Pneumothorax is a rare complication of pulmonary TB in the era of TB therapy. A case series from Turkey reported pneumothoraces in 1.5% of cases of pulmonary TB.31 However, in settings with high TB prevalence, pulmonary TB is a leading cause of secondary pneumothorax.63 The pneumothorax can be associated with active or inactive pulmonary TB.
RIGHT MIDDLE LOBE SYNDROME The rare occurrence of atelectasis of the right middle lobe occurs when bulky perihilar lymphadenopathy compresses the middle lobe bronchus, leading to collapse of its feeding lung. Initial management should focus on therapy for TB. Persistence of lymphadenopathy or failure of the middle lobe to re-expand should lead to consideration of other or additional diagnoses.
MYCETOMA Healed pulmonary cavitary lesions can become colonized by Aspergillus spp., resulting in formation of a mycetoma (aspergilloma). These are usually asymptomatic and are often incidental findings on chest radiography, appearing as an ‘air-crescent’ sign in a cavitary lesion (Fig. 29.8). However, scant haemoptysis may be a harbinger of massive haemoptysis; thus surgical intervention should be considered if feasible, when cardiopulmonary function allows.64 There is little evidence that anti-fungal therapies improve prognosis, although they are often administered peri-operatively when surgical management is pursued. Resection is the only known effective cure; however, bronchial artery embolization can be used to treat haemoptysis.65
29
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME After initiation of antiretroviral therapy for patients with AIDS, serum HIV RNA levels decline and CD4 counts rise. As immune function is restored, antigens from ongoing or past infections can provoke an inflammatory response, leading to a syndrome known as immune reconstitution inflammatory syndrome (IRIS). Mycobacterial disease has been reported to cause at least one-third of IRIS cases.66 The fraction attributable to TB is likely much higher in regions with high TB prevalence. Symptoms of mycobacterium-associated IRIS usually present 4–12 weeks after highly active antiretroviral therapy (HAART) initiation in patients who have experienced a significant rise in CD4 count from a low nadir (often <100 cells/mm3) and suppression of HIV replication67,68 Symptoms are often systemic, but may include prominent pulmonary symptoms including pneumonitis and acute respiratory distress syndrome.66 In addition to treating TB disease, corticosteroids may relieve symptoms.
PARADOXICAL REACTION After weeks or months of clinical and radiological improvement, some individuals experience a dramatic worsening in clinical status. When this occurs during treatment of susceptible disease it is known as a ‘paradoxical reaction’ or ‘paradoxical response’. A paradoxical reaction involves clinical or radiographic worsening of symptoms that is sometimes accompanied by fever. It is probably a immunological phenomenon and is usually characterized by increased cellmediated response to tuberculin antigens (increased induration with TST) and may share some immunological similarities with the HIVassociated IRIS. However, the biological mechanisms of the reaction have not been elucidated. A recent study identified paradoxical reaction among 16% of 104 patients treated for any TB and 7% of patients treated for exclusively pulmonary TB. Patients with HIV have an increased rate of paradoxical reaction.69 The most common finding among patients with pulmonary TB is a new or worsening pleural effusion and the median time to development of the paradoxical reaction is 56 days, ranging from 20 to 109 days.70 Before the diagnosis of paradoxical reaction can be made, other potential causes of decline, including emergence of drug resistance, should be ruled out.
PREVENTION
Fig. 29.8 Chest radiograph showing a fungus ball (mycetoma or aspergilloma) in a preexisting tuberculous cavity. Note the characteristic crescent of air (arrowheads) over the superior margin of the fungus ball. Mason RJ, Broaddus VC, Murray JF (eds). Murray & Nadel’s Textbook of Respiratory Medicine, 4th edn. Philadelphia: WB Saunders, 2005: Figure 33.15.
The foundation of TB control is identifying individuals with pulmonary TB, ideally through community-wide active case-finding, and completing TB therapy so they are no longer infectious. Thus identifying individuals at highest risk for transmitting TB – sputum smear-positive with chronic cough – is the first priority of TB control programmes. However, smear-negative individuals account for a fifth of transmission.71 In addition, the large fraction of asymptomatic or subclinical disease adds to delays in diagnosis with half of individuals asymptomatic at the time of screening in some cross-sectional prevalence surveys.6 Patients with chronic cough (and suspected pulmonary TB) should be identified and, ideally, isolated. Once patients are diagnosed and started on treatment, they should avoid crowded places, ideally staying in their place of residence, until they become sputum smear-negative. Although patients have a significant initial reduction in bacilli, 90% by 2 weeks, they may remain sputum
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SECTION
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CLINICAL PRESENTATIONS OF TUBERCULOSIS
smear-positive for 4–6 weeks.72,73 Furthermore, patients with drug-resistant TB or who are non-adherent to therapy may remain potentially contagious for a longer duration. There is no evidence that a family member being treated for TB places family members at high risk for infection. Most family members either were infected prior to diagnosis of the index case or will not become infected during this brief period of continued infectivity.74 Another important method for preventing TB disease is to treat for latent TB infection (Chapter 77). This reduces the pool of individuals at risk for reactivation and eventual transmission.
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CONCLUSION Lack of sensitivity and accuracy of symptoms and radiological findings combined with slow and imperfect investigative tests hamper the diagnosis and control of TB. Clinicians need to have a high index of suspicion and investigate early appropriately. In addition, all contacts with the medical system should be considered opportunities for active case-finding. Additional diagnostic tools for TB are also urgently needed.
16. Carvalho AC, DeRiemer K, Nunes ZB, et al. Transmission of Mycobacterium tuberculosis to contacts of HIV-infected tuberculosis patients. Am J Respir Crit Care Med 2001;164(12):2166–2171. 17. Davies PD, Yew WW, Ganguly D, et al. Smoking and tuberculosis: the epidemiological association and immunopathogenesis. Trans R Soc Trop Med Hyg 2006;100(4):291–298. 18. Hussein MM, Mooij JM, Roujouleh H. Tuberculosis and chronic renal disease. Semin Dial 2003;16(1): 38–44. 19. Corbett EL, Churchyard GJ, Clayton T, et al. Risk factors for pulmonary mycobacterial disease in South African gold miners. A case-control study. Am J Respir Crit Care Med 1999;159(1):94–99. 20. Coker R, McKee M, Atun R, et al. Risk factors for pulmonary tuberculosis in Russia: case-control study. BMJ 2006;332(7533):85–87. 21. Tuberculosis Research Centre Indian Council of Medical Research. Additional risk of developing TB for household members with a TB case at home at intake. Int J Tuberc Lung Dis 2007;11(3):282–288. 22. Medlar EM. The pathogenesis of minimal pulmonary tuberculosis: a study of 1225 necropsies in cases of sudden and unexpected death. Am Rev Tuberc 1948;58:583–611. 23. Poulsen A. Some clinical features of tuberculosis. Acta Tuberc Scand 1957;33(1–2):37–92. 24. Small PM, Hopewell PC, et al. The epidemiology of tuberculosis in San Francisco. A population-based study using conventional and molecular methods. N Engl J Med 1994;330(24):1703–1709. 25. Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001;358(9294):1687–1693. 26. Garay SM. Pulmonary tuberculosis. In: Rom WN, Garay SM (eds). Tuberculosis, 2nd edn. Philadelphia: Lippincott Williams & Wilkins, 2004: 345–394. 27. Barnes PF, Verdegem TD, Vachon LA, et al. Chest roentgenogram in pulmonary tuberculosis. New data on an old test. Chest 1988;94(2):316–320. 28. Morris CD, Bird AR, Nell H. The haematological and biochemical changes in severe pulmonary tuberculosis. Q J Med 1989;73(272):1151–1159. 29. MacGregor RR. A year’s experience with tuberculosis in a private urban teaching hospital in the postsanatorium era. Am J Med 1975;58(2):221–228. 30. Miller LG, Asch SM, Yu EI, et al. A population-based survey of tuberculosis symptoms: how atypical are atypical presentations? Clin Infect Dis 2000;30(2): 293–299. 31. Aktogu S, Yorgancioglu A, Cirak K, et al. Clinical spectrum of pulmonary and pleural tuberculosis: a report of 5,480 cases. Eur Respir J 1996;9(10): 2031–2035. 32. Verver S, Bwire R, Borgdorff MW. Screening for pulmonary tuberculosis among immigrants: estimated effect on severity of disease and duration of infectiousness. Int J Tuberc Lung Dis 2001;5(5): 419–425. 33. Kanagarajan K, Perumalsamy K, Alakhras M, et al. Clinical characteristics and outcome of culture negative tuberculosis. Chest 2003;124(4):40. 34. Batungwanayo J, Taelman H, Dhote R, et al. Pulmonary tuberculosis in Kigali, Rwanda. Impact of human immunodeficiency virus infection on clinical
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adults with suspected tuberculosis, Botswana. Int J Tuberc Lung Dis 2003;7(8):714–723. Kudjawu Y, Massari V, Sow O, et al. Benefit of amoxicillin in differentiating between TB suspects whose initial AFB sputum smears are negative. Int J Tuberc Lung Dis 2006;10(4):441–446. Dooley KE, Golub J, Goes FS, et al. Empiric treatment of community-acquired pneumonia with fluoroquinolones, and delays in the treatment of tuberculosis. Clin Infect Dis 2002;34(12):1607–1612. Ginsburg AS, Hooper N, Parrish N, et al. Fluoroquinolone resistance in patients with newly diagnosed tuberculosis. Clin Infect Dis 2003; 37(11):1448–1452. TB Partnership. The Global Plan to Stop TB 2006– 2015. [online]. Accessed 14 March 2007. Available from URL:http://www.stoptb.org/globalplan/ Aaron L, Saadoun D, Calatroni I, et al. Tuberculosis in HIV-infected patients: a comprehensive review. Clin Microbiol Infect 2004;10(5):388–398. Hnizdo E, Singh T, Churchyard G. Chronic pulmonary function impairment caused by initial and recurrent pulmonary tuberculosis following treatment. Thorax 2000;55(1):32–38. Thompson JR. Mechanisms of fatal pulmonary hemorrhage in tuberculosis. Am J Surg 1955;89: 637–644. Muthuswamy PP, Akbik F, Franklin C, et al. Management of major or massive hemoptysis in active pulmonary tuberculosis by bronchial arterial embolization. Chest 1987;92(1):77–82. Mal H, Rullon I, Mellot F, et al. Immediate and long-term results of bronchial artery embolization for life-threatening hemoptysis. Chest 1999;115(4): 996–1001. Lee J-H, Kwon S-Y, Yoon H-I, et al. Haemoptysis due to chronic tuberculosis vs. bronchiectasis: comparison of long-term outcome of arterial
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73. Morris CD. Sputum examination in the screening and diagnosis of pulmonary tuberculosis in the elderly. Q J Med 1991;81(296):999–1004. 74. Fox W, Andrews RH, Ramakrishnan CV. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21: 51–144. 75. Canueto-Quintero J, Caballero-Granado FJ, HerreroRomero M, et al. Epidemiological, clinical, and prognostic differences between the diseases caused by Mycobacterium kansasii and Mycobacterium tuberculosis in patients infected with human immunodeficiency virus: a multicenter study. Clin Infect Dis 2003;37(4):584–590. 76. Gallant JE, Ko AH. Cavitary pulmonary lesions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;22(4):671–682. 77. Casado JL, Navas E, Frutos B, et al. Salmonella lung involvement in patients with HIV infection. Chest 1997;112(5):1197–1201. 78. Post FA, Wood R, Pillay GP. Pulmonary tuberculosis in HIV infection: radiographic appearance is related to CD4þ T-lymphocyte count. Tuber Lung Dis 1995;76(6):518–521. 79. Johnson JL, Vjecha MJ, Okwera A, et al. Impact of human immunodeficiency virus type-1 infection on the initial bacteriologic and radiographic manifestations of pulmonary tuberculosis in Uganda. Makerere University-Case Western Reserve University Research Collaboration. Int J Tuberc Lung Dis 1998;2(5):397–404. 80. Keiper MD, Beumont M, Elshami A, et al. CD4 T lymphocyte count and the radiographic presentation of pulmonary tuberculosis. A study of the relationship between these factors in patients with human immunodeficiency virus infection. Chest 1995; 107(1):74–80.
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Pleural effusion and empyema in adult tuberculosis Helmuth Reuter
Tuberculosis is the most common cause of pleural effusions in young adults in countries where TB is endemic and a common manifestation of extrapulmonary TB, especially in people who are coinfected with the human immunodeficiency virus (HIV) and TB.1–8 The relative frequency of pulmonary and extrapulmonary disease depends on the degree of immune deficiency in the patients studied. In the USA, over 70% of TB patients with advanced HIV disease have extrapulmonary TB, as compared with 24–45% of those with less severe immune deficiency.9 Similarly increased rates of extrapulmonary TB associated with HIV have been reported from Africa, where the majority of people coinfected with HIV and TB live.1,5,10–12 Tuberculous pleurisy is categorized as extrapulmonary TB despite the intimate anatomical relationship between the pleural membranes and the lungs.13–18 Tuberculous pleural effusion is a common form of extrapulmonary TB and amounts to > 20% of all extrapulmonary TB cases.6,7,19,20 Tuberculous pleurisy has been shown to be particularly strongly associated with HIV in studies from Africa and the USA.1,7,21,22 Pleural TB can be seen as an early progression of primary disease or it can be a complication of postprimary disease. Prior to the HIV epidemic, pleural TB was seen early in postprimary disease when, in the absence of treatment, about 65% of patients would go on to develop chronic organ TB within 5 years.23 Prior to the advent of the HIV epidemic the majority of cases responded well to treatment,2 but more recent reports suggest that the prognosis is less favourable in HIV-infected tuberculous pleurisy patients with an all-cause mortality exceeding 20% during the first 2 months of anti-TB treatment.6,7
EPIDEMIOLOGY OF PLEURAL TUBERCULOSIS Early reports of patients with tuberculous pleurisy suggested that the disease had usually an acute onset and occurred in young adults.24,25 Although several authors have more recently reported that the mean patient age has gradually risen,26,27 this tendency has not been universal and in several large studies the mean age of presentation has been younger than 35 years.6,7,21,28,29 Overall, pleural TB is more frequently diagnosed in males than in females.6,7,30
PATHOGENESIS There are two mechanisms by which the pleural space may become involved in TB, and the difference in pathogenesis results in different clinical presentations, approaches to diagnosis,
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treatment and sequelae. In the majority of cases, tuberculous pleurisy arises as the result of a delayed-type hypersensitivity response to Mycobacterium tuberculosis organisms that gain access to the pleural space presumably during the first 6–12 weeks after primary infection,28 although in some patients the pleurisy seems to present as manifestation of reactivation TB.31 Although a significant proportion of patients have no radiographic evidence of involvement of the lung parenchyma, subpleural parenchymal disease is nearly always demonstrable by lung dissections.24 This suggests that pleural TB usually develops from the rupture of a subpleural caseous focus and the accompanying discharge of tubercle bacilli into the pleural cavity.24,28 Exposure of the mycobacterial antigens to pleural lymphocytes and macrophages results in a localized cellmediated immune response characterized by granulomatous inflammation of the pleura and the accumulation of lymphocytic pleural exudates.32–35 The majority of pleural biopsy samples in proven tuberculous pleurisy demonstrate granulomatous lesions (with or without caseating necrosis), but about 30% of biopsy samples demonstrate non-specific fibrinous or histiocyte-rich chronic inflammatory changes without granulomata.6,36 The normal pleural space contains less than 20 mL of fluid, which has an electrolyte composition of interstitial fluid and low protein content. An accumulation of pleural fluid occurs when the balance of capillary permeability, lymph drainage, and hydrostatic and osmotic forces are disturbed; in the case of tuberculous pleurisy, the increased capillary permeability due to inflammatory response plays the most important role and results in some individuals with clinically detectable pleural effusion.15,24,28 Tuberculous pleural exudate is characterized by a predominance of lymphocytes.6,17 In HIV-uninfected patients the majority of the infiltrating leucocytes are CD4þ CD29þ T-lymphocytes, which are highly responsive to M. tuberculosis-derived proteins.37,38 Pleural lymphocyte counts are generally lower in HIV-infected patients with tuberculous pleural effusions than in HIV-uninfected tuberculous pleurisy patients.6,7 In addition, the lymphocytic infiltrate is not dominated by CD4þ T-lymphocytes,6 which is similar to the findings in HIV-infected patients with tuberculous pericardial effusion,39 as well as with bronchoalveolar lavage findings from HIV-infected individuals with pulmonary disease.40 Recent evidence suggests that patients with tuberculous pleural effusion have significantly higher levels of interferon-gamma (IFN-g) in the pleural fluid than in peripheral blood, thus exemplifying localization of a predominantly Th1 immune response in the pleural fluid comparable to the process described in the pathogenesis of tuberculous pericardial effusion.17,39,41,42 The high levels of IFN-g in
CHAPTER
Pleural effusion and empyema in adult tuberculosis
tuberculous pleural effusion can provide a highly sensitive and specific diagnostic test for pleural TB.17,41,43 The majority of pleural tissue and pleural fluid cultures from patients diagnosed with pleural TB are culture-negative,6,7,34 suggesting low numbers of viable tubercle bacilli in the pleural exudate. Several studies have shown that, in HIV-infected patients with tuberculous pleurisy pleural fluid smears, pleural biopsy histology and cultures are more likely to be positive for M. tuberculosis than in HIV-uninfected patients with tuberculous pleural effusions.6,7,44 It seems likely that the diminished number of CD4þ T-lymphocytes favours extension of M. tuberculosis infection from the lung to the pleural space and also results in a less effective mycobactericidal response in the pleural cavity, leading to increased numbers of tubercle bacilli demonstrable in the pleural exudate compared with that of HIV-uninfected or -infected patients with higher CD4 counts. Kitinya and colleagues36 demonstrated significant histomorphological differences in tuberculous pleurisy between HIV-infected and -uninfected patients, and found that the former group with hypo- or non-reactive morphology had less favourable clinical outcomes on anti-TB chemotherapy. The second variety of tuberculous involvement of the pleura is a true empyema, which refers to the presence of pus in the pleural compartment. This condition is much less common than tuberculous pleurisy with effusion and usually results from rupture of a cavity (Fig. 30.1) or an adjacent parenchymal focus containing caseous material and large numbers of tubercle organisms which are discharged into the pleural space.45 Less often, rupture of caseous paratracheal lymph nodes, paravertebral abscesses or osteomyelitis of the ribs can result in empyema thoracis.18 In patients with tuberculous empyema the pleural fluid is generally thick and cloudy and may look like frank pus or chyle (pseudochylous
30
effusion) due to high levels of cholesterol in the fluid. The fluid usually has a high leucocyte count with a predominance of lymphocytes. Direct microscopy of smears and mycobacterial cultures are usually positive, making pleural biopsy unnecessary.18
CLINICAL FEATURES OF PLEURAL TUBERCULOSIS Pleural TB usually manifests as a unilateral pleural effusion. In the majority of cases symptom duration ranges from a few days to a few weeks and the most frequently encountered symptoms include pleuritic chest pain, non-productive cough, dyspnoea and fever.7,18 The onset is usually acute although occasionally it may be more protracted with patients having less distinctive complaints, which may include mild chest discomfort, non-productive cough, weight loss, anorexia and low-grade fever. HIV-infected patients usually present with more severe disease and longer duration of symptoms than HIV-uninfected patients.6,7,46 In HIV-prevalent settings extrapulmonary TB should be expected in all patients who have unintentional weight loss associated with night sweats, fever, dyspnoea and enlarged lymph nodes. If the physical examination reveals absent or reduced breath sounds, diminished chest wall movement and dullness to percussion, tuberculous pleural effusion should be suspected. The sharp stabbing pain of classical pleurisy is often not present and a pleural effusion may develop entirely painlessly until it causes local discomfort or dyspnoea by virtue of its size. Effusions are usually unilateral and affect the left and right side equally.7 Rarely, patients present with an entity known as tuberculous polyserositis, referring to patients with coexistent bilateral pleural, peritoneal and pericardial tuberculous disease. Occasionally, tuberculous pleurisy goes entirely unnoticed, and the process resolves spontaneously within a few weeks or months. However, a significant number of patients subsequently develop more serious forms of TB23 and this seems to be more prevalent in HIV-infected individuals.6,7 HIV-infected patients with tuberculous pleurisy often have other HIV-associated features such as oral candidiasis, chronic diarrhoea, severe wasting, herpes zoster, maculopapular rash and generalized lymphadenopathy.6,7 Although TB is the most likely diagnosis in HIV-infected individuals, other causes of pleural effusion should be considered, specifically Kaposi’s sarcoma, parapneumonic effusion, non-Hodgkin’s lymphoma and rarely pleural cryptococcosis.6,7 HIV-associated nephropathy or cardiomyopathy may present with transudative pleural effusions. The presentation of tuberculous empyema is usually severe and symptoms are dominated by high swinging fever, dyspnoea, chest pain and often cough with expectoration. Physical examination may reveal chest wall tenderness, dullness to percussion and digital clubbing. This type of pleural involvement has a tendency to burrow through soft tissues and may drain spontaneously through the chest wall, presenting as a fluctuant mass of the chest wall or as a draining sinus.18
DIAGNOSTIC TESTS Fig. 30.1 The chest radiograph of a 35-year-old male patient who presented with a 6-month history of productive cough, weight loss and night sweats.The radiograph demonstrates a large cavity in the right upper lobe with an effusion with an air–fluid level at the base. Aspiration yielded purulent fluid culture positive for M. tuberculosis, confirming diagnosis of tuberculous empyema.
The diagnostic approach to a patient with suspected tuberculous pleural effusion is four-pronged. The clinical findings give important clues as to underlying TB and chest radiology will define the extent and localization of the fluid and may point to pulmonary and sometimes extrapulmonary disease. Thirdly, the pleural fluid itself must be examined biochemically, cytologically and microbiologically. Finally,
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a pleural biopsy may be needed to make a definitive diagnosis. HIV testing should be offered to all patients suspected of pleural or any other form of extrapulmonary TB and patients found to be positive should be referred for HIV care or be started on antiretroviral therapy according to national guidelines.
CHEST RADIOLOGY Pleural TB usually presents as a unilateral pleural effusion, which may occasionally, and in the case of tuberculous empyema more commonly, be encysted or multiloculated. The size of the pleural effusion may vary from a small effusion obliterating the costophrenic angle (Fig. 30.2) to a massive effusion (Fig. 30.3). HIV-coinfection does not
seem to influence the size of effusion,7 but it is associated with a higher frequency of concomitant parenchymal disease and atypical chest radiography (Fig. 30.2), such as mediastinal lymphadenopathy and miliary disease.7,21,46 The radiographic differentiation between encysted effusions and mass lesions of the pleura, mediastinum, chest wall or lungs may be difficult. Encystment usually occurs in the costoparietal regions, especially along the posterior parietal pleural surface on the right side.18 A lateral decubitus film aids in distinguishing subpulmonic encystment from subpulmonic collection of free fluid as both these conditions present with a raised hemidiaphragm with or without a blunted costophrenic angle. Ultrasonography of the chest plays an important role in diagnosing pleural thickening, pleural fluid collection, fibrin bands and septations. It can thus be used to identify multiloculated pleural effusions and differentiate between encysted fluid and free fluid.18 Encysted mediastinal pleural effusion can present as a mediastinal mass lesion and this rare diagnosis can be best confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). In addition to visualizing pleural and mediastinal fluid collections, contrast-enhanced CT scan and MRI of the thorax may be useful in identifying the underlying pulmonary lesion, pericardial disease, and mediastinal, hilar or paratracheal lymphadenopathy and assessing the pleural loculation and thickening.
AETIOLOGICAL DIAGNOSIS OF TUBERCULOUS PLEURISY When a patient is found to have a pleural effusion an effort should be made to determine the cause and the first step is to determine whether the effusion is a transudate or an exudate, because the differential diagnosis of pleural effusions is based thereon (Box 30.1). A definitive diagnosis of tuberculous pleural effusion is made if the patient satisfies any one of the following criteria:47 Fig. 30.2 The chest radiograph of a 38-year-old HIV-infected woman with a CD4þ lymphocyte count of 52 cells/mL who presented with symptoms of TB. The radiograph demonstrates diffuse nodular changes and blunted right costophrenic angle suggestive of a pleural effusion. Sputum smear was positive for acid-fast bacilli.
1. positive stain for acid-fast bacilli (AFB) and/or positive culture for M. tuberculosis from pleural fluid, pleural tissue, sputum, aspirated lymph node or any other body site; and/or 2. demonstration of necrotizing granulomata and/or AFB in pleural biopsy sample; and/or 3. the patient has a positive purified protein derivative (PPD) skin test ( 10 mm) and a pleural biopsy sample showing granulomata. These criteria are, however, not invariably satisfied and numerous studies support the diagnostic use of differential leucocyte count and biochemical markers such as IFN-g, adenosine deaminase (ADA), ADA isoenzymes and polymerase chain reaction for M. tuberculosis.13,28,29,41,43,48–55
BIOCHEMICAL TESTS
Fig. 30.3 The chest radiograph of a 22-year-old man who presented with dyspnoea, night sweats and loss of weight demonstrates a large right-sided pleural effusion.
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In patients with tuberculous pleurisy the pleural fluid is typically clear or straw-coloured, although cloudy or serosanguinous fluid may also be obtained.13–16 Tuberculous effusion is characterized by a protein content > 30 g/L and glucose concentration below the serum glucose concentration.6,13–16 Pleural aspirates are classified as exudates if they fulfil more than one of the following criteria: protein level 30 g/L, pleural fluid/serum protein ratio 0.5, pleural fluid LDH 200 U/L and pleural fluid/serum LDH ratio 0.6.56 Three biochemical tests have been shown to be particularly useful in the diagnosis of pleural TB, namely the determination of ADA activity, the measurement of IFN-g levels and lysozyme estimation.16,43,53–55 ADA is an enzyme of purine metabolism which catalyses conversion of adenosine into inosine
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Pleural effusion and empyema in adult tuberculosis
Box 30.1 Differential diagnoses of pleural effusions Transudative pleural effusions Congestive cardiac failure. Nephrotic syndrome. Cirrhosis. Pulmonary emboli. Peritoneal dialysis. Hypothyroidism. Superior vena cava obstruction. Constrictive pericarditis. Urinothorax. Exudative pleural effusions Infectious diseases TB Bacterial infections (parapneumonic effusions or empyema) Parasitic infections Fungal infections Viral infections. Neoplastic disease Metastatic disease Mesothelioma Kaposi’s sarcoma Lymphoma. Connective tissue diseases Rheumatoid pleuritis Systemic lupus erythematosus Adult Still’s disease. Gastrointestinal disease Pancreatic disease Amoebiasis Intraabdominal abscesses After abdominal surgery Oesophageal perforation. Haemothorax. Miscellaneous causes Uraemia Drug-induced pleural disease Asbestos exposure Chylothorax Post-cardiac injury syndrome. Adapted from WHO recommendations for HIV-prevalent and resource constrained settings (http://www.who.int/tb/publications/2006/tbhiv_recommendations.pdf)
and is found in most human tissues particularly in the lymphoid tissues. High ADA activity has also been reported in effusions due to rheumatoid arthritis, lymphoma, chronic lymphatic leukaemia, empyema, parapneumonic effusions and mesothelioma,16,54 and it should be used in conjunction with differential white blood cell count.55 ADA exists as two isoenzymes, ADA1 and ADA2, each with unique biochemical properties. In tuberculous pleural effusion, ADA2 isoenzyme is considered to be primarily responsible for total ADA activity, while, in parapneumonic effusions, the ADA1 isoenzyme is the major isoenzyme of ADA.55 The clinical usefulness of measuring isoenzymes of ADA in pleural effusions still needs to be established. Lysozyme, a bacteriolytic protein widely distributed in body fluids and in many cells, is a marker of general inflammatory response. Lysozyme estimation has been found to help in identifying TB pleural effusion.16 IFN-g is a cytokine produced by activated T-lymphocytes and plays a fundamental role in the cell-mediated immune response to
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M. tuberculosis; detecting markedly elevated levels of pleural fluid IFN-g is highly specific for the diagnosis of pleural TB.17,41,43 Aside from measuring IFN-g directly in pleural fluid, it is possible to measure IFN-g released by sensitized T cells after stimulation with two M. tuberculosis-specific antigens, namely early secreted antigenic target 6 (ESAT6) and culture filtrate protein 10 (CFP-10). Two assays are currently available as commercial kits: the T-Spot.TB test (Oxford Immunotec, Oxford, UK) and the QuantiFERON-TB Gold (QFT-G; Cellestis, Carnegie, Australia) assay.57 Studies suggest that these sensitive and specific T-cell assays can be used for the diagnosis of tuberculous pleurisy,58 but the use is currently limited by high cost and the non-availability of adequate laboratory infrastructure to perform enzyme-linked immunospot assays, and by the absence of conclusive evidence on which to base formal recommendations.
PLEURAL FLUID DIFFERENTIAL WHITE BLOOD CELL COUNT AND CYTOLOGY Cytology plays an important role in the differentiation of pleural diseases and has been used effectively for the diagnosis of pleural TB.18,59,60 The pleural fluid leucocyte count is usually between 800 and 5000 106 cells/L with 50–90% of these being lymphocytes.7,13–16,18 Pleural fluid leucocyte and lymphocyte counts are generally 30–40% lower in HIV-infected patients with tuberculous pleurisy than in HIV-uninfected patients with pleural TB.7 Rarely, and usually early in the disease, the pleural fluid may reveal predominant neutrophils.13–18 The presence of a large number of mesothelial cells (> 1% of white blood cells) provides strong evidence against the diagnosis of pleural TB, although cases with numerous mesothelial cells in the fluid have been reported.13–17 The presence of neoplastic cells is highly suggestive of malignant involvement of the pleura and the predominance of neutrophils suggests a diagnosis of a parapneumonic effusion or bacterial empyema.
NUCLEIC ACID AMPLIFICATION TECHNIQUES Many of the nucleic acid amplification (NAA) techniques are not widely available. Of these molecular methods, polymerase chain reaction (PCR) has been applied to pleural fluid to detect various sequences representing the DNA of M. tuberculosis. The sensitivity and specificity for the diagnosis of pleural TB varied between 22% and 81% and between 77% and 100%, respectively.43,48,49,51,52 PCR test results should thus be interpreted with cautious consideration of the clinical setting and a PCR result alone should not be construed as the sole evidence on which TB treatment is initiated or withheld.
TUBERCULIN SKIN TESTS Tuberculin positivity in HIV-uninfected patients with pleural TB varies between 73% and 93%,17,26,31 but it is not clear how sensitive the test is in HIV-infected patients. The usefulness of the tuberculin skin test is furthermore limited by its inability to differentiate latent TB infection from active disease, and the fact that it is not specific for M. tuberculosis infection.
MICROBIOLOGICAL EXAMINATION Whenever possible, the diagnostic process should include a smear examination for AFB and culture for M. tuberculosis. In patients with tuberculous pleural effusions smear microscopy is positive in
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< 15% and mycobacterial culture positive in 12–70%, respectively.6,7,13–16,18 Liquid media are superior to solid media for the culture of pleural tissue and pleural fluid specimens.7,34,61 Mycobacterial cultures are more likely to be positive in HIV-infected patients with pleural TB than in HIV-uninfected patients with the disease,6,7,44 with the highest proportion of positivity among those patients with the lowest CD4 counts.7 A positive culture provides the definitive proof of TB and, in addition, data on drug susceptibility of the tubercle bacilli; it is advisable to send pleural fluid, and when available also pleural tissue, for culture on liquid media. The major disadvantage of culture is the long duration needed before the results become available.
PLEURAL BIOPSY Percutaneous needle biopsy of the parietal pleura was first described in 1955 and has been a useful tool in the diagnosis of pleural TB.62,63 Specimens of parietal pleura can be obtained by means of a Cope needle, an Abrams needle,64,65 or by videoassisted thoracoscopy and biopsy. Kirsch and colleagues47 have suggested a modified Abrams technique that allows suctioning of each specimen into a syringe placed at the hub of the needle without the necessity of complete needle withdrawal after each sample. The sensitivity of the histological study of pleural biopsy specimens for the diagnosis of tuberculous pleurisy ranges from 40% to 80%,62,66,67 and depends largely on whether the specimen contains pleural tissue as opposed to fat and intercostal muscle for analysis. There is uncertainty about the optimal number of pleural biopsy specimens that should be sent for histology and culture. Even in the hands of experienced operators up to 50% of pleural biopsy specimens may not contain any pleural tissue, and it is thus suggested to obtain more than six biopsies;62 six for histological analysis and one specimen for mycobacterial culture because of the additional diagnostic yield gained by culturing pleural biopsy samples for mycobacteria.7,68 It is standard procedure to send at least one pleural biopsy sample for culture.62,69–72 It is important to note that negative histological analysis does not preclude a positive culture for M. tuberculosis, especially in HIV-coinfected individuals.6,7,62 Combining pleural biopsy histology and pleural tissue culture increases the diagnostic yield to 90%.62
Box 30.2 Guidelines for the diagnosis and immediate management of suspected pleural tuberculosis in resource-constrained settings Essential investigations HIV test (rapid if possible). Chest radiograph. Sputum smears. Aspiration and inspection of pleural fluid.a Differential white cell count and protein determination of aspirate. High suspicion of TB if: Unilateral effusion. Aspirate of fluida is Clear, straw-coloured and clots on standing in a tube without anticoagulants. History of weight loss, night sweats and fever. Evidence of TB elsewhere. Findings that suggest non-tuberculous aetiology Bilateral effusions (possibly cardiac failure, nephrotic syndrome or parapneumonia). Clinical evidence of Kaposi’s sarcoma or other malignancy. Aspirate of fluida is Cloudy or resembling pus (probably empyema). Fails to clot on standing in a tube without anticoagulants (does not exclude TB, but cardiac failure or hypoalbuminaemia are more likely). Immediate management Features of TB only Start TB treatment. Features of non-tuberclous effusion Send aspirate for differential white cell count, protein and, if available, cytology: 50% lymphocytes and protein > 30 g/L suggests TB. Treat for TB if the only unusual finding is failure of aspirate to clot or there is no alternative diagnosis by 7 days. a
The aspirate should be put in a plain tube (with no anticoagulant) in order to observe appearance and clotting. A second aliquot should be placed in an anticoagulated tube, so that a differential white blood cell count or protein determination can be requested if there are any findings to suggest a non-tuberculous diagnosis. Adapted from WHO.73
DIAGNOSTIC APPROACH IN RESOURCE-CONSTRAINED SETTINGS The World Health Organization (WHO) recommends that, in resource-constrained settings with a high TB burden, treatment for extrapulmonary TB should be initiated as soon as possible and that the identification of underlying HIV infection should not be delayed.73 Despite its high diagnostic yield pleural biopsy is not recommended because it is unnecessarily invasive and has the potential to cause additional complications and diagnostic delay. Suspected pleural effusion should be confirmed by chest radiography and immediate aspiration of fluid whenever possible. Treatment with broad-spectrum antibiotics is not required before TB treatment in patients with unilateral effusions if the pleural fluid is clear and clots on standing unless there is clinical concern about bacterial pneumonia.73 Patients with unusual findings such as bilateral effusions or cloudy or bloody aspirates should undergo additional investigations detailed in Box 30.2 The formation of
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visible clots in the aspirate within a few minutes of being placed into a plain tube (no anticoagulant) confirms a high protein content of the fluid, which suggests pleural TB. According to the WHO no further investigations are needed if the aspirate is clear and strawcoloured and there are no features suggestive of a diagnosis other than TB.73 Failure of the aspirate to clot does not exclude TB and such patients can still be started on TB treatment immediately if there are no other unusual findings (Box 30.2), but laboratory analysis of fluid is needed to determine protein content and differential white blood cell count (expect 50% lymphocytes in a tuberculous effusion). The pleural fluid protein content will usually exceed 30 g/L in patients with pleural TB, but it may be lower in severely wasted patients.73 If thoracentesis is not available, TB treatment should be started immediately, particularly if the patient is HIV-infected, unless there are clinical or radiological features suggestive of a diagnosis other than TB.
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Pleural effusion and empyema in adult tuberculosis
TREATMENT OF PLEURAL TUBERCULOSIS The treatment for pleural TB is the same as for smear-positive pulmonary TB, namely directly observed treatment, short-course (DOTS) according to the WHO guidelines.74 While 6 months of treatment may be sufficient for most patients, each patient must be individually assessed and, where relevant as for example in patients with disseminated disease or those with a slow clinical response, treatment duration may have to be extended.75 For a patient started on anti-TB treatment without bacteriological or histological confirmation, the clinical and radiographic responses to treatment should be assessed after 1 month. If there is no improvement, the patient needs to be reassessed and an alternative diagnosis sought. All patients receiving anti-TB therapy should be carefully monitored for adverse drug reactions. HIV-infected patients who present with TB should be considered for cotrimoxazole preventive therapy,76 and pyridoxine should be given in addition to the patient’s anti-TB treatment.77 Patients need to be evaluated for antiretroviral therapy according to local practice and guidelines.78 The effect of adjunctive corticosteroids on the treatment outcomes of pleural TB is uncertain. Wyser and colleagues79 found that early complete drainage of the pleural space is adequate and that the addition of adjunctive prednisone does not relieve symptoms earlier and also does not influence residual pleural thickening. A systematic review of all randomized and quasi-randomized trials on the effect of adjunctive corticosteroids conducted in HIV-uninfected patients with tuberculous pleural effusion rendered similar results.80 There was no difference in residual lung function between patients with TB pleural effusion who received corticosteroid treatment and those who did not at completion of treatment; the authors concluded that there was insufficient evidence to know whether adjunctive corticosteroid treatment is effective in patients with TB pleural effusion. In a more recent randomized trial that included HIVinfected patients Elliott and colleagues81 found no benefit in the group of patients who received adjunctive corticosteroids, and, if anything, their study suggested possible harm to HIV-infected patients. Based on the current evidence corticosteroids should thus not be given routinely as an adjunct to TB treatment for patients with pleural TB. However, corticosteroids may be valuable in selected patients who present with pleural effusion with significant pyrexia, including those with an immune reconstitution inflammatory syndrome,82 and also in those with severe pleuritic chest pain not responding well to anti-TB drugs alone.
MANAGEMENT OF EMPYEMA The principles of treatment are obliteration of the empyema space and eradication of the infection. In the first instance, therefore, treatment involves draining of the pleural space by chest drain, open thoracotomy or video-assisted thorascopic surgery.
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The two surgical procedures achieve the best drainage in gross empyema or loculated effusions, but are limited by cost, operative risk and local availability.83 The anatomical features of complicated pleural infections are better characterized by thoracic ultrasonography or CT scanning than by frontal chest radiograph.84 Knowing the extent of pleural septation and loculation guides the decisions on the size and placement of the intercostal drain and the need for surgical drainage. The use of adjunctive intrapleural streptokinase is controversial and has not specifically been studied for tuberculous empyema. Several studies have shown that fibrinolysis increases the volume of fluid drained and that the use of fibrinolytic agents reduces the need for surgical procedures in patients with complicated loculated parapneumonic effusions,85–87 but not specifically in cases of tuberculous empyema.87–89 In a large randomized controlled trial the use of adjunctive streptokinase was not associated with any benefit, and although the enrolment criteria in this trial were less stringent and based on chest radiography rather than ultrasonography or CT, the routine use of streptokinase in tuberculous empyema cannot currently be recommended.90 The accepted management of empyema includes the insertion of an intercostal chest drain using a sterile technique and daily rinse therapy with 100 mL of normal saline. The rinse therapy should be continued for 7 days or until the net drainage of pleural fluid is less than 100 mL per day. After injection of the normal saline the drain should be clamped for 2 hours before letting the pleural fluid drain. Ideally, all patients should be investigated ultrasonographically before the chest drain is removed, because chest radiography does not allow sensitive differentiation between residual pleural fluid, pleural thickening and underlying parenchymal disease. After removal of the drain, chest radiography is mandatory to exclude the presence of a pneumothorax. It is likely that in the majority of patients with empyema the initial diagnosis will be that of bacterial empyema and broadspectrum antibiotics will usually be administered parenterally until bacterial cultures of the aspirated pleural fluid and blood are negative and a definitive alternative diagnosis of tuberculous empyema has been made. It is important to secure adequate pain relief and also consider the fluid and nutritional needs of the usually toxic ill patient. In patients with chronic tuberculous empyema, the procedure of choice is surgical decortication by open or even a video-assisted thoracoscopic approach.91,92 To prevent the development of fibrothorax (Fig. 30.4), the surgical intervention should not be delayed too long.
ACKNOWLEDGEMENTS The chest radiographs and computerized tomography images illustrating this chapter were provided by Professor Elvis Irusen, Cochairman and Clinical Director of Pulmonology Unit, University of Stellenbosch.
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Fig. 30.4 (A) A chest radiograph of a 46-year-old man following 9 months of anti-TB treatment for pleural TB demonstrating scoliosis, rib crowding (on the left), pleural thickening, calcification and a pseudotumour. (B, C) Computed tomography images of the chest of same patient demonstrating the contracted left hemithorax, pleural thickening, calcification and absence of parenchymal ‘tumour’.
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Pleural effusion and empyema in adult tuberculosis 19. Antonucci G, Girardi E, Armignacco O, et al. Tuberculosis in HIV-infected subjects in Italy: a multicentre study. The Gruppo Italiano di Studio Tubercolosi e AIDS. AIDS 1992;6:1007–1013. 20. Jones BE, Young SMM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993;148:1292–1297. 21. Batungwanayo J, Taelman H, Allen S, et al. Pleural effusion, tuberculosis and HIV-1 infection in Kigali, Rwanda. AIDS 1993;7:73–79. 22. Frye MD, Pozsik CJ, Sahn SA. Tuberculous pleurisy is more common in AIDS than in non-AIDS patients with tuberculosis. Chest 1997;112:393–397. 23. Roper WH, Waring JJ. Primary serofibrinous pleural effusion in military personnel. Am Rev Tuberc 1955;71:616–634. 24. Stead WW, Eichenholz A, Strauss HK. Operative and pathologic findings in twenty-four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous. Am Rev Respir Dis 1955;30:473–502. 25. Levine H, Szanto PB, Cugell DW. Tuberculous pleurisy. An acute illness. Arch Intern Med 1968;122:329–332. 26. Epstein DM, Kline LR, Albelda SM, et al. Tuberculous pleural effusions. Chest 1987;91:106–109. 27. Moudgil H, Sridhar G, Leitch AG. Reactivation disease: the commonest form of tuberculous pleural effusion in Edinburgh, 1980–1991. Respir Med 1994;88:301–304. 28. Valde´s L, A´lvarez D, San Jose´ E, et al. Tuberculous pleurisy. Arch Intern Med 1998;158:2017–2021. 29. Poyraz B, Kaya A, Ciledag A, et al. Diagnostic significance of gamma-interferon in tuberculous pleurisiy. Tu¨berk Toraks 2004;52:211–217. 30. Farer LS, Lowell LM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979;109:205–217. 31. Antoniskis D, Amin K, Barnes PF. Pleuritis as a manifestation of reactivation tuberculosis. Am J Med 1990;89:447–450. 32. Paterson HC. The pleural reaction to inoculation with tubercle bacilli in vaccinated and normal guinea pigs. Am Rev Tuberc Pulmon Dis 1917;1:353. 33. Yamamoto S, Dunn CJ, Wiloughby DA. Studies on delayed hypersensitivity pleural exudates in guinea pigs, II: the interrelationship of monocytic and lymphocytic cells with respect to migration activity. Immunology 1976;30:513–519. 34. Berger HW, Mejia E. Tuberculous pleurisy. Chest 1973;63:88–92. 35. Ellner JJ. Pleural fluid and peripheral blood lymphocyte function in tuberculosis. Ann Intern Med 1978;89:932–933. 36. Kitinya JN, Richter C, Perenboom R, et al. Influence of HIV-status on pathological changes in tuberculous pleuritis. Tuber Lung Dis 1994;75:195–198. 37. Barnes PF, Mistry SD, Cooper CL, et al. Compartmentalization of a CD4þ T lymphocyte subpopulation in tuberculous pleuritis. J Immunol 1989;142:1114–1119. 38. Orme IM, Anderson P, Boom WH. T cell responses to Mycobacterium tuberculosis. J Infect Dis 1993;167:1481–1497. 39. Reuter H, Burgess LJ, Carstens ME, et al. Characterization of the immunologic features of tuberculous pericardial effusions in HIV-positive and HIV-negative patients in contrast with nontuberculous effusions. Tuberculosis 2006;86:125–133. 40. Law KF, Jagirdar J, Weiden MD, et al. Tuberculosis in HIV-positive patients—cellular response and immune activation in the lung. Am J Respir Crit Care Med 1996;153:1377–1384. 41. Sharma SK, Suresh V, Mohan A, et al. A prospective study of sensitivity and specificity of adenosine deaminase estimation in the diagnosis of tuberculosis pleural effusion. Indian J Chest Dis Allied Sci 2001;43:149–155. 42. Burgess LJ, Reuter H, Carstens ME, et al. Cytokine production in patients with tuberculous pericarditis. Int J Tuberc Lung Dis 2002;6:439–446.
43. Villegas MV, Labrada LA, Saravia NG. Evaluation of polymerase chain reaction, adenosine deaminase and interferon-g in pleural fluid for the differential diagnosis of pleural tuberculosis. Chest 2000; 118:1355–1364. 44. Richter C, Perenboom R, Swai ABM, et al. Diagnosis of tuberculosis in patients with pleural effusion in an area of HIV infection and limited diagnostic facilities. Trop Geogr Med 1994;46:293–297. 45. Johnson TM, McCann W, Davey WH. Tuberculous bronchopleural fistula. Am Rev Respir Dis 1973; 107:30–41. 46. Richter C, Perenboom R, Mtoni I, et al. Clinical features of HIV-seropositive and HIV-seronegative patients with tuberculous pleural effusion in Dar es Salaam, Tanzania. Chest 1994;106:1471–1475. 47. Kirsch CM, Kroe M, Jensen WA, et al. A modified Abram’s needle biopsy technique. Chest 1995; 108:982–986. 48. De Lassence A, Lecossier D, Pierre C, et al. Detection of mycobacterial DNA in pleural fluid from patients with tuberculous pleurisy by means of the polymerase chain reaction: comparison of two protocols. Thorax 1992;47:265–269. 49. De Wit D, Maartens G, Steyn L. A comparative study of the polymerase chain reaction and conventional procedures for the diagnosis of tuberculous pleural effusion. Tuber Lung Dis 1992;73:262–267. 50. Valde´s L, San Jose´ E, A´lvarez D, et al. Diagnosis of tuberculous pleurisy using biological parameters adenosine deaminase, lysozyme and interferongamma. Chest 1993;103:458–465. 51. Verma A, Dasgupta N, Aggrawal AN, et al. Utility of a Mycobacterium tuberculosis GC-rich repetitive sequence in the diagnosis of tuberculous pleural effusion by PCR. Indian J Biochem Biophys 1995;32:429–436. 52. Querol JM, Minguez J, Garcia-Sanchez E, et al. Rapid diagnosis of pleural tuberculosis by polymerase chain reaction. Am J Respir Crit Care Med 1995;152:1977–1981. 53. Perez-Rodriguez E, Perez Walton IJ, Sanchez Hernandez JJ, et al. ADA1/ADAp ratio in pleural tuberculosis: an excellent diagnostic parameter in pleural fluid. Respir Med 1999; 93:816–821. 54. Ocana I, Martinez-Vazquez JM, Segura RM, et al. Adenosine deaminase in pleural fluids. Test for diagnosis of tuberculous pleural effusion. Chest 1983;84:51–53. 55. Burgess LJ, Maritz FJ, Le Roux I, et al. Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio increased specificity for the diagnosis of tuberculous pleuritis. Chest 1996;109:414–419. 56. Light RW, MacGregor MI, Luchsinger PC, et al. Pleural effusion: the diagnostic separation of transudates and exudates. Ann Intern Med 1972; 77:507–513. 57. Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007; 92:446–452. 58. Pai M, Riley LW, Colford JM Jr . Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761–776. 59. Spriggs AI, Boddington MM. Absence of mesothelial cells from tuberculous pleural effusions. Thorax 1960;15:169–177. 60. Yam LT. Diagnostic significance of lymphocytes in pleural effusions. Ann Intern Med 1967;66:972–978. 61. Cheng AF, Tai VH, Li MS, et al. Improved recovery of Mycobacterium tuberculosis from pleural aspirates: bedside inoculation, heparinised containers and liquid culture media. Scand J Infect Dis 1999; 31:485–487. 62. Kirsch CM, Kroe M, Azzi RL, et al. The optimal number of pleural biopsy specimens for a diagnosis of tuberculous pleurisy. Chest 1997;112:702–706. 63. Sahn SA. State of the art: the pleura. Am Rev Respir Dis 1988;138:184–234. 64. Cope C. New pleural-biopsy needle. JAMA 1958;167:1107–1108. 65. Abrams LD. A pleural-biopsy punch. Lancet 1958;1:30–31.
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66. Mestiz P, Purves MJ, Pollard AC. Pleural biopsy in the diagnosis of pleural effusion; a report of 200 cases. Lancet 1958;1349–1353. 67. Frist B, Kahan AV, Koss LG. Comparison of the diagnostic values biopsies of the pleura and cytologic evaluation of pleural fluids. Am J Clin Pathol 1979;72:48–51. 68. Scharer L, McClement JH. Isolation of tubercle bacilli from needle biopsy specimens of parietal pleura. Am Rev Respir Dis 1968;97:466–468. 69. Levine H, Metzger W, Lacera D, et al. Diagnosis of tuberculous pleurisy by culture of pleural biopsy specimen. Arch Intern Med 1970;126:269–271. 70. Iles PB, Ogilvie C. Pleural aspiration and biopsy. BMJ 1980;1:693–695. 71. Bueno CE, Clemente MG, Castro BC, et al. Cytologic and bacterial analysis of fluid and pleural biopsy specimens with Cope’s needle; study of 414 patients. Arch Intern Med 1990;150: 1190–1194. 72. Silver MR, Bone RC. The technique of closed pleural biopsy: how to get the best results with either the Cope or Abram’s needle. J Crit Illness 1988;3:53–60. 73. World Health Organization. Improving the Diagnosis and Treatment of Smear-Negative Pulmonary and Extrapulmonary Tuberculosis among Adults and Adolescents. Recommendations for HIV-Prevalent and Resource-Constrained Settings. Geneva: World Health Organization, 2006. Accessed 29 November 2006. Available at URL:http://www.who.int/tb/ publications/2006/tbhiv_recommendations.pdf 74. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. Geneva: World Health Organization, 2003. Accessed 29 November 2006. Available at URL:http://www.who. int/tb/publications/cds_tb_2003_313/en/ 75. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662. 76. World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-Related Infections in among Children, Adolescents and Adults in ResourceLimited Settings. Recommendations for a Public Health Approach. Geneva: World Health Organization, 2006. Accessed 29 November 2006. Availabe at URL: http://www.who.int/hiv/pub/guidelines/ctx/en/ index.html 77. World Health Organization. TB/HIV: A Clinical Manual, 2nd edn. WHO/HTM/TB/2004.330/ WHO/HTM/HIV/2004.1. Geneva: World Health Organization, 2004. Accessed 29 November 2006. Available at URL: http://www.who.int/ bookorders/anglais/detart1.jsp?sesslan=1&codlan= 4&codcol=15&codcch=568 78. World Health Organization. Antiretroviral Therapy in Adults and Adolescents in Resource-Limited Settings: Towards Universal Access. Recommendations for a Public Health Approach. Geneva: World Health Organization, 2006. Accessed 29 November 2006. Available at URL:http://www.who.int/hiv/pub/guidelines/ adult/en/index.html 79. Wyser C, Walzl G, Smedema JP, et al. Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo-controlled, randomized study. Chest 1996;110:333–338. 80. Matchaba PT, Volmink J. Steroids for treating tuberculous pleurisy. Cochrane Database Syst Rev 2000;2:CD001876. 81. Elliott AM, Luzze H, Quigley MA, et al. A randomized, double-blind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis 2004;190:869–878. 82. Lawn S, Bekker LG, Miller R. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:361–373. 83. Sahn SA. Management of complicated parapneumonic effusions. Am Rev Respir Dis 1993;148:813–817.
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84. Moulton JS. Image-guided management of complicated pleural fluid collections. Radiol Clin North Am 2000;38:345–374. 85. Chin NK, Lim TK. Controlled trial of intrapleural streptokinase in the treatment of pleural empyema and complicated parapneumonic infections. Chest 1997;111:275–279. 86. Sahn SA. The use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas. Thorax 1998;53(Suppl 2):S65–S72. 87. Diacon AH, Theron J, Schuurmans MM, et al. Intrapleural streptokinase for empyema and
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complicated parapneumonic effusions. Am J Respir Crit Care Med 2004;170:49–53. 88. Bouros D, Schiza S, Patsourakis G, et al. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med 1997;155:291–295. 89. Bouros D, Schiza S, Tzanakis N, et al. Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema: a randomized, double-blind study. Am J Respir Crit Care Med 1999;159:317–342.
90. Maskell NA, Davies CWH, Nunn AJ, et al. UK controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005;352: 865–874. 91. Thurer RJ. Decortication in thoracic empyema. Indications and surgical technique. Chest Surg Clin N Am 1996;6:461–490. 92. Waller DA, Rengarajan A. Thoracoscopic decortication: a role for video-assisted surgery in chronic postpneumonic pleural empyema. Ann Thorac Surg 2001;71:1813–1816.
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31
Tuberculous pericarditis and myocarditis in adults and children Bongani M Mayosi
BACKGROUND In Africa, heart disease is still dominated by non-ischaemic causes such as rheumatic heart disease, hypertensive heart disease, cardiomyopathy and TB-related conditions (i.e. tuberculous pericarditis and cor pulmonale).1 Tuberculous pericarditis, which accounts for a tenth of all patients hospitalized for heart failure in Africa, is important to recognize because it is a potentially curable cause of heart disease.2 By contrast, isolated tuberculous myocarditis (i.e. not as a complication of tuberculous pericarditis) is extremely rare, particularly since the introduction of drugs effective against TB.3,4 Most cases of myocardial TB are clinically silent and are diagnosed only at autopsy.3 Tuberculous pericarditis is a serious form of extrapulmonary TB associated with substantial morbidity (i.e. cardiac tamponade and constrictive pericarditis) and death during treatment for TB. Tuberculosis is said to be the most frequent cause of constrictive pericarditis in Africa and Asia.2 While acute cardiac tamponade is rare, constrictive pericarditis occurs in approximately 18% of patients with tuberculous pericardial effusion despite treatment with anti-TB medication and corticosteroids.5 Recent studies indicate that tuberculous pericarditis is associated with a mortality of 26% at 6 months; the mortality rises to 40% in patients with clinical features of immunosuppression who are not treated with antiretroviral drugs.6 The epidemiology, clinical presentation and management of pericardial and myocardial TB in adults and children is similar;7–9 therefore, the approach outlined in this chapter applies to all age groups. This chapter is devoted mainly to the review of tuberculous pericarditis. A brief summary of the pathology and clinical features of tuberculous myocarditis is presented at the end.
EPIDEMIOLOGY Tuberculous pericarditis is found in 1% of all autopsied cases of TB and in 1–8% of cases of pulmonary TB.10 Tuberculosis is the most common cause of pericarditis in Africa and other countries where TB remains a major public health problem.11 In one series from the Western Cape Province of South Africa, tuberculous pericarditis accounted for 69.5% (162 out of 233) of cases referred for diagnostic pericardiocentesis.12 By contrast, tuberculous pericarditis accounts for only 4% of cases of pericarditis in developed countries.13 The incidence of tuberculous pericarditis in sub-
Saharan Africa is increasing as a result of the human immunodeficiency virus (HIV) epidemic, and this trend is likely to occur in other parts of the world where the spread of HIV is leading to a resurgence of TB.14,15 In the Western Cape, at least half the patients presenting with large pericardial effusions are infected with HIV.12
PATHOLOGY Pericardial involvement usually develops by retrograde lymphatic spread of Mycobacterium tuberculosis from peritracheal, peribronchial or mediastinal lymph nodes or by haematogenous spread from primary tuberculous infection.11 The pericardium is infrequently involved by breakdown and contiguous spread from a tuberculous lesion in the lung or by haematogenous spread from distant secondary skeletal or genitourinary infection. The immune response to the M. tuberculosis bacilli penetrating the pericardium is responsible for the morbidity associated with tuberculous pericarditis. Protein antigens of the bacillus induce delayed hypersensitivity responses, stimulating lymphocytes to release lymphokines that activate macrophages and influence granuloma formation. The cytokine profile suggests that tuberculous pericardial effusions arise as a result of a hypersensitivity reaction orchestrated by the T-helper type 1 lymphocytes.16 The demonstration of complement-fixing antimyolemmal and antimyosin-type antibodies in 75% of patients with tuberculous pericardial effusion has been cited as possible evidence that cytolysis mediated by antimyolemmal antibodies may contribute to the development of exudative tuberculous pericarditis.17 Four pathological stages of tuberculous pericarditis are recognized: 1. fibrinous exudation with initial polymorphonuclear leucocytosis, relatively abundant mycobacteria and early granuloma formation with loose organization of macrophages and T cells; 2. serosanguineous effusion with a predominantly lymphocytic exudate with monocytes and foam cells; 3. absorption of effusion with organization of granulomatous caseation, and pericardial thickening due to fibrin, collagenosis and, ultimately, fibrosis; and 4. constrictive scarring. In the last stage, the fibrosing visceral and parietal pericardium contracts on the cardiac chambers, and may become calcified,
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encasing the heart in a fibrocalcific skin which impedes diastolic filling and causes the classical syndrome of constrictive pericarditis.18 Recent data suggest that the histological pattern is affected by the immune status of the patient, with fewer granulomas being observed in HIV-infected patients with severely depleted CD4 lymphocytes.19 The lymphatic drainage of the pericardium to the anterior and posterior mediastinal and tracheobronchial lymph nodes is reflected by the pattern of lymphadenopathy seen in tuberculous pericarditis.20 The mediastinal node enlargement of tuberculous pericardial effusion is not visible on a routine chest radiograph but can be seen on computed tomography (CT) or magnetic resonance imaging (MRI).21 In other conditions associated with mediastinal lymph node involvement, such as lymphoma, malignancy and sarcoid, hilar lymph node involvement is prominent.
SYMPTOMS AND SIGNS Tuberculous pericarditis presents clinically in three forms, namely pericardial effusion (80% of cases), constrictive pericarditis (5% of cases) or as a combination of effusion and constriction, i.e. effusive–constrictive pericarditis (15% of cases).22
TUBERCULOUS PERICARDIAL EFFUSION Tuberculous pericardial effusion usually develops insidiously, presenting with non-specific systemic symptoms such as fever, night sweats, fatigue and weight loss. Chest pain, cough and breathlessness are common, although severe pericardial pain of acute onset characteristic of idiopathic pericarditis is unusual. In African patients with tuberculous pericardial effusions, evidence of chronic cardiac compression mimicking heart failure is the most common presentation with acute cardiac tamponade being a rare exception.23 Tuberculous pericarditis is a common cause of heart failure in sub-Saharan Africa, being less common than rheumatic heart disease and more common than hypertensive heart disease and cardiomyopathy in the Eastern Cape of South Africa and Zimbabwe.23,24 While there is marked overlap between the physical signs of pericardial effusion and constrictive pericarditis (Table 31.1), the presence of a pericardial friction rub and increased cardiac dullness extending to the right of the sternum favours a clinical diagnosis of pericardial effusion.23
CONSTRICTIVE PERICARDITIS The clinical presentation is highly variable, ranging from asymptomatic to severe constriction, and the diagnosis is often missed on cursory clinical examination.25 The diastolic lift (pericardial knock) which coincides with a high-pitched early diastolic sound and sudden inspiratory splitting of the second heart sound are subtle but specific physical signs, found in 21%, 45% and 36% of patients with constrictive pericarditis, respectively (Table 31.1).23 These signs are often missed by the inexperienced observer. Furthermore, if the investigation is not guided by clinical examination, echocardiography has the potential to miss signs suggestive of constriction.
EFFUSIVE–CONSTRICTIVE PERICARDITIS This mixed form of tuberculous pericarditis is a common presentation in Southern Africa.25 In addition to physical signs of pericardial
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Table 31.1 Physical signs documented by a single observer in 88 patients with pericardial effusion and 67 23 patients with constrictive pericarditis in South Africa Physical signs
Pericardial effusion (n ¼ 88)
Constrictive pericarditis (n ¼ 67)
Sinus tachycardia
68 (77%) (transient AF in 3) 32 (36%) 74 (84%) 53 (60%) — 83 (94%) 69 (78%) — —
47 (70%) (persistent AF in 2) 32 (48%) 67 (100%) 39 (58%) 14 (21%) 17 (25%) 51 (76%) 30 (45%) 24 (36%)
16 (18%) 84 (95%) 64 (73%) 22 (25%)
— 67 (100%) 60 (89%) 63 (94%)
Significant pulsus paradoxus Raised jugular venous pulse Apex palpable Pericardial knock Increased cardiac dullness Heart sounds soft Third heart sound Sudden inspiratory splitting of the second heart sound Pericardial friction rub Hepatomegaly Ascites Oedema
AF, atrial fibrillation. Adapted from Strang JI. Tuberculous pericarditis in Transkei. Clin Cardiol 1984;7:667–670.
effusion, a diastolic knock may be detected on palpation and an early third heart sound on auscultation. Effusive–constrictive pericarditis is due to increased pericardial pressure owing to effusion in the presence of visceral constriction; the diagnosis is confirmed when the venous pressure remains elevated after pericardial aspiration.
INVESTIGATIONS DIAGNOSIS OF PERICARDIAL EFFUSION Echocardiography (or cardiac ultrasound) is an accurate and noninvasive method for the diagnosis of pericardial effusion (Fig. 31.1).26 Imaging by CT scanning or MRI can also be used, but is seldom available in rural areas in the developing world. The chest radiograph (Fig. 31.2), which shows an enlarged cardiac shadow in over 90% of cases, demonstrates features of active pulmonary TB in 30% of cases and pleural effusion in 40–60% of cases.27 The electrocardiogram (ECG) is abnormal in virtually all cases of tuberculous pericardial effusion, usually in the form of non-specific ST–T wave changes.28 The PR segment deviation and ST segment elevation characteristic of acute pericarditis are found in only 9–11% of cases (Fig. 31.3).28 The presence of microvoltage (i.e. complexes < 5 mm in limb leads and < 10 mm in precordial leads) suggests a large pericardial effusion, and cardiac tamponade is unlikely in the absence of ECG microvoltage.28 Atrial fibrillation is usually transient while electrical alternans, a marker of cardiac tamponade, is rare in tuberculous pericardial effusion.25 Echocardiographic findings of effusion with fibrinous strands on the visceral pericardium are typical but not specific for a tuberculous aetiology (Fig. 31.1).26,29 In addition to features of pericardial disease (i.e. pericardial effusion and thickening of the pericardium), CT of the chest shows typical changes in mediastinal lymph nodes (i.e. enlargement > 10 mm with matting and hypodense centres and sparing of hilar lymph nodes) in almost 100% of cases.20
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Fig. 31.1 Apical four-chamber view of a two-dimensional echocardiogram of a patient with tuberculous pericardial effusion showing multiple fibrin strands as linear or band-like structures crossing the pericardial space or protruding from the epicardium or parietal pericardium and exudates. LA, left atrium; LV, left ventricle; Per eff, pericardial effusion; RA, right atrium; RV, right ventricle.
Fig. 31.2 A chest radiograph of a patient with pericardial effusion (A) before (i.e. globular cardiomegaly) and (B) after pericardial aspiration (i.e. reduced cardiac size with pneumopericardium). Courtesy of Professor PJ Commerford, Cardiac Clinic, Groote Schuur Hospital.
DIAGNOSIS OF PERICARDIAL CONSTRICTION The diagnosis of pericardial constriction is made on the basis of clinical features (Table 31.1), and confirmed by evidence from several investigations including chest radiography, ECG and imaging by echocardiography, CT scan or MRI. The diagnosis is confirmed by cardiac catheterization. On chest radiography 70% of patients have a cardiothoracic ratio greater than 55%, although only 6% had a ratio greater than 75%.23 The shape of the heart is often abnormal, showing an absence of the notch at the root of the right lung and a distended superior vena cava; pericardial calcification is rare (Fig. 31.4).11 It is uncommon to find concomitant pulmonary TB. Non-specific but generalized T-wave changes are seen on ECG in most cases, while low-voltage complexes occur in about 30% of cases. Atrial fibrillation occurs in less than 5% of cases, is persistent
and usually occurs with a calcified pericardium (Fig. 31.4). As with tuberculous pericardial effusion, the ECG is useful only in drawing attention to the presence of a cardiac abnormality.25 While there is no single feature that is diagnostic of constriction on echocardiography, the ultrasound examination must be guided by clinical suspicion and the following strategy adopted.25 First, the presence of significant valvular and myocardial disease must be excluded. Second, the pericardium must be examined carefully for the presence of thickening greater than 5 mm. Third, a combination of haemodynamic features suggestive of constriction, including early diastolic bounce of the interventricular septum (coinciding with the diastolic knock), increased transmitral and transtricuspid inflow velocities with abnormally rapid deceleration times (causing an increase in the ratio of the velocity of the early diastolic filling wave (E wave) to the velocity of the late diastolic
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Fig. 31.3 A 12-lead resting electrocardiogram showing widespread ST segment elevation and PQ/PR segment deviation in all leads. These features are diagnostic of acute pericarditis, which is uncommon in TB pericarditis. Courtesy of Professor PJ Commerford, University of Cape Town.
atrial filling wave (A wave) or E:A ratio) and dilatation (‘plethora’) of the inferior vena cava with blunted respiratory fluctuations in diameter, must be sought. Finally, ventricular interdependence is demonstrated by reciprocal respiratory variation in ventricular size and atrioventricular flow velocities. CT and MRI of the heart offer the advantage of better imaging of the pericardium with more accurate measurement of pericardial thickening ( 3 mm).11 This is important as constriction is almost always associated with pericardial thickening; reports of constriction in the face of normal pericardial thickness have not included TB as a cause.30 Contrast MRI has the added advantage of identifying ingoing pericardial and myocardial inflammation. Cardiac catheterization shows the constrictive physiology with the ‘square root’ sign of the ventricular pressure trace and equalization of the right and left ventricular end-diastolic pressures.
DIAGNOSIS OF EFFUSIVE–CONSTRICTIVE PERICARDITIS The diagnosis of effusive–constrictive pericarditis requires the demonstration of a pericardial effusion, and persisting features of constriction following the removal of the pericardial fluid. In practice, these patients present with features of effusive disease in the face of significant pericardial thickening (Fig. 31.5).
Fig. 31.4 A lateral view of the chest radiograph showing pericardial calcification in a patient with presumed tuberculous pericarditis. Courtesy of Professor PJ Commerford, University of Cape Town.
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DIRECT METHODS FOR THE DIAGNOSIS OF A TUBERCULOUS AETIOLOGY Pericardiocentesis is recommended in all patients in whom TB is suspected. Even in children, the ‘best practice’ is that a diagnostic
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31
Fig. 31.5 Tuberculous effusive–constrictive pericarditis. The two-dimensional and M-mode image taken along the parasternal long axis of the heart shows significant visceral pericardial thickening and the presence of pericardial effusion. The patient showed evidence of constrictive physiology on haemodynamic assessment following drainage of the pericardial fluid, which confirmed the diagnosis of effusive–constrictive pericarditis.
tap is advisable whenever possible to distinguish bacterial (i.e. tuberculous or septic effusion) from viral causes. Cardiac tamponade, present in only 10% of patients with tuberculous pericardial effusion in a study conducted in South Africa,8 is an absolute indication for pericardiocentesis. The pericardial fluid is bloodstained in 80% of cases. However, because malignant disease and the late effects of penetrating trauma may also cause bloody pericardial effusion, confirmation of TB as the cause is essential. Tuberculous pericardial effusions are typically exudative and characterized by a high protein content and increased leucocyte count, with a predominance of lymphocytes and monocytes. Light’s criteria (whereby an exudate is defined as having one or more of the following: pericardial fluid protein divided by serum protein > 0.5; pericardial fluid lactate dehydrogenase (LDH) divided by serum LDH > 0.6; and/or pericardial fluid LDH level > 2/3 the upper limit of normal for serum LDH) are the most reliable diagnostic tools for identifying pericardial exudates.31 The tuberculous aetiology of pericarditis must be established as far as possible by a search for acid-fast bacilli (AFB) and culture of the pericardial fluid. The variability in the detection of tubercle bacilli in the direct smear examination of pericardial fluid is well documented; the yield ranges from 0% to 42%.11 Culture of tubercle bacilli from pericardial fluid can be improved considerably by inoculation of the fluid into double-strength liquid Kirchner culture medium at the bedside, resulting in a 75% yield compared with a 53% yield with conventional culture.32 If diagnostic information cannot be obtained from pericardial fluid, sputum examination, gastric washings, urine culture and right scalene lymph node biopsy may be used. Sputum yield (with AFB or positive culture) is found in 10–55% of patients with tuberculous pericarditis.33 Pericardial biopsy specimens may also be used to diagnose tuberculous pericarditis. Pericardial biopsy and drainage by inferior pericardiotomy is a minor procedure performed under either local or general anaesthesia by a surgeon.34 Unfortunately, surgeons often perform the procedure via a thoracotomy, with marked morbidity and prolongation of the hospital stay.35 A prospective comparison of pericardial fluid culture versus histology in a TB-endemic area has demonstrated that culture of pericardial fluid confirmed TB more often than did histology of the pericardium.8 Tissue histology
is more appropriate as an initial test in cases where pericardial fluid cannot be obtained safely by the percutaneous route.36 Furthermore, the probability of obtaining a definitive bacteriological result is greatest when pericardial fluid and biopsy specimens are examined early in the effusive stage of the disease.32 The diagnostic sensitivity of pericardial biopsy for TB ranges from 10% to 64%.37 Therefore, a normal pericardial biopsy specimen does not exclude tuberculous pericarditis because, in some patients, examination of the pericardium removed at pericardiectomy or autopsy is required to demonstrate clear-cut evidence of TB.11 Polymerase chain reaction (PCR) has also been suggested as a direct method for detecting M. tuberculosis DNA or RNA in pericardial fluid.11 Cegielski et al.38 examined the diagnostic utility of PCR in 13 specimens of pericardial fluid and 15 specimens of pericardial tissue from 20 patients. Tuberculosis was correctly diagnosed by PCR in 13 (81%) patients; there was one false-positive result for a patient with Staphylococcus aureus pericarditis. Considering the individual specimens as the unit of analysis, M. tuberculosis was identified by PCR in 14 of 28 specimens (50%) from patients with tuberculous pericarditis. The sensitivity of PCR was higher with tissue specimens (80%) than with fluid specimens (15%). Current evidence suggests that PCR is less sensitive than established methods and is prone to false-positive results.39 Serum antibody tests against specific tuberculoprotein epitopes have also not offered a diagnostic advantage over existing methods.40 In areas and communities where TB is endemic, tuberculin skin testing is of little value in the diagnosis of tuberculous pericarditis in adults because of the high prevalence of primary TB, mass Bacillus Calmette–Gue´rin (BCG) immunization and the likelihood of cross-sensitization from mycobacteria present in the environment.40 The limited utility of the tuberculin skin test has also been documented in a prospective study performed in a non-endemic area.13 In children, however, the tuberculin skin test provides supportive evidence for the diagnosis of a tuberculous aetiology, and warrants treatment in children under the age of 5 years.9 It is not known whether the interferon-gamma release assays, such as the enzyme-linked immunospot (Elispot) test that detects T cells specific for M. tuberculosis antigens in other body fluids, will perform better in tuberculous pericarditis than the tuberculin skin test.41
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INDIRECT METHODS FOR THE DIAGNOSIS OF TUBERCULOUS PERICARDITIS The high mortality rate associated with untreated tuberculous pericarditis, together with the long culture periods required for traditional tests, means that therapeutic decisions are often made before results from direct methods for diagnosis become available.11 This has led to more emphasis being placed on indirect diagnostic methods, such as pericardial adenosine deaminase (ADA) activity, lysozyme and interferon-gamma (IFN-g) levels. Recent studies have demonstrated that elevated pericardial ADA activity is suggestive of tuberculous pericarditis.42 A pericardial ADA level 40 U/L has a sensitivity and specificity of 88% and 83%, respectively. The usefulness of ADA as a diagnostic tool applies to both HIV-infected and -uninfected patients, although lower ADA levels are observed in HIV-infected patients with severe CD4 lymphocyte depletion.33 High ADA levels have been regarded as a strong prognostic indicator for the development of constrictive pericarditis in pericardial TB.37 Pericardial lysozyme has also been advocated as a diagnostic test for tuberculous pericarditis. A recent study using a cut-off level of 6.5 g/dL as being diagnostic of tuberculous pericarditis demonstrated a sensitivity and specificity of 100% and 91.17%, respectively.43 The measurement of IFN-g levels in pericardial fluid may offer another means of early diagnosis of a tuberculous aetiology of pericardial effusion. A first study involving 12 patients with definite tuberculous pericardial effusion and 19 controls indicated that elevated IFN-g measured by radioimmunoassay in a pericardial aspirate is a sensitive (92%) and highly specific (100%) marker of TB.44 These findings were confirmed in a larger study of 30 consecutive patients with diverse aetiologies of pericardial effusion in which a sensitivity and a specificity of 100% using a cut-off level of > 200 pg/L of IFN-g for the diagnosis of tuberculous pericarditis was demonstrated.45 The pericardial IFN-g and lysozyme assays, if confirmed in larger series, are to be the most promising tests for the rapid diagnosis of tuberculous effusions (Table 31.2). Technical and financial constraints may, however, limit the diagnostic utility of IFN-g in many developing countries. Further, high levels of ADA, IFN-g and/or lysozyme are more diagnostic of TB pericarditis in the presence of lymphocyte predominance in the pericardial fluid.
AN INTEGRATED APPROACH OF TUBERCULOUS PERICARDITIS The diagnostic criteria for tuberculous pericarditis are outlined in Table 31.3.11 Accordingly, a ‘definite’ diagnosis of tuberculous pericarditis is based on the demonstration of tubercle bacilli in pericardial fluid or on histological section of the pericardium, and a ‘probable’ diagnosis is made when there is proof of TB elsewhere in a patient with unexplained pericarditis, a lymphocytic pericardial exudate with elevated Table 31.2 Indirect biochemical methods for the diagnosis of tuberculosis in pericardial fluid: sensitivity and specificity in TB-endemic areas Test Adenine deaminase (ADA) enzyme activity 40 U/L33 Interferon-gamma level 50 pg/L44 Lysozyme level 6. mg/dL43
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Sensitivity (%)
Specificity (%)
87
89
92
100
100
91
Table 31.3 Diagnostic criteria for tuberculous pericarditis Diagnostic category
Criteria
Definite tuberculous pericarditis
Probable tuberculous pericarditis
Tubercle bacilli are found in stained smear or culture of pericardial fluid; and/or Tubercle bacilli or caseating granulomata are found on histological examination of pericardium Evidence of pericarditis in a patient with TB demonstrated elsewhere in the body; and/or Lymphocytic pericardial exudate with elevated ADA activity, IFN-g or lysozyme assay; and/or Good response to anti-TB chemotherapy
ADA levels (and/or IFN-g or lysozyme) and/or a good response to anti-TB chemotherapy. An integrated approach to the diagnostic work-up of a patient with suspected tuberculous pericardial effusion in endemic and non-endemic regions is presented in Table 31.4.
DIFFERENTIAL DIAGNOSIS OF CONGESTIVE PERICARDITIS It may be difficult to separate congestive pericarditis from myocardial disease (i.e. dilated cardiomyopathy in the case of chronic effusive pericarditis, or restrictive cardiomyopathy in the case of constrictive pericarditis). The distinction is vital because pericardial effusion is treatable and pericardiectomy is one of the most satisfying operations in terms of cure of constrictive pericarditis. Points of differentiation are as follows. 1. Clinical: murmurs of mitral and tricuspid regurgitation are strong pointers against pericardial disease. 2. Electrocardiography: left axis deviation favours myocardial disease. 3. Chest radiograph: pericardial calcification supports the diagnosis of constrictive pericarditis. 4. Echocardiography: concentric left ventricular hypertrophy with a ‘sparkling granular’ appearance may be seen in restrictive cardiomyopathy due to amyloidosis. Left ventricular hypertrophy may be present in haemochromatosis. Endomyocardial fibrosis is characterized by obliteration of the right ventricular or left ventricular cavity. The ejection fraction is normal in constrictive pericarditis, whereas in heart muscle disease left ventricular function is frequently depressed. On tissue Doppler imaging, a peak early velocity of longitudinal expansion (peak Ea) of 7.0 cm/s differentiates patients with constriction from restriction with 89% sensitivity and 100% specificity.2 5. CT and MRI: these are diagnostic when they show thickening of the pericardium of 3 mm. 6. Cardiac catheterization: when the right ventricular and left ventricular end-diastolic pressures differ by more than 6 mmHg, restrictive cardiomyopathy is likely to be present. A mean pulmonary artery pressure of more than 50 mmHg strongly favours restrictive cardiomyopathy. 7. Endomyocardial biopsy: diagnostic of infiltration in amyloid disease and haemochromatosis. Extensive fibrosis is indicative of restrictive cardiomyopathy.
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Tuberculous pericarditis and myocarditis in adults and children
31
Table 31.4 An integrated approach to the diagnosis of tuberculous pericarditis Initial non-invasive evaluation
Pericardiocentesis
Pericardial biopsy
Empiric anti-TB chemotherapy
Chest radiograph may reveal changes suggestive of pulmonary TB in 30% of cases. In an echocardiogram, the presence of a large pericardial effusion with frond-like projections, and thick ‘porridge-like’ fluid is suggestive of an exudate but not specific for a tuberculous aetiology. CT scan and/or MRI of the chest are alternative imaging modalities where available: for evidence of pericardial effusion and thickening (> 5 mm), and typical mediastinal and tracheobronchial lymphadenopathy (> 10 mm, hypodense centres, matting), with sparing of hilar lymph nodes. Culture of sputum, gastric aspirate and/or urine should be considered in all patients. Right scalene lymph node biopsy if pericardial fluid is not accessible and lymphadenopathy present. Tuberculin skin test is not helpful in adults regardless of the background prevalence of TB. Therapeutic pericardiocentesis is absolutely indicated in the presence of cardiac tamponade. Diagnostic pericardiocentesis should be considered in all patients with suspected tuberculous pericarditis, and the following tests performed on the pericardial fluid: 1. direct inoculation of the pericardial fluid into double-strength liquid Kirchner culture medium (or equivalent medium) at the bedside, and culture for M. tuberculosis; 2. biochemical tests to distinguish between an exudate and a transudate (fluid and serum protein; fluid and serum LDH); 3. white cell analysis and count, and cytology: a lymphocytic exudate favours TB pericarditis; 4. indirect tests for tuberculous infection: adenosine deaminase (ADA), interferon-gamma (IFN-g) or lysozyme assay. ‘Therapeutic’ biopsy: as part of surgical drainage in patients with severe tamponade relapsing after pericardiocentesis or requiring open drainage of pericardial fluid for whatever reason. Diagnostic biopsy: in areas where TB is endemic, a diagnostic biopsy is not required prior to commencing empiric anti-TB treatment. In areas where TB is not endemic, a diagnostic biopsy is recommended in patients with > 3 weeks of illness and without aetiological diagnosis having been reached by other tests. TB endemic in the population: trial of empiric antituberculous chemotherapy is recommended for exudative pericardial effusion, after excluding other causes such as malignancy, uraemia and trauma. TB not endemic in the population: when systematic investigation fails to yield a diagnosis of tuberculous pericarditis, there is no justification for starting anti-TB treatment empirically.
An exploratory thoracotomy is justified if all these tests fail to make a distinction between constrictive pericarditis and restrictive cardiomyopathy.
MANAGEMENT TUBERCULOUS PERICARDIAL EFFUSION In areas with a high prevalence of TB, a pericardial effusion is often considered to be tuberculous in origin unless an alternative aetiology is obvious; furthermore, treatment often needs to be commenced on the basis of results of indirect tests before a bacteriological diagnosis is established.25 In approximately two-thirds of cases treated for tuberculous pericarditis the diagnosis is based on bacteriology, histology or analysis of the pericardial fluid. In the remaining patients, an adequate response to anti-TB chemotherapy serves as support for the diagnosis (Table 31.3). By contrast, when systematic investigation fails to yield a diagnosis of tuberculous pericarditis in patients living in non-endemic areas, there is no justification for starting anti-TB treatment empirically.13 Antituberculosis chemotherapy increases survival dramatically in tuberculous pericarditis. In the preantibiotic era, mortality was 80–90%; it ranges currently from 18% to 40%.6 A regimen consisting of rifampicin, isoniazid, pyrazinamide and ethambutol for at least 2 months, followed by isoniazid and rifampicin (total of 6 months of therapy), has been shown to be highly effective in treating patients with extrapulmonary TB; treatment for 9 months or longer gives no better results, but has the disadvantages of increased cost and poor compliance.46 The use of adjunctive corticosteroids in tuberculous pericarditis is controversial.47,48 Three clinical trials with a total of 326 participants have assessed the effectiveness of adjunctive steroids in tuberculous
pericardial effusion.8,49,50 Two tested adjunctive steroids in participants with suspected tuberculous pericarditis in the pre-HIV era.8,49 Schrire49 described the use of three anti-TB drugs (namely streptomycin, isoniazid and para-aminosalicylic acid) in a series of 28 patients who were allocated to steroids or no steroids on alternate days; the duration of the different formulations of adjunctive steroids was not specified. The study by Strang et al.8 involved the use of streptomycin, isoniazid, pyrazinamide and rifampicin, together with prednisolone or placebo for the first 11 weeks; 240 patients were enrolled in the steroid versus placebo comparison. Fewer participants died in the intervention group, but the potentially large reduction in mortality was not statistically significant (relative risk (RR) 0.55; 95% confidence interval (CI) 0.25, 1.24).2,48 One trial with 58 HIV-infected patients also showed a promising but non-significant mortality trend (RR 0.50; 95% CI 0.19, 1.28).2,48 There was no significant beneficial effect of steroids on the reaccumulation of pericardial effusion or progression to constrictive pericarditis.2,48 The recent claim by Troughton et al.51,52 that steroids prevent progression to constriction is thus not based on the best available evidence. The findings of the systematic review and meta-analysis of the trials of adjunctive steroids show no conclusive evidence of benefit for all the major outcomes in tuberculous pericardial effusion (Table 31.5).2,48 Large placebo-controlled trials are required to address the question of the effectiveness of adjunctive corticosteroids in reducing morbidity and mortality associated with tuberculous pericarditis; such studies should include sufficient numbers of HIV-infected and -uninfected participants and an adequate adjunctive steroid dose.11 In the study by Strang et al.8 comparing prednisolone and placebo, 122 consenting participants were also randomized to open complete drainage by substernal pericardiotomy and biopsy under general anaesthesia on admission or percutaneous pericardiocentesis as required to control symptoms and signs. One hundred and one patients were analysed in this comparison. Complete open
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Table 31.5 Findings of the systematic review and meta-analysis of randomized controlled trials of adjunctive corticosteroids 2,48 in tuberculous pericarditis Outcome
HIV-uninfected patients (n ¼ 411)
HIV-infected patients (n ¼ 58)
Repeat pericardiocentesis for cardiac tamponade Improvement in functional status following completion of treatment Development of constriction
No significant beneficial effect on re-accumulation of pericardial fluid No significant difference in functional class following re-analysis in the systematic review No significant reduction in the tendency to develop constriction RR 0.65, 95% CI 0.36–1.16, n ¼ 350; p ¼ 0.14 No difference found over 11 weeks of treatment.
No significant difference in the rate of resolution of pericardial effusion as determined by serial echocardiography Significant difference found in favour of adjunctive corticosteroids Not tested
Deatha Corticosteroid side-effects a
RR 0.50, 95% CI 0.19–1.28; p ¼ 0.15 No difference found over 6 weeks of treatment.
Adjunctive steroids are associated with no significant reduction in the risk of death in both HIV-infected and -uninfected individuals.
drainage abolished the need for pericardiocentesis (RR 0.04; 95% CI 0.00, 0.64; p ¼ 0.02) but did not significantly influence the need for pericardiectomy for subsequent constriction (RR 0.39; 95% CI 0.08, 1.91; p ¼ 0.20) or the risk of death from pericarditis (RR 1.29; 95% CI 0.30, 5.49; p ¼ 0.70). The impact of anti-TB treatment on the development of constrictive pericarditis in patients with chronic pericardial effusion of unknown cause has been investigated in a randomized trial in India.52 Twenty-five adults were randomized in a prospective 2:1 fashion to receive either three-drug anti-TB treatment (group A) or placebo (group B) for 6 months. Twenty-one patients (14 in group A and seven in group B) completed the study protocol and were included in the analysis. The primary end-points were the development of pericardial thickening diagnosed by CT scan and constrictive pericarditis diagnosed by cardiac catheterization. There was no significant difference between the groups in the development of the combined end-point of pericardial thickening and constrictive pericarditis (group A: n ¼ 3, 21.4% versus group B: n ¼ 2, 29.6%; p ¼ NS) and pericardial fluid had disappeared in 10 patients (six in group A and four in group B). Thus, anti-TB treatment did not prevent the development of constrictive pericarditis nor alter the clinical course in patients with large chronic pericardial effusions of undetermined aetiology in patients living in a TB-endemic area. The results of this trial should be considered with caution owing to the small sample size and because three unspecified anti-TB drugs were used. Nevertheless, the study challenges the practice of administering empirical anti-TB chemotherapy, which is not without hazard, to patients with large pericardial effusions in the absence of proof of TB.2 There appears to be no role for intrapericardial instillation of adjunctive corticosteroids in this disease.53
The role of adjunctive corticosteroids in tuberculous pericardial constriction is uncertain.48 In a double-blind, randomized, controlled trial in South Africa, 143 patients with tuberculous pericarditis and clinical signs of a constrictive physiology were allocated to receive prednisolone or placebo in addition to anti-TB drugs during the first 11 weeks of treatment.7 One hundred and fourteen patients were available for evaluation at 24 months; 20% of patients were excluded from analysis, mainly owing to loss to follow-up and non-compliance with medication. Although the prednisolone group experienced more rapid clinical improvement, a lower requirement for pericardiectomy (RR 0.66; CI 0.34, 1.29; p ¼ 0.29) and a lower mortality from pericarditis at 24 months (RR 0.31; CI 0.07, 1.43; p ¼ 0.13), these findings were not statistically significant.2 The remarkable finding of this study is that constriction resolved on anti-TB chemotherapy within 6 months in most patients and only 29 (25%) of the 114 patients required pericardiectomy for persistent or worsening constriction during the follow-up of 2 years. These benefits were maintained for up to 10 years.54
TUBERCULOUS EFFUSIVE–CONSTRICTIVE PERICARDITIS The treatment of effusive–constrictive pericarditis is problematic because pericardiocentesis does not relieve the impaired filling of the heart and surgical removal of the fibrinous exudate coating the visceral pericardium is not possible. Antituberculosis drugs should be given and serial echocardiography performed to detect the development of a pericardial skin amenable to surgical stripping. The place of corticosteroids in such patients is unknown.11
TUBERCULOUS CONSTRICTIVE PERICARDITIS The treatment of tuberculous pericardial constriction involves the use of standard anti-TB drugs for 6 months, and pericardiectomy for persistent constriction in the face of drug therapy.2 The presence of calcific constrictive pericarditis is an absolute indication for pericardiectomy. The majority of patients with non-calcific constrictive pericarditis improve on medical therapy.7 Therefore the therapeutic strategy in these patients involves a trial of antiTB medication for 6–8 weeks, and referral to surgery for patients with no improvement or worsening signs of constriction.11 The risk of death following pericardiectomy in patients with tuberculous constrictive pericarditis ranges from 3% to 16%.11
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UNANSWERED QUESTIONS AND CONTROVERSIES IN MANAGEMENT Despite the global prevalence of tuberculous pericarditis, a number of issues remain unresolved. These include the difficulty in establishing a bacteriological or histological diagnosis, the role of pericardioscopy in the diagnosis of the disease55 and the use of adjunctive corticosteroids (particularly in HIV-infected patients). To answer these questions large prospective studies of tuberculous pericarditis are necessary, such as the Investigation of the Management of Pericarditis in Africa (IMPI Africa) Registry.22
CHAPTER
Tuberculous pericarditis and myocarditis in adults and children
PROGNOSIS Before the advent of anti-TB drugs, tuberculous pericarditis was fatal in almost all cases due to either cardiac tamponade in the acute stages or pericardial constriction in later stages.46 The introduction of anti-TB chemotherapy resulted in a dramatic decrease in the case-fatality rate to as low as 8% in the late 1980s.7 Whereas some investigators have suggested that HIV-infected patients with tuberculous pericarditis have an outcome similar to that of non-infected cases,56 others have shown that there may be an increase in mortality to between 17% and 34% in HIV-infected individuals.50 This trend towards a higher mortality in association with HIV infection has been confirmed in a pan-African multicentre prospective study of 185 patients which revealed a mortality of 40% in patients with advanced HIV infection.6
IMPACT OF HIV INFECTION There is an increase in the incidence of tuberculous pericarditis as a result of the HIV epidemic. The effect of HIV coinfection on clinical features, diagnostic evaluation and initial treatment has been studied in the IMPI Africa Registry of 185 patients with suspected tuberculous pericarditis from Cameroon, Nigeria and South Africa.22 Forty per cent (74) of patients enrolled in this study had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea and electrocardiographic features of myopericarditis. Further, a positive HIV serological status was associated with greater cardiomegaly and haemodynamic instability. These findings may suggest that more intensive management of the cardiac disease may be warranted in patients with HIV-associated pericardial TB. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on steroids.
TUBERCULOUS MYOCARDITIS Myocardial TB is an exceedingly rare disease associated with a high mortality. Tuberculous myocarditis may lead to arrhythmias, including atrial fibrillation and ventricular tachycardia, complete atrioventricular block, congestive heart failure, left ventricular aneurysms and sudden death.3,4,57 The diagnosis is usually established post mortem and the incidence may therefore be greater than currently reported.58 Infection can arise from retrograde lymphatic extension from mediastinal lymph nodes, haematogenous seeding or direct extension of pericardial involvement. In accord, three types of myocardial involvement have been described: tuberculomata of the myocardium with central caseation, miliary tubercles of the myocardium complicating generalized miliary disease and a diffuse infiltrative type associated with tuberculous pericarditis. The last has traditionally been considered as the least common but may represent a more frequently occurring entity in the context of HIVassociated tuberculous pericarditis. The value of non-invasive investigations in establishing a diagnosis of TB myocarditis is limited to case reports only. Tuberculomata may be identified with echocardiography, MRI or CT when calcified.59–61 Echocardiography can detect non-specific wall motion abnormalities and dysfunction in diffuse disease and may also demonstrate non-specific mural infiltration, but in this context MRI is
31
probably a more powerful imaging modality where with gadolinium enhancement disseminated intracardiac tuberculomata have been demonstrated.59,60 MRI is an additionally useful modality in the diagnosis of perimyocarditis with utilization of delayed contrast enhancement. Myocardial scintigraphy using Tc-99m pyrophosphate has also been shown to be useful in perimyocarditis, in particular TB perimyocarditis, while combining Tc-99m sestamibi with gallium-67 SPECT has been demonstrated to be superior to
Box 31.1 Summary of main points being made in the chapter 1.
2.
3. 4. 5. 6. 7. 8.
9.
The diagnosis of tuberculous myocarditis requires confirmation directly by endomyocardial biopsy or indirectly by an appropriate clinical response to a trial of anti-TB medication. Tuberculous pericarditis is a common and serious form of extrapulmonary TB associated with an overall case fatality rate of 26% over 6 months of anti-TB treatment. Tuberculous myocarditis is rare in the absence of pericarditis. Cardiac ultrasound or echocardiography is essential for the diagnosis of the pericardial syndrome. Pericardiocentesis is indicated in all cases of suspected tuberculous pericarditis. Treatment is for 6 months with standard antitubercular medication. Pericardiectomy is indicated for all patients with calcific constrictive pericarditis. In patients with non-calcific constrictive pericarditis, a trial of medical therapy with anti-TB medication is indicated before consideration for surgery. Pericardiectomy is reserved for patients with persistent or worsening constriction after at least 4–8 weeks of treatment. HIV infection is associated with larger pericardial effusions, greater myocardial involvement and a higher mortality in the absence of antiretroviral treatment.
Box 31.2 Key points on new knowledge on tuberculous pericarditis and myocarditis 1.
CT scan of the mediastinum provides additional diagnostic information with regard to the presence, distribution and consistency of the mediastinal lymphadenopathy present. Whereas the chest radiograph does not reveal mediastinal lymphadenopathy, the CT scan (or MRI) reveals enlargement (> 10 mm with matting and hypodense centres) of the anterior and posterior mediastinal and peribronchial lymph nodes, with sparing of the hilar lymph nodes in almost all cases of tuberculous pericarditis. In other conditions associated with mediastinal lymph node involvement, such as lymphoma, malignancy and sarcoid, hilar lymph node involvement is prominent. 2. HIV infection is associated with a more severe form of pericardial TB, which is associated with a larger pericardial effusion, greater myocardial involvement (in the form of myopericarditis and left ventricular dysfunction) and higher mortality in the absence of antiretroviral medication.
Box 31.3 Remaining key questions and controversies on tuberculous pericarditis and myocarditis 1.
What is the best approach for the rapid diagnosis of tuberculous pericardial effusion? 2. What place does pericardioscopy have in the diagnosis of tuberculous pericarditis? 3. How effective are adjunctive oral corticosteroids in reducing progression to constriction and mortality in tuberculous pericarditis?
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MRI in localizing a bioprosthetic valve abscess in a case report,62 and may have value in investigating tuberculous disease. It may be that gallium scintigraphy, which has a lower sensitivity than
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40. 41.
indium in the detection of acute inflammation but higher sensitivity in chronic inflammation, may be a more useful investigation in trying to identify TB myopericarditis.62
computed tomography. Am J Med 2003;114: 319–322. Mayosi BM, Wiysonge CS, Ntsekhe M, et al. Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry. BMC Infect Dis 2006;6:2. Strang JI. Tuberculous pericarditis in Transkei. Clin Cardiol 1984;7:667–670. Hakim JG, Manyemba J. Cardiac disease distribution among patients referred for echocardiography in Harare, Zimbabwe. Cent Afr J Med 1998;44:140–144. Commerford PJ, Strang JIG. Tuberculous pericarditis. In: Coovadia HM, Benatar SR (eds). A Century of Tuberculosis: South African Perspectives. Cape Town, South Africa: Oxford University Press, 1991: 123–136. George S, Salama AL, Uthaman B, et al. Echocardiography in differentiating tuberculous from chronic idiopathic pericardial effusion. Heart 2004;90:1338–1339. Reuter H, Burgess LJ, Doubell AF. Role of chest radiography in diagnosing patients with tuberculous pericarditis. Cardiovasc J S Afr 2005;16:108–111. Smedema JP, Katjitae I, Reuter H, et al. Twelve-lead electrocardiography in tuberculous pericarditis. Cardiovasc J S Afr 2001;12:31–34. Liu P-Y, Li Y-H, Tsai W-C, et al. Usefulness of echocardiographic intrapericardial abnormalities in the diagnosis of tuberculous pericardial effusion. Am J Cardiol 2001;87:1133–1135. Syed FF, Ntsekhe M. Tuberculous pericardial constriction. SA Heart 2006;3:62–68. Burgess LJ, Reuter H, Carstens ME, et al. Cytokine production in patients with tuberculous pericarditis. Int J Tuberc Lung Dis 2002;6:439–446. Strang G, Latouf S, Commerford P, et al. Bedside culture to confirm tuberculous pericarditis. Lancet 1991;338:1600–1601. Reuter H, Burgess LJ, Carstens ME, et al. Adenosine deaminase activity: more than a diagnostic tool in tuberculous pericarditis. Cardiovasc J S Afr 2005;16:143–147. Hofmeyr GJ, Purry NA. Inferior pericardiotomy in the treatment of pericardial effusions. S Afr Med J 1979;55:280–284. Louw VJ, Reuter H, Smedema J, et al. Clinical experience with pericardiocentesis and extended drainage in a population with a high prevalence of HIV. Neth Heart J 1992;10:399–406. Corey GR, Campbell PT, Van Trigt P, et al. Etiology of large pericardial effusions. Am J Med 1993;95: 209–213. Komsuoglu B, Goldeli O, Kulan K, et al. The diagnostic and prognostic value of adenosine deaminase in tuberculous pericarditis. Eur Heart J 1995;16:1126–1130. Cegielski JP, Devlin BH, Morris AJ, et al. Comparison of PCR, culture, and histopathology for diagnosis of tuberculous pericarditis. J Clin Microbiol 1997;35:3254–3257. Lee J-H, Lee CW, Lee S-G, et al. Comparison of polymerase chain reaction with adenosine deaminase activity in pericardial fluid for the diagnosis of tuberculous pericarditis. Am J Med 2002;113: 519–521. Ng TT, Strang JI, Wilkins EG. Serodiagnosis of pericardial tuberculosis. QJM 1995;88:317–320. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cellbased assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003;361:1168–1173.
42. Tuon FF, Litvoc MN, Lopes MIBF. Adenosine deaminase and tuberculous pericarditis—A systematic review with meta-analysis. Acta Trop 2006;99:67–74. 43. Aggeli C, Pitsavos C, Brili S, et al. Relevance of adenosine deaminase and lysozyme measurements in the diagnosis of tuberculous pericarditis. Cardiology 2000;94:81–85. 44. Latouf SE, Ress SR, Lukey PT, et al. Interferongamma in pericardial aspirates: a new, sensitive and specific test for the diagnosis of tuberculous pericarditis. Circulation 1991;84 (Suppl):II–149. 45. Burgess LJ, Reuter H, Carstens ME, et al. The use of adenosine deaminase and interferon-gamma as diagnostic tools for tuberculous pericarditis. Chest 2002;122:900–905. 46. Mayosi BM, Ntsekhe M, Volmink JA, et al. Interventions for treating tuberculous pericarditis. Cochrane Database Syst Rev 2002;4:CD000526. 47. Wragg A, Strang JI. Tuberculous pericarditis and HIV infection. Heart 2000;84:127–128. 48. Ntsekhe M, Wiysonge C, Volmink JA, et al. Adjuvant corticosteroids for tuberculous pericarditis: promising, but not proven. QJM 2003;96:593–599. 49. Schrire V. Experience with pericarditis of Groote Schuur Hospital, Cape Town: an analysis of one hundred and sixty cases over a six-year period. S Afr Med J 1959;33:810–817. 50. Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183–188. 51. Troughton RW, Asher CR, Klein AL. Pericarditis. Lancet 2004;363:717–727. 52. Dwivendi SK, Rastogi P, Saran RK, et al. Antituberculous treatment does not prevent constriction in chronic pericardial effusion of undetermined aetiology. Indian Heart J 1997;49: 411–414. 53. Reuter H, Burgess LJ, Louw VJ, et al. Experience with adjunctive corticosteroids in managing tuberculous pericarditis. Cardiovasc J S Afr 2006;17:233–238. 54. Strang JI, Nunn AJ, Johnson DA, et al. Management of tuberculous constrictive pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years follow-up. QJM 2004;97:525–535. 55. Weich H, Doubell AF. Pericardioscopy in tuberculous pericarditis. SA Heart 2006;3:72. 56. Cegielski JP, Lwakatare J, Dukes CS, et al. Tuberculous pericarditis in Tanzanian patients with and without HIV infection. Tuber Lung Dis 1994;75:429–434. 57. Chan AC, Dickens P. Tuberculous myocarditis presenting as sudden cardiac death. Forensic Sci Int 1992;57:45–50. 58. Agarwal R, Malhotra P, Awasthi A, et al. Tuberculous dilated cardiomyopathy: an underrecognized entity? BMC Infect Dis 2005;5:29. 59. Immer FF, Pirovino M, Saner H. Isolated tuberculosis of the heart: a clinical and echocardiography followup. Z Kardiol 1997;86:15–19. 60. Breton G, Leclerc S, Longuet P, et al. Myocardial localisation of tuberculosis: the diagnostic value of cardiac MRI. Presse Med 2005;34:293–296. 61. Rodriguez E, Soler R, Juffe A, et al. CT and MR findings in a calcified myocardial tuberculoma of the left ventricle. J Comput Assist Tomogr 2001;25: 577–579. 62. Salem R, Boucher L, Laflamme L. Dual Tc-99m sestamibi and Gallium-67 SPECT localize a myocardial abscess around a bioprosthetic aortic valve. Clin Nucl Med 2004;29:799–800.
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Intrathoracic tuberculosis in children The most common clinical presentations Robert P Gie, Jeffrey R Starke, and H Simon Schaaf
INTRODUCTION In most parts of the industrialized world the number of children who develop TB is declining; the USA recorded a 47% decline from 1992 (26,673 childhood cases) to 2005 (14,097 childhood cases).1 In these countries the greatest burden of childhood TB occurs amongst foreign born children (55% in the USA in 2005).1 In stark contrast, the number of childhood TB cases in high-burden countries from the developing world remains on the rise, the magnitude of which has not been accurately determined (see Chapter 5). The most common form of TB in children is intrathoracic TB followed by peripheral (usually cervical) lymph node disease. The term intrathoracic TB is used because many experts as well as the World Health Organization (WHO) regard mediastinal lymph node enlargement and pleural effusion as extrapulmonary manifestations of a primary TB infection. We have argued that in the vast majority of paediatric TB cases the site of organism entry is the lung, leading to the development of an intrathoracic Ghon complex (also called Ranke’s complex).2 It therefore seems logical that the clinical and radiological picture that follows the development of the Ghon complex and its complications should be classified as intrathoracic TB. One of the obstacles in the approach to the diagnosis and treatment of children with intrathoracic TB has been the absence of consistent terminology for classifying the extent of intrathoracic TB. In the absence of a universally acceptable classification system we are unable to compare the diagnostic yields of different tests, the outcome of children treated for TB with different drug regimens or the severity of disease in children from different parts of the world.
RADIOLOGICAL CLASSIFICATION OF INTRATHORACIC CHILDHOOD TUBERCULOSIS Infection usually occurs after inhalation of a droplet containing Mycobacterium tuberculosis into the terminal bronchioli or alveoli. A localized pneumonic process develops, which is referred to as the Ghon focus. From the Ghon focus bacilli drain via the local lymphatics to the regional lymph nodes, which enlarge in response to the infection. The combination of the Ghon focus, local lymphangitis and enlarged regional lymph nodes is called the Ghon complex; sometimes a visible pleural reaction (thickening or fluid) may overlie the Ghon focus. The formation of the Ghon complex is often subclinical and is rarely seen on a chest radiograph. In the
greater majority of cases only a single element of the Ghon complex is visualized on the chest radiograph, most commonly unilateral hilar lymph node enlargement. Disease progression may occur at the site of the Ghon focus and/or the regional lymph node. If containment is particularly poor, systemic dissemination occurs; leading to haematogenous spread and disseminated (miliary) TB. Penetration of adjacent anatomical structures can lead to additional intrathoracic manifestations, including pleural and pericardial effusions. Enlarged regional lymph nodes often attach to adjacent airways, especially the large bronchi. The associated clinical and radiological manifestations depend on the degree of airway involvement. See Chapter 33 for a more comprehensive description of the pathological processes leading to complicated intrathoracic childhood TB. A recently proposed radiological classification of intrathoracic TB in children is presented in Table 32.1.2 The classification is based on the underlying pathological changes that accompany the development of the Ghon complex and its potential complications. This chapter concentrates on the most common manifestations of intrathoracic TB in children and adolescents. The most common form of intrathoracic TB in children younger than 5 years is hilar adenopathy (lymph node disease) as seen on chest radiography (see Chapter 25). In older children and especially in adolescents, uncomplicated pleural effusion and adult-type cavitating TB becomes more common.
CLINICAL PICTURE The clinical picture of intrathoracic TB in children is partly dependent on the time delay that occurs since primary infection and/or disease onset, which is influenced by the point of entry into the healthcare system. Children found to have TB by active contact tracing are more likely to be asymptomatic, have no abnormalities on physical examination and have uncomplicated lymph node enlargement on chest radiograph.3 It is estimated that 50% of children with uncomplicated lymph node enlargement are asymptomatic.4 The clinical and radiological picture of asymptomatic children differs considerably from those who present with symptoms of chronic disease. Symptomatic children have more advanced disease with a greater likelihood of intrathoracic complications.3 In industrialized countries with well-functioning contact tracing programmes, health workers are more likely to discover children with early asymptomatic and uncomplicated lymph node enlargement on chest radiograph. When case series of children discovered mostly by contact tracing in industrialized countries are compared with symptomatic children presenting to health workers in the
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Table 32.1 Radiological classification of childhood intrathoracic tuberculosis Principal disease site/entity
Potential local complications
Complications following intrabronchial spread
Lung parenchyma Ghon focus
With cavitation
and bronchopneumonic consolidation
Adult-type disease Lymph node Lymph node disease Airway obstruction With alveolar opacification cavitation bronchopneumonic opacification With bronchial and/ or tracheal compression With hyperinflation or collapse Infiltration of With bronchopneumonic adjacent opacification structures With tracheo- or bronchooesophageal fistula With diaphragmatic palsy Pleural effusion With tuberculous empyema With pneumothorax Pericardial effusion Disseminated (miliary) disease First identify the principal disease site/entity. Then specify the principal disease entity according to the radiological complications. More than one principal disease entity may be present at the same time. Some radiological appearances will be difficult to classify accurately. Extremely rare forms of TB, e.g. congenital TB, are not included. Adapted from Weber HC, Beyers N, Gie RP, et al. The clinical and radiological features of tuberculosis in adolescents. Ann Trop Paediatr 2000;20:5–10.
developing world, the proportion of children in the developing world with well-defined symptoms and signs of chronic disease will be much larger than those found in the industrialized world. Similarly chest radiographs from children in the developing world demonstrate more extensive disease. Children in the developing world often have other factors that contribute to the development of more extensive intrathoracic disease, including poor access to healthcare, malnutrition and the high prevalence of human immunodeficiency virus (HIV) infection (see Chapter 33). One of the main factors which determine whether the initial TB infection will be successfully contained is the age of the child. Young children, especially those less than 1 year of age, have a high risk of developing disseminated TB disease, presenting with a miliary picture on the chest radiograph. In a large case series of miliary TB 52% of the children were younger than 1 year.5 This demonstrates the inability of young children to contain TB infection and the urgency needed when evaluating young children exposed to an infectious TB source case. During adolescence TB pleural effusion and adult-type upper lobe cavitating disease develop with increasing frequency. The symptoms
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of these disease entities are similar to those in adults. With pleural effusion localized chest pain and intermittent fever are prominent symptoms, while a persistent non-remitting cough with associated systemic symptoms commonly occurs in children and adolescents with adult-type cavitating disease. In the HIV-uninfected population, adolescence is the only time that the TB incidence of female patients exceeds the incidence in males.6 The reason for this temporary excess of TB disease in female adolescent patients is yet to be explained, although it seems to correlate with the earlier onset of puberty in girls.
DIAGNOSTIC TESTS INTERFERON GAMMA RELEASE ASSAYS (IGRA) Several studies have evaluated the usefulness of these tests to diagnose active TB in children. Certain countries recommend that these tests replace tuberculin skin tests, but in a recent review it is emphasized that the accuracy and reliability of these assays to diagnose either TB infection or disease in children and adolescents have not been established.7 Starke best expresses the position of these assays: ‘the interferon assays show great promise for improving diagnosis of TB infection, but too little is known about their characteristics in children to recommend their use at this time’.8 In industrialized countries where non-tuberculous mycobacterial (NTM) disease is more common, IGRAs show great promise in differentiating disease caused by NTM (excluding Mycobacterium bovis and a few rare NTM diseases) from disease caused by Mycobacterium tuberculosis.9
BACTERIOLOGICAL CONFIRMATION Culture yields for M. tuberculosis are reported to be low in children, only 30–40% in those judged on clinical grounds to have probable TB. However, the culture yield is highly dependent on the severity of the intrathoracic TB; yields of up to 77% have been reported in children with complicated intrathoracic disease.10 In children from the industrialized world, mostly presenting with uncomplicated lymph node disease, yields of up to 30% can be expected. Newer techniques for collecting specimens in children have been explored; to date, nebulized hypertonic saline-induced sputum has shown the most promising results. One specimen obtained with induced sputum provided the same yield as three gastric aspirates but the overall yield using this technique remains low (15% with one and 20% with three induced sputum specimens).11 Further studies are needed to see whether this method of specimen collection is widely applicable. Older children and adolescents with adult-type cavitating disease are best investigated by routine sputum smear microscopy and/or culture.12 Yields for sputum microscopy and culture are similar to those found in adults with pulmonary TB.
RADIOLOGY (SEE ALSO CHAPTER 25) The most common finding is isolated mediastinal unilateral lymph node enlargement (47–80%). An abnormal radiograph is often used to differentiate TB infection from disease, but the great difficulty and variability in interpretation of the chest radiograph remains a big problem. In a comparative study, intraobserver error among paediatric pulmonologists in determining whether lymph node enlargement was present ranged from fair to moderate.13 It is hardly surprising that the reading is difficult since it has been demonstrated that, in only 50% of children with suspected TB, lymph nodes observed on computed tomography of the chest exceeded 1 cm in
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diameter.14 Even with this extremely sensitive tool, interobserver variability amongst radiologists in determining whether TB lymph nodes are present remained modest.15 This illustrates why it is hardly surprising that determining whether changes observed on a chest radiograph are likely to indicate TB is inconsistent. The chest radiograph findings should be interpreted in the context of the child’s clinical signs and symptoms. The difficulty of using the chest radiograph to establish a diagnosis of TB in a child is further compounded by the fact that in the prechemotherapy era transient hilar lymph node enlargement was observed in 50–60% of children soon after primary infection. The majority of these children did not develop progressive disease, indicating that isolated asymptomatic hilar lymph node enlargement is not indicative of disease.16
CASE DEFINITION The diagnosis of what constitutes a case of intrathoracic TB is far from clear. Owing to the fact that bacterial confirmation of disease is difficult the gold standard for the diagnosis remains uncertain. In clinical practice the diagnosis is made by giving careful consideration to a history of recent exposure to an infectious TB source case, a positive tuberculin skin test indicative of TB infection (or positive IGRA), symptoms suspicious of TB and chest radiograph changes suggestive of TB. Using the above to make the diagnosis of intrathoracic TB in children is fraught with imprecision. It is precisely this imprecision that creates confusion and leads to the widespread belief that childhood TB is difficult to diagnose. The problem mostly lies in distinguishing infection from disease. It is well known that children with severe disease can have a nonreactive tuberculin skin test. On the other hand children infected with TB could have transient lymph node enlargement on chest radiography and can even have M. tuberculosis cultured from gastric aspirate or other specimens (respiratory secretions, urine) early on during a primary infection.16 The problem is further complicated by the finding that children with a positive tuberculin skin test and a normal chest radiograph may have lymph nodes present on chest computed tomography, as observed in nine out of 15 (60%) children with documented TB exposure/infection.17 It is this overlap in findings that can make the decision of whether a child is merely infected with M. tuberculosis or has TB disease so difficult.
REFERENCES 1. Starke JR. New concepts in childhood tuberculosis. Curr Opin Pediatr 2007;19:306–313. 2. Marais B, Gie RP, Schaaf HS, et al. A proposed radiological classification of childhood intrathoracic tuberculosis. Pediatr Radiol 2004;34:886–894. 3. Marais BJ, Gie RP, Hesseling AC, et al. Radiographic signs and symptoms in children treated for tuberculosis. Pediatr Infect Dis J 2006;25:237–240. 4. Shingadia D, Novelli V. Diagnosis and treatment of tuberculosis in children. Lancet Infect Dis 2003;3: 624–632. 5. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children. Pediatr Infect Dis 1991;10:832–836. 6. Weber HC, Beyers N, Gie RP, et al. The clinical and radiological features of tuberculosis in adolescents. Ann Trop Paediatr 2000;20:5–10. 7. Pai M, Kalantri S, Dheda K. New and emerging technologies for the diagnosis of tuberculosis: part 1.
8.
9.
10.
11.
12.
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Despite the confusing overlap of symptoms, signs and radiological findings in some cases, it is often underappreciated that the diagnosis of TB disease can be established with a high degree of certainty in the majority of cases, even though it may not be bacteriologically confirmed. In HIV-infected children the problem is more pronounced due to additional difficulty in differentiating symptoms, signs and radiological pictures of TB from other HIV-related lung diseases. It is for this reason that the WHO recommend that in high-HIV-prevalence areas (> 5%) all children suspected of TB should be offered a HIV test after appropriate counselling,12 as knowledge of the HIV test result influences clinical decision making.
OUTCOME OF CHILDREN TREATED FOR TUBERCULOSIS In children suffering from uncomplicated TB the outcome after treatment is excellent, with survival rates approaching 100%. However, the outcome is more guarded in children with an inability to contain the organism, such as very young, severely malnourished or HIV-infected children. A case fatality rate of 14% has been reported in children with disseminated TB.5 In the absence of highly active antiretroviral therapy, HIV-infected children who have culture-proven TB have fatality rates of as high as 39%, despite TB treatment, with TB being directly accountable for 14% of the deaths.18 Risk factors identified were age less than 1 year, severe malnutrition and a negative tuberculin skin test,18 all of which indicate severe immune suppression and an inability to contain the disease.
FUTURE DEVELOPMENTS To make true progress new tools that distinguish between TB infection and active disease need to be developed while new drugs are required to treat cases of drug-resistant TB and to dramatically shorten the duration of treatment. For children living in TBendemic settings additional urgent requirements include better access to existing diagnostic and treatment options, although the ultimate prize would be effective vaccines to reduce the incidence of both TB and HIV.
Latent infection. Expert Rev Mol Diagn 2006;6:413–422. Starke JR. Interferon gamma release assays for the diagnosis of tuberculosis infection in children. Pediatr Infect Dis J 2006;25:941–942. Detjen AK, Keil T, Roll S, et al. Interferon gamma release assays improve the diagnosis of tuberculosis from non-tuberculous mycobacterial disease in children in a country with a low incidence of tuberculosis. Clin Infect Dis 2007;45:322–328. Marais BJ, Hesseling AC, Gie RP, et al. The bacteriological yield in children with intrathoracic tuberculosis. Clin Infect Dis 2006;42:e69–e71. Zar H, Hanslo D, Appolis P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: prospective study. Lancet 2005;365:130–134. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. WHO/HTM/TB/2006.371. Geneva: World Health Organization, 2006.
13. Du Toit G, Swingler G, Iloni K. Observer variation in detecting lymphadenopathy on chest radiography. Int J Tuberc Lung Dis 2002;6:814–817. 14. Andronikou S, Joseph E, Lucas S, et al. CT scanning for the detection of tuberculous mediastinal and hilar lymphadenopathy in children. Pediatr Radiol 2004;34:232–236. 15. Andronikou S, Brauer B, Galpin J, et al. Interobserver variability in the detection of mediastinal and hilar lymph nodes on CT in children with suspected pulmonary tuberculosis. Pediatr Radiol 2005; 35:425–428. 16. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuberculosis: old wisdom new challenges. Am J Respir Crit Care Med 2006;173:1078–1090. 17. Delacourt C, Mani TM, Bonnerot V, et al. Computer tomography with normal chest radiography in tuberculous infection. Arch Dis Child 1993;69:430–432. 18. Hesseling AC, Westra AER, Werschkull H, et al. Outcome of HIV-infected children with cultureconfirmed tuberculosis. Arch Dis Child 2005;90:1171–1174.
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Management of complicated intrathoracic and upper airway tuberculosis in children Pierre Goussard, Sharon Kling, and Robert P Gie
AIRWAY DISEASE An understanding of the pathogenesis of primary TB enables one to explain the clinical and radiological presentation of airway disease. When the primary infection is not contained, the infected lymph nodes adjacent to the large airways, particularly the bronchi, increase in size, compressing the airway and infiltrating the airway wall. The clinical and radiological pictures that arise depend on the degree of airway narrowing and nodal ulceration into the airway. If the nodes ulcerate into the airway the caseous material can be inhaled into either the lobe or a segment. There is an initial hypersensitivity reaction to the inhaled tuberculous material. As the obstruction of the airway by the ulcerating node increases and then becomes complete, the reaction changes from a hypersensitivity reaction to caseation and liquefaction of the lung tissue. The reaction in the lung is an expansile process, which is recognized radiologically as an expansile pneumonia.1 These forms of TB are collectively called lymphobronchial tuberculosis. Lymphobronchial TB was more common in the prechemotherapeutic era with compression syndromes detected in up to 67.8% and bronchial perforation in 27.8% of the patients studied.2 Other risk factors for this type of TB are a young age and severe malnutrition.3,4
CLINICAL PRESENTATION The clinical presentation depends on which anatomical part of the airway is involved. The involvement can be supraglottic, extrathoracic, intrathoracic or a combination of these. The clinical signs and symptoms will also depend on the degree of external compression and whether the nodes have ulcerated through the airway wall. Bilateral airway involvement especially of the large bronchi will present differently from unilateral involvement. Airway obstruction can be either complete or incomplete. Extrathoracic airway obstruction presents with stridor, which may be either inspiratory or present during both inspiration and expiration. Intrathoracic obstruction presents with monophonic wheezing. The wheeze may be audible on one or both sides of the chest, depending on the degree of obstruction. Occasionally the involved nodes obstruct the bronchi, causing a clinical picture that may be confused with asthma, but responds poorly to bronchodilators. Children with partial obstruction of the airway may develop a ball-valve effect, where air can enter the lung but is trapped on expiration. These children have hyperinflation and hyperresonance of the affected side of the chest. Air entry over the involved lung is decreased on auscultation and wheezing with prolonged expiration
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is heard. When the obstruction is complete, lung or lobar collapse can develop, with reduced or no ventilation to the affected part of the lung.
CHEST RADIOGRAPHIC APPEARANCES Airway compression Lymphadenopathy may be clearly visible on a chest radiograph (CXR), or there may be indirect evidence of its presence indicated by airway narrowing or deviation. Mediastinal lymph nodes are usually visible in cases of bronchial obstruction. In younger patients often the only sign of lymph node airway compression is narrowing of the major airways.3 Tracheal deviation to the right is normal and a shift to the left is abnormal except when a right-sided aortic arch is present. Tracheal deviation to the left might be the only sign of paratracheal lymph node enlargement. Subcarinal nodes may also be difficult to detect. In a patient without cardiac disease a double shadow below the carina is often a sign of subcarinal lymph node enlargement especially if there is also a shift in the para-oesophageal adhesion line. Further evidence of subcarinal lymph node enlargement is compression of both main bronchi. The frontal high-kilovolt (kV) radiograph has been used to assess the effect of TB lymph nodes on the tracheobronchial tree. It has been demonstrated that the specificity for the detection of TB lymph nodes increased from 74.4% to 86.6% with the addition of the high-kV radiographs (Fig. 33.1).5 However, the authors felt the data did not support the routine use of high-kV radiographs in the diagnosis of childhood pulmonary TB. If the airway obstruction is complete, lung collapse with volume loss will be seen on the CXR. Bronchus intermedius is a common region for complete airway obstruction, resulting in collapse of the right middle and lower lobes. In most cases the obstruction clears on treatment. Unilateral hyperinflation (Fig. 33.2) This is not a common radiological picture. As the airways start to narrow, a point is reached where the narrowing acts as a ‘check valve’ allowing air to be trapped in the affected lobe or lung. On the CXR unilateral hyperinflation with a flattened hemidiaphragm is seen. The involved lung has reduced vascularity and herniates across the midline if severe air trapping is present. The bronchus of the involved lung is narrowed and enlarged lymph nodes may be visible. On the lateral chest radiograph air is visible in the anterior mediastinum. The diagnosis is best made by combining the clinical examination with the radiological picture.
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Management of complicated intrathoracic and upper airway tuberculosis in children
Fig. 33.1 High-kilovolt chest radiograph demonstrating TB lymph node compression of both main bronchi.
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Fig. 33.3 Tracheobronchogram performed with non-ionic, water-soluble contrast medium in an intubated patient suspected of having TB nodal obstruction, showing obstruction of bronchus intermedius, splaying of the carina and narrowing of the left main bronchus.
(63%). The largest group of nodes was located in the subcarinal area in 87% of cases. The most common site of airway compression was the left main bronchus (21%), followed by the right main bronchus (14%) and bronchus intermedius (8%).
BRONCHOSCOPIC FINDINGS
Fig. 33.2 Chest radiograph of a child with a ball-valve effect (left-sided hyperinflation) caused by lymph node compression of the left main bronchus.
A bronchogram (Fig. 33.3) can be performed with non-ionic, water-soluble contrast medium in intubated patients and is useful when bronchoscopy is not available. The procedure is safe, but can cause transient desaturation.6
COMPUTED TOMOGRAPHY (CT) SCAN APPEARANCE A chest CT scan should be done in children with clinically and radiologically significant airway compression. The CT scan shows the location of nodal involvement and the relationship of these nodes to the airways, and will assist in assessing whether a patient will benefit from lymph node enucleation. Patients with small lymph nodes or lymph nodes that have already calcified will not benefit from enucleation. The CT scan also guides the surgeon in deciding from which side the thoracotomy must be done. Andronikou et al.7 have shown that the most common locations for tuberculous lymph node enlargement are the subcarinal area (90%), right hilum (74%), left hilum (72%), both hila (61%), anterior mediastinum (79%), precarinal (64%) and right paratracheal
Both flexible and rigid bronchoscopy play a role in the management of children with airway obstruction. The advantage of the flexible bronchoscope is that the smaller airways can be reached and the airway obstruction bypassed to evaluate the airway distal to the area of obstruction. Rigid bronchoscopes are best used for transbronchial lymph node enucleation, as the patient can be ventilated during the procedure and larger instruments can be used (Fig. 33.4). It is possible to remove tissue via a flexible bronchoscope, but this is limited by the size of the forceps that can be passed through the working channel (Fig. 33.5).
Indications for bronchoscopy Bronchoscopy is not indicated for routine specimen collection in TB. The yield for positive culture via bronchoscopy is less than that of gastric aspirate culture.8–10 Bronchoscopy can be used to confirm the diagnosis of TB, as well as the site and extent of airway obstruction. Chest radiographs underestimate the presence and the degree of airway obstruction, which may be present without visibly enlarged hilar and mediastinal lymph nodes. Tuberculous lymph nodes may cause obstruction by compression of or ulceration into the airways, with granulation tissue and caseating material obstructing the airway. The granulation tissue and caseating material can be removed via a rigid bronchoscope. Repeated bronchoscopies may be required to remove the material if the patient’s clinical condition or radiological picture fails to improve.11 Bronchoscopy findings The most common bronchoscopic findings are extrinsic compression of the bronchi or the trachea (37%) (Fig. 33.6).12 Bronchial involvement, with granulation tissue and caseous material causing obstruction
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Fig. 33.4 Nodal compression of the left main bronchus (A) before and (B) during bronchoscopic enucleation, demonstrating drainage of caseating material from the left upper lobe.
Fig. 33.5 Lymph node herniating into the left main bronchus, being removed with flexible bronchoscope.
and mucosal inflammation, was found in 48% of children without detectable lymphadenopathy on the chest radiographs.12
MEDICAL MANAGEMENT Standard three-drug anti-TB treatment (isoniazid, rifampicin, pyrazinamide) is used in children with airway obstruction. A fourth drug is added when cavities are present on chest radiograph. There is very little information about the use of corticosteroids in the treatment of lymph node obstruction of the airways. There are conflicting data in the literature. Early reports from the 1960s were that corticosteroids were effective in decreasing airway obstruction if given early in the course of the disease.13–15 These
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Fig. 33.6 Bronchoscopic picture of near complete obstruction of bronchus intermedius.
claims were not supported in a double-blind study looking at the effect of prednisone on lymph node disease.16 In a follow-up study the 36% of the group receiving prednisone had an improved outcome when compared with the placebo group.17 It seems that corticosteroids give a more rapid improvement and less nodal ulceration into the airways than conventional treatment, but the eventual outcome is similar.18 In view of the potential side-effects of corticosteroids, care should be taken with their use in childhood TB. We prescribe prednisone (2 mg/kg/day) in children who are symptomatic due to airway obstruction. The prednisone is given for 1 month and then weaned over the next month. The children are followed up every 2 months. If the child is still symptomatic after 1 month’s therapy, bronchoscopy is indicated. Children with unilateral hyperinflation due to a ball-valve effect do respond to
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Management of complicated intrathoracic and upper airway tuberculosis in children
medical treatment, but they may become very symptomatic with severe airway obstruction if superimposed infection develops. This is usually seen in infants less than 6 months of age.
SURGICAL MANAGEMENT Surgical intervention can be used as adjuvant treatment for tracheobronchial complications stemming from mediastinal tuberculous lymphadenitis. The surgical intervention can be either endoscopic or via thoracotomy. Endoscopic enucleation is indicated in children where the lymph nodes have herniated through and ulcerated into the airways (Figs 33.7 and 33.8). The advantage of endoscopic enucleation is that tissue can be sent for culture. Only a small group of children benefit from endoscopic enucleation. The reason for this is that the enucleated lymph nodes, which are situated outside the airway, continue to leak caseous material into the airways and granulation material continues to form. Endoscopic enucleation is best suited for children with single lesions causing lobar collapse. Acute perforation of a major airway is rare
Fig. 33.7 Chest radiograph showing collapse of the right middle and lower lobe. The right hilar nodes are enlarged.
Fig. 33.8 Bronchoscopy showing lymph nodes, which have herniated into bronchus intermedius.
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but can present with severe respiratory embarrassment. Bronchoscopy for removal of the caseous material and relief of the obstruction is indicated.19 Endoscopic enucleation of nodes is safe, but care must be taken that too much tissue is not removed. Complications include bleeding, perforation of the bronchus wall with a pneumothorax and creation of a broncho-oesophageal fistula. Endoscopic enucleation is mostly done through a rigid bronchoscope, but can also be done via a flexible bronchoscope. No studies looking at the outcome of endoscopic enucleation have been published. Four studies on surgical transthoracic enucleation have been published. There are no clear indications when to perform enucleation. The presence of lymph nodes alone is not an indication for surgery unless they cause complications, such as acute perforation of a major airway with severe respiratory embarrassment, pressure and occlusion of a major airway with lung collapse or hyperinflation, bronchial stenosis due to fibrosis and, rarely, superior vena cava obstruction or subcarinal oesophageal obstruction.19 A number of factors must be taken into account when considering surgery. These include the age of the child, the degree of airway involvement as assessed by bronchoscopy, the position and character of the lymph nodes causing the obstruction and the clinical response to antituberculous therapy together with corticosteroids. Clear indications for surgery include assisted ventilation for airway obstruction and life-threatening airway obstruction. A symptomatic child who has received 1 month’s therapy should have a repeat bronchoscopy performed. If at bronchoscopy the airway narrowing is judged to be more than 75%, enucleation should be considered. Prior to bronchoscopy a CT scan of the chest should be done to determine the size, site and character of the lymph nodes. Lymph nodes that are calcified will not be successfully enucleated. The situation of the lymph nodes will determine the side from which the thoracotomy will be done (Fig. 33.9). The most common lymph nodes obstructing the main bronchi are the subcarinal and paratracheal groups, compressing the proximal main bronchi or the distal trachea between them. 20 Decompression of the subcarinal lymph nodes is important if both the left and right main bronchus are compressed (Fig. 33.10). The lymph nodes are easier to enucleate earlier in the disease process. During enucleation overzealous dissection must be avoided. The procedure entails partial resection of the lymph nodes and evacuation of mucopus within the gland by careful curettage. Lung resection
Fig. 33.9 Transthoracic surgical enucleation of TB nodes, caseating material visible.
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Fig. 33.10 Bronchoscopic pictures (A) before and (B) after surgical transthoracic enucleation of nodes.
should be avoided at all cost as nearly all children improve with time.19 The reported complication rate resulting from enucleation is low and includes bronchial tear, pulmonary artery laceration and bronchopleural fistula.20,21 Bronchopleural fistulae mostly resolve with intercostal drainage; if unsuccessful, surgery may be necessary.
COMPLICATIONS The role of surgery in airway compression caused by TB is not only to relieve airway compression but also to prevent future damage to the lung parenchyma. Untreated airway compression can lead to lung collapse and bronchiectasis. Hewitson and van Oppel20 reported that the indications for pulmonary resection are symptomatic bronchiectasis not controlled with conservative measures, destroyed lung parenchyma that is the site for recurrent or chronic infection and infected pulmonary cavitation with or without fungal infection. Pulmonary resection is best avoided during the acute phase, as the surgery is difficult and resulting bronchiectasis rare. The lung heals by fibrosis with a small risk of infection. Bronchiectasis of the lower lobes is the most common indication for resection. Chronic bronchus intermedius obstruction can lead to right middle and lower lobe destruction requiring resection. Gross parenchymal destruction may be the source of secondary bacterial or fungal suppurative infections, which result in bronchiectasis.
can be differentiated from other causes of empyema in that the children are not toxically ill, although they can have a high fever. These large pleural effusions are difficult to differentiate radiologically from other causes of pleural effusion, as hilar adenopathy is seldom visible. The effusion can vary in size from complete opacification of the hemithorax to obliteration of the costophrenic angle. After draining the effusion the enlarged glands or primary focus may become visible. Parenchymal consolidation (59%) is the most common associated radiographic finding.24 In younger children the effusion is mostly part of complicated lung disease. The pleural effusion is normally an inconsequential part of miliary TB, or lobar or bronchopneumonic TB. The diagnosis of TB pleural effusion is made from the clinical and radiological pictures. The diagnosis can be further substantiated by doing a diagnostic tap, with TB characterized by the predominance of lymphocytes in the fluid. In nearly all cases the TB effusion clears up rapidly on treatment. After 3–4 weeks of treatment the pleural effusion will have cleared with only slight pleural thickening still being present. Complicated pleural TB is rare in children. Chest CT scan features of complicated pleural effusions include pleural thickening and enhancement, and fluid collections with associated parenchymal lesions and lymphadenopathy (Fig. 33.11).
PLEURAL DISEASE CLINICAL PRESENTATION Pleural effusion due to Mycobacterium tuberculosis is categorized as extrapulmonary TB.22,23 It develops as a complication of primary TB in 2–38% of children with pulmonary TB. Effusion is not a common feature of primary TB in young children. As adolescence approaches the number of children presenting with large pleural effusions becomes more common. An effusion occurs when the primary focus ruptures into the pleural cavity, releasing the tuberculoprotein and a small number of bacilli. The pleural effusion results from a hypersensitivity immune response to the tuberculoprotein in the pleural cavity. It is usually unilateral. Children with pleural effusions usually present with fever and an insidious onset of shortness of breath. Clinically the TB effusion
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Fig. 33.11 Chest CT scan demonstrating complicated pleural disease caused by TB. A pericardial effusion is also visible.
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Chronic tuberculous empyema is characterized by persistent and grossly purulent pleural fluid. This fluid contains numerous tubercle bacilli. Chest CT scan is used to differentiate between pleural thickening and a chronic loculated effusion or empyema, as they have the same appearance on chest radiograph.25
MANAGEMENT The approach to children presenting with an effusion suggestive of TB is as follows. If the effusion is small, only a diagnostic tap may be necessary. If the effusion is large and the child is symptomatic, the fluid can be aspirated, with either a needle or a pigtail catheter. Very large effusions must be drained slowly because of the risk of re-expansion pulmonary oedema. If it is not possible to drain the fluid, it is either loculated or an organized pleural effusion. If the fluid is loculated, an ultrasound-guided aspiration can be attempted. Tuberculosis effusions are exudative with protein > 30 g/L or lactate dehydrogenase (LDH) > 200 U/L, with a lymphocytic predominance. The fluid must be sent for Ziehl–Neelsen (ZN) stain and TB culture. The ZN recovery rate from pleural fluid is very low (5.5%).24 Several biochemical markers have been used for the diagnosis of tuberculous pleural effusions including adenosine deaminase (ADA), lysozyme, interferon-g and M. tuberculosis DNA detected with polymerase chain reaction (PCR). The most extensively studied have been ADA.26 Ena et al.27 have confirmed in a meta-analysis that ADA has a high sensitivity and a high negative predictive value in the diagnosis of TB pleural effusion. A pleural exudate with high ADA levels (40 U/L) is usually due to TB or rheumatoid arthritis; other possibilities are haematological malignancies and empyema. If the pleural fluid is rich in lymphocytes and has a high ADA, the most likely diagnosis is TB. If the ADA is low, haematological malignancies are the most likely cause. A high ADA in a neutrophil-predominant pleural effusion suggests parapneumonic effusion, particularly empyema.26 The combination of culture and histological examination has been described as the most sensitive diagnostic test for pleural TB. The histological changes seen on pleural biopsy are granulomatous inflammation. Several adult studies on tuberculous pleurisy have suggested that corticosteroid therapy may reduce morbidity, decrease pleural thickening and cause more rapid absorption of the pleural fluid.8,29–32 Randomized controlled trials of corticosteroid therapy failed to show clinically relevant earlier symptom relief or a beneficial effect on residual pleural thickening after early complete drainage of the effusion.33,34 No childhood studies on the use of corticosteroids are available. Chronic tuberculous empyema must be drained surgically, and decortication may be necessary to expand the lung. Biopsies should be taken for culture and histology. Radiographic clearing of chronic TB empyema may take up to 1 year.
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Fungal pneumonia in immunocompromised and neutropenic children caused by Aspergillus fumigatus presents as expansile pneumonia with the characteristic halo sign appearance on CT scan.37,38 Tuberculosis is seldom considered as a cause of expansile pneumonia in countries with a low incidence of TB, but in areas with a high incidence this clinical presentation is relatively common. In the literature there is confusion as to what the correct terminology is for describing the combination of airway and parenchymal disease in children with TB. Initially the clinical term ‘epituberculosis’ was used to describe a chronic illness in children with indefinite clinical signs but with a homogeneous opacity extending from the hilar region into part of the lobe on the chest radiograph. These children were not very ill, and in most cases the lesion resolved without therapy.39 The term ‘endobronchial TB’ was used when lymph node involvement of the airway led to obstruction of the bronchus. Seal and Thomas40 described tuberculous pneumonia as aspiration of caseous material due to perforation of the airway by lymph nodes distal to lobar or segmental bronchial obstruction. It was thought that the lobe became congested and oedematous, and these enlarged lobes on chest radiography were termed a ‘wet’ or ‘drowned’ lung.41 Others used the term ‘lymphobronchial TB’ to describe the lesions that result from lymph node involvement of the airways in children. Expansile pneumonia is one of the radiological pictures of lymphobronchial TB.42
PATHOLOGY The term lymphobronchial TB is useful, as it partially explains the pathogenesis of the disease. Other radiological pictures of lymphobronchial TB are bronchial compression, unilateral hyperinflation and lobar or segmental collapse. It is speculated that the pathogenesis of these lesions follows narrowing of the airways by mediastinal lymph nodes. The enlarged nodes infiltrate the bronchial wall, eventually rupturing into the bronchus. The caseating material, containing both viable organisms and tuberculous material (tuberculoprotein), is aspirated into the affected lobe. In the lobe, an allergic response develops, causing the expansile pneumonia. This hypothesis is supported by the observation that lesions similar to those seen in these children develop after the injection of tuberculoprotein into the lobes of rabbits.43
CLINICAL PRESENTATION Children with expansile pneumonia caused by M. tuberculosis are mostly younger than 24 months but this presentation can also be seen in older children. The children present with three distinct clinical pictures: non-resolving pneumonia, large airway obstruction with unremitting monotonic wheezing and persistent lobar collapse. Most patients will be referred with pneumonia that has not responded to antibiotics. The great majority of these children will be culture positive for M. tuberculosis.1
CHEST RADIOGRAPHIC FEATURES
EXPANSILE PNEUMONIA Expansile pneumonia is a radiological diagnosis. It is characterized by increased volume of the affected lobe or segment due to pneumonia. It has the appearance of a densely consolidated lobe or segment with bulging fissures and is rare in childhood. The most common bacterial causes of expansile pneumonia are Klebsiella pneumoniae and Staphylococcus aureus. Expansile pneumonia caused by K. pneumoniae usually involves the upper lobes.35,36
Homogeneous opacification with displacement of the fissures of the affected lobe or lobes is seen in all cases (Fig. 33.12). The involvement is usually lobar, but segmental involvement has also been seen. Air bronchograms are seldom visualized in the consolidated lobe. Hilar lymphadenopathy is difficult to see because the hilar regions are obscured by the consolidated lobe or lobes. Indirect evidence of mediastinal lymphadenopathy resulting in compression of the large airways can be seen in most cases. The upper lobes are most frequently involved, with the left upper lobe more commonly
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third picture consists of a combination of the foregoing, with a homogeneously opacified lobe and areas of necrotic liquefaction as well as lobes with homogeneous opacification, patent airways and visible air bronchograms. Chest CT scan provides additional information regarding subcarinal lymphadenopathy and tracheal compression not seen on routine chest radiographs (Fig. 33.14). Hilar lymphadenopathy with ring enhancement is also visible in all cases.1
BRONCHOSCOPY FINDINGS Severe airway compression is seen in a large number of children with expansile pneumonia caused by M. tuberculosis. These infants are also at risk of these nodes herniating into the airways. There is a correlation between the chest CT scan findings and the bronchoscopic findings. In one study, patients with necrotic liquefaction of the lobe had a degree of airway obstruction greater than 75%, compared with those with homogeneous opacification without evidence of liquefaction and patent airways on CT scan who had less than 75% obstruction of the lobar bronchus.1 Fig. 33.12 Expansile pneumonia of the right upper lobe with bilateral bronchial compression.
involved than the right upper lobe. The middle lobe, lingula and lower lobes are less frequently involved. Pleural effusions in combination with expansile pneumonia are rare.1
COMPUTED TOMOGRAPHY APPEARANCE Three patterns of CT appearance have been identified. The first is that of a dense homogeneous opacification with no evidence of liquefaction of the affected lobe and patent airways, so that air bronchograms are visible. The second, the most common picture, consists of homogeneous opacification with areas of necrotic liquefaction in the opacified lobe, together with nodal obstruction of the airways and absence of air bronchograms (Fig. 33.13). The
MANAGEMENT Bronchoscopy must be done in children with signs and symptoms of severe large airway obstruction. Children with expansile pneumonia on chest radiograph but without signs and/or symptoms of airway obstructions do not warrant bronchoscopy. Chest CT scan can be done to confirm the diagnosis and to determine the cause and degree of airway obstruction. These children are treated with isoniazid (INH) (5–10 mg/kg/ day), rifampicin (10 mg/kg/day), pyrazinamide (25 mg/kg/day) and ethambutol (20 mg/kg/day) for 2 months (intensive phase) and with INH and rifampicin for a further 4 months during the continuation phase. Prednisone (2 mg/kg/day) is added for the first 30 days and then weaned over the next month.18 During the first month of treatment children must be closely monitored. If there is no or very little improvement in the clinical and/or
Fig. 33.13 (A) Chest CT scan demonstrating homogeneous opacification of right upper lobe. In the opacified lobe, extensive areas of liquefaction are visible. (B) The right upper lobe bronchus is also obstructed.
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Fig. 33.14 Chest CT scan demonstrating homogeneous opacification with areas of liquefaction of the right upper lobe. Large subcarinal lymph nodes causing airway compression are also present.
radiological condition of the child after 1 month, bronchoscopy is indicated. The airways must be evaluated for obstruction by lymph nodes and where possible an attempt made to enucleate the obstructing lymph nodes. If bronchoscopic enucleation is not possible or unsuccessful, and the child’s clinical condition warrants it, surgical nodal enucleation via thoracotomy is indicated. Expansile pneumonia caused by M. tuberculosis has a good short- and longterm prognosis, if treated correctly. Most children will have considerable improvement in their chest radiographic appearance after 6 months of TB treatment. Although volume loss has subsequently been seen in the affected lobe in 68% of cases, recurrent infection and bronchiectasis are rare.
BRONCHO-OESOPHAGEAL FISTULA CLINICAL PRESENTATION The sudden onset of coughing following ingestion of fluids, in particular if combined with symptoms and signs of acute pneumonia or a history of repeated respiratory tract infections, should alert the physician to the possibility of a tracheo- or bronchooesophageal fistula. Congenital tracheo-oesophageal fistulas are often considered in the differential diagnosis, while acquired fistulas are seldom thought of, as they are rare. Fifty per cent of acquired oesophago-respiratory fistulae in adult patients are due to benign causes.44 In adults, 10–19% of acquired non-malignant broncho-oesophageal fistulae (BOF) are caused by M. tuberculosis. In children, acquired broncho-oesophageal fistula is an uncommon complication of trauma, foreign body ingestion and pulmonary TB.45,46 In children, BOF caused by M. tuberculosis are rare and mostly fatal. This complication has been described in seven children in the English language literature.45–51 BOF caused by M. tuberculosis present as one of three clinical pictures: acutely with severe respiratory distress requiring ventilation, a chronic picture with repeated aspiration and following surgery for tuberculous node enucleation. BOF caused by M. tuberculosis are mostly left-sided, although one case of right-sided BOF has been reported.47 Tuberculous BOF results from the erosion of tuberculous peribronchial lymph nodes into both the oesophagus and bronchus (Fig. 33.15). They may also result from direct extension of tuberculous ulceration or perforation of a tuberculous abscess. Less frequently, a fistula may follow direct spread
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Fig. 33.15 Postmortem specimen showing a broncho-oesophageal fistula opening in the oesophagus.
from thoracic vertebral TB or be a complication of endotracheobronchial TB.46 Oesophageal TB is rare and is almost always secondary to pulmonary TB.
DIAGNOSIS In many cases in which a tracheobroncho-oesophageal fistula is clinically suspected, the diagnosis can be confirmed by barium swallow (Fig. 33.16). Water-soluble contrast medium must be used to reduce the complication of aspiration. These fistulas are mostly left-sided and are seen on contrast studies, just distal to the origin of the left main bronchus. Bronchoscopy is a useful additional investigation for a suspected fistula. When M. tuberculosis is the cause of the fistula the origin is mostly in the bronchus, and not in the trachea as with congenital tracheo-oesophageal fistulas. The origin of the fistula is close to the carina. Visualization of the
Fig. 33.16 Barium study demonstrating a broncho-oesophageal fistula between the left main bronchus and the oesophagus.
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origin might be difficult as it is hidden in a granuloma caused by caseating lymph nodes that have herniated into the airway. Communication between the tracheobronchial tree and the oesophagus can be demonstrated by instilling methylene blue into the oesophagus and visualizing the dye in the tracheobronchial tree. In ventilated children a tracheobronchogram can be used to demonstrate the fistula by means of radiocontrast medium being instilled via the endotracheal tube.47
MANAGEMENT The management depends on the clinical presentation. The child presenting with a chronic picture with repeated episodes of aspiration is managed conservatively. These children must be treated with INH, rifampicin and pyrazinamide for 2 months and with INH and rifampicin for a further 4 months during the continuation phase. Although there is no evidence to support it, it is thought advisable to treat these patients for a longer period of time. To prevent repeated episodes of aspiration the child must be fed via a nasogastric tube. In contrast to the adult literature, the cases of broncho-oesophageal fistula in children failed to close on anti-TB treatment alone. Surgical intervention after 6 months of TB treatment was required.47 Ligation of the fistula can be difficult because of all the adhesions that have formed. Treating children with a broncho-oesophageal fistula who present with respiratory failure needing ventilation can be a major challenge. The survival rate of children with BOF requiring ventilation is very poor, with only one survivor reported.52 The patients died because adequate ventilation could not be achieved by either conventional mechanical ventilation or high-frequency oscillatory ventilation (HFOV). The reasons for not achieving adequate ventilation include the fact that not only is there a large air leak between the airway and the oesophagus, but these children also have nodal compression of the large airways in addition to their significant parenchymal disease. This results in very ineffective ventilation with hypercarbia and severe hypoxia. Previous interventions included attempts to ligate these fistulae surgically, passing a Sengstaken–Blakemore tube and selective intubation into the right main bronchus during the acute phase. These efforts were all unsuccessful as the patients succumbed during surgery. Extracorporeal membrane oxygenation (ECMO) might be an alternative form of treatment if it is available. Recently the use of an oesophageal stent to aid in the ventilation of a child with an acquired broncho-oesophageal fistula caused by M. tuberculosis was described (Fig. 33.17).52 The covered stent was able to seal the air leak by compressing the fistula between the endotracheal tube and the stent. In this case the stent provided time for the parenchymal lung disease to improve, and made successful extubation possible. Radecke et al.53 have shown that in 73.3% of adult patients the leak in the oesophagus could be successfully sealed by stent placement. They have also shown that this is a safe, technically feasible, effective and relatively inexpensive option to treat oesophageal fistulae, perforations and anastomotic leaks. Studies on the use of these stents in children with TB are lacking. The management of a child with a broncho-oesophageal fistula requiring ventilation includes the following: 1. Intubate with a cuffed endotracheal tube. 2. Pass a nasogastric tube to decompress the stomach. Place the nasogastric tube on suctioning. 3. Confirm BOF with flexible bronchoscopy.
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Fig. 33.17 Chest radiograph demonstrating the placement of a stent in the oesophagus of a child with a broncho-oesophageal fistula.
4. Place a Sengstaken–Blakemore tube for short-term relief. 5. Place a covered stent in the oesophagus. 6. Oral feeding is not possible in the first couple of days. This complicates the use of standard TB treatment. Alternative intravenous therapy, which could include rifampicin, ofloxacin (ciprofloxacin) and amikacin, should be prescribed. 7. Add prednisone 2 mg/kg/day to the treatment. The optimal duration of stenting is unknown. In the cases of BOF that present with respiratory failure requiring ventilation the stent mst be removed before the child can be extubated. The use of stents to close the fistula in the long-term management of BOF has yet to be determined, but they might have a role to play in the treatment of these patients.
OESOPHAGEAL PERFORATION CLINICAL PRESENTATION Tuberculous involvement of the oesophagus is rare in both adults and children.54 Oesophageal TB is the least common of all tuberculous lesions of the gastrointestinal tract.55 Erosion and perforation of the oesophagus is an unusual complication. Oesophageal TB can be either primary or secondary. Secondary oesophageal TB results from the swallowing of infected sputum, direct involvement from the lungs, mediastinal lymph nodes or thoracic spine, retrograde lymphatic spread or haematogenous spread.56 The commonest causes of oesophageal perforation in tuberculous disease is thought to be from a mediastinal abscess bursting into the oesophagus47 or the formation of a traction diverticulum secondary to adjacent inflammation in the mediastinum.57 Tuberculous lymph nodes may lead to erosion and eventual perforation by pressure necrosis in combination with an inflammatory reaction.58 This condition rarely causes symptoms because the perforation is often walled off by the mediastinal lymph nodes.59 Symptoms and signs include dysphagia, cough, chest pain, fever and weight loss.60 The imaging features that have been described include the leaking of contrast with or without fistula formation on contrast swallow, and large low-density lymph nodes and mediastinal air visible on chest CT scan.
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Management of complicated intrathoracic and upper airway tuberculosis in children
MANAGEMENT These children are managed conservatively with anti-TB drugs and prednisone. If there is perforation into the airway, they are managed in the same way as a broncho-oesophageal fistula. In children with mediastinal abscesses surgical drainage can be considered if the perforation of the oesophagus does not respond to medical treatment alone and for persistent fever. The use of an oesophageal stent can be considered if there is a significant leak into the mediastinum.
CHYLOTHORAX Chylothorax is a rare complication of TB described in adult patients.61,62 A small number of cases have been seen in both human immunodeficiency virus (HIV)-uninfected and -infected children. They present with a combination of mediastinal lymph node enlargement and pleural effusions (Fig. 33.18). Left- and right-sided as well as bilateral chylothoraces have been seen. The aetiology is not known but it is postulated that it is secondary to infiltration of the main lymphatic vessels by TB lymph nodes. The aspirated pleural fluid has the characteristics of a true chylothorax. The pleural fluid appears milky with very high lymphocyte counts and triglyceride levels. Chest CT scan is indicated to exclude other causes of chylothorax. On CT scan large mediastinal nodes typical of those seen in TB are visualized. The treatment consists of the standard threedrug anti-TB regimen to which prednisone (2 mg/kg/day) is added. The child’s diet must be adjusted to include mostly medium chain fatty acids and the pleural fluid must be tapped if the child is symptomatic. Children treated with this regimen showed complete resolution of the chylothorax with no residual pleural disease.63
PHRENIC NERVE INVOLVEMENT This is an extremely rare complication of TB with only a single case previously described in a child.64 We have described seven cases in children (Goussard P, personal communication). In all our
Fig. 33.18 Bilateral pleural effusions visible on chest radiograph. Aspirated fluid was milky and fulfilled the criteria for a chylothorax. Nodal compression of both main bronchi is present.
33
cases of phrenic nerve palsy the involvement occurred on the left side. Phrenic nerve palsy presents either coincidentally in asymptomatic children previously treated for TB or as part of extensive intrathoracic TB. A third of left upper lobe expansile pneumonia cases in one study were associated with phrenic nerve palsy.1 Phrenic nerve palsy should be suspected if the diaphragm on the left side is elevated on the chest radiograph (Fig. 33.19). Phrenic nerve palsy must be confirmed with fluoroscopy, which will show paradoxical movement of the diaphragm. In our patients with extensive intrathoracic TB diaphragmatic function was absent on initial evaluation. Phrenic nerve function did not recover on antituberculous treatment and steroids. In one case surgical decompression of the glandular mass was performed but this also failed to improve phrenic nerve function. A complicating factor in the group with extensive intrathoracic TB was that the left main bronchus had nodal obstruction of varying degrees in all the cases. At autopsy in the one child who died, infiltration of the phrenic nerve by the tuberculous process could be demonstrated. These children are at high risk of developing respiratory failure, especially if they also have severe parenchymal disease. Spontaneous recovery of phrenic nerve function does not occur after infiltration by tuberculous nodes. Plication of the diaphragm might be necessary to stabilize lung function in symptomatic children;65 this is best delayed until after completion of anti-TB treatment.
TUBERCULOSIS OF THE UPPER AIRWAYS Tuberculous involvement of the upper airways in children is rare and most of the reports of upper airway TB have been in adults.66 Two forms of upper airway TB have been described: laryngeal TB and retropharyngeal abscess.
LARYNGEAL TUBERCULOSIS Laryngeal TB is well recognized in the adult population, but is rare in children. Children present with stridor, dysphagia and hoarseness. The pathogenesis of laryngeal TB in children is postulated to be different from that in adults. In adults it is secondary to cavitating pulmonary disease, while in children it is postulated to be primary infection of the larynx. The modes of infection in laryngeal TB are through bronchogenic spread by direct infection via highly infectious sputum from active pulmonary TB, or by haematogenous or lymphatic spread.67 Many children with laryngeal TB do not have pulmonary disease.68 Laryngoscopy and bronchoscopy with biopsy are necessary to confirm the diagnosis. Tuberculosis tends to be localized to the vocal cords and posterior larynx.69 The most frequently encountered types of laryngeal lesions are infiltrative mucosal hypertrophy, a gross tumour-like surface appearance and ulcerative mucosal lesions. These lesions can mimic laryngeal cancer, and the laryngoscopic appearances often simulate malignancy. CT scan findings of laryngeal TB include bilateral involvement, thickening of the free margin of the epiglottis and good preservation of the pre-epiglottic and para-laryngeal fat spaces.70 Management depends on the severity of the upper airway obstruction. In severe cases tracheostomy may be lifesaving, but most children respond to anti-TB treatment and oral corticosteroids. Standard three-drug therapy is used. Biopsy may be necessary to confirm the diagnosis. Tissue must be sent for culture and histology.
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Fig. 33.19 Left phrenic nerve palsy with elevated left hemidiaphragm on (A) anteroposterior and (B) lateral chest radiographs.
TUBERCULOUS RETROPHARYNGEAL ABSCESS This is a very rare presentation in children. A cold abscess develops in the retropharyngeal space and causes severe airway obstruction with stridor. These children are not toxically ill when compared with those with other bacterial causes of retropharyngeal abscess. The enhancing abscess can be seen on CT scan of the neck. Management includes surgical decompression if the airway is compromised. Standard three-drug anti-TB treatment is used.
OTHER UNCOMMON CHILDHOOD PRESENTATIONS OF TUBERCULOSIS HAEMOPTYSIS
high swinging fever. Chest CT scan confirmed widespread alveolar involvement and mediastinal lymphadenopathy, but the patients also had large liquefied nodes in the anterior and posterior mediastinum (Fig. 33.20).63 The children required surgery to drain the liquefied nodes. The pus from the nodes was Ziehl–Neelsen positive on microscopy but M. tuberculosis was not cultured. After drainage of the abscesses the patients’ symptoms resolved. This condition has been seen in both HIV-uninfected and -infected children.
Management In children with persistent swinging fever not responding to antiTB treatment, intrathoracic cold abscess must be considered. The diagnosis is confirmed by chest CT scan. In addition to anti-TB treatment surgical drainage of the abscesses is required.
Haemoptysis is an uncommon problem in childhood pulmonary TB, but can be a potentially serious problem. It may be the presenting sign of pulmonary TB in adults and older children, but seldom in infants. Most patients presenting with haemoptysis will have cavities on their chest radiographs. Salazar et al.71 found that 12% of definite paediatric TB cases presented with haemoptysis. Children presenting with severe haemoptysis are treated with cough suppressants, antibiotics to cover infection and four-drug anti-TB treatment. In severe cases bronchoscopy may be indicated to determine the location of the bleeding. Transcatheter embolization of bronchial vessels and lobectomy may be necessary if conservative measures have failed to control the bleeding. Before surgery is done it is important to have localized the zone of bleeding by means of bronchoscopy.72
INTRATHORACIC COLD ABSCESS FORMATION A small number of children not responding to antituberculous therapy were found to have intrathoracic cold abscess formation on CT scan, and they improved only after drainage of the pus. These children had been on treatment for 3–6 months, were severely malnourished and not gaining weight and had a persistent
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Fig. 33.20 Large subcarinal lymph nodes with ring enhancement. At surgery pus was drained from these nodes. This picture represents a large intrathoracic cold abscess.
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Management of complicated intrathoracic and upper airway tuberculosis in children
CHEST WALL TUBERCULOSIS 73
The chest wall is an uncommon site for osteoarticular TB. It is usually secondary to haematogenous spread and less commonly due to direct spread from the underlying pleural or parenchymal disease.74 Radiographic changes include bone erosion, periosteal reaction, bone sequestrum and soft-tissue masses.74 The affected areas are the rib shaft, the costovertebral joint and the posterior arch.73,74 Sternal involvement is very rare.75 CT scan findings of the chest wall are similar to those seen on chest radiography.3 The diagnosis can be made by fine needle aspiration or with CT scan-guided biopsy, which are sent for histology and culture. Children with a chest wall mass need biopsy or fine needle aspiration to exclude unusual causes of chest wall masses such as actinomycosis.
REFERENCES 1. Goussard P, Gie RP, Kling S, Beyers N. Expansile pneumonia in children caused by Mycobacterium tuberculosis: clinical, radiological and bronchoscopic appearances. Pediatr Pulmonol 2004;38:451–455. 2. Forstad S. Segmental atelectasis in children with primary tuberculosis. Am Rev Tuberc 1959; 79:597–605. 3. Schaaf HS, Gie RP, Beyers N, et al. Tuberculosis in infants less than 3 months of age. Arch Dis Child 1993;69:371–374. 4. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402. 5. De Villiers RVP, Andronikou S, Van der Westhuizen S. Specificity and sensitivity of chest radiographs in the diagnosis of paediatric pulmonary tuberculosis and the value of additional high-kilovolt radiographs. Australas Radiol 2004;48:148–153. 6. Cheung YF, Lee SL, Leung MP, et al. Tracheobronchography and angiocardiography of paediatric cardiac patients with airway disorders. J Paediatr Child Health 2002;38:258–264. 7. Andronikou S, Joseph E, Lucas S, et al. CT scanning for the detection of tuberculous mediastinal and hilar lymphadenopathy in children. Pediatr Radiol 2004;34:232–236. 8. Chan S, Abadco DL, Steiner P. Role of flexible fiberoptic bronchoscopy in the diagnosis of childhood endobronchial tuberculosis. Pediatr Infect Dis J 1994;13:506–509. 9. Somu N, Swaminathan S, Paramasivan CN, et al. Value of bronchoalveolar lavage and gastric lavage in the diagnosis of pulmonary tuberculosis in children. Tuber Lung Dis 1995;76:295–299. 10. Abadco DL, Steiner P. Gastric lavage is better than bronchoalveolar lavage for isolation of Mycobacterium tuberculosis in childhood pulmonary tuberculosis. Pediatr Infect Dis J 1992;11:735–737. 11. De Blic J. The value of flexible bronchoscopy in childhood pulmonary tuberculosis. Pediatr Pulmonol 1995;11(Suppl):24–25. 12. De Blic J, Azevedo I, Burren CP, et al. The value of flexible bronchoscopy in childhood pulmonary tuberculosis. Chest 1991;100:688–692. 13. Gerbeaux J. Tuberculose Primaire de Infant. Paris: Edition Medicale Flammarion, 1967. 14. Gerbeaux J, Baculard A, Couvreur J. Primary tuberculosis in childhood. Am J Dis Child 1965;110:507–518. 15. Rosenzweig DY, Stead WW. The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis. Am Rev Respir Dis 1966; 93:769–785. 16. Nemir RL, Cordona J, Lacoius A, David M. Prednisone as an adjunct in the chemotherapy of lymph node-bronchial tuberculosis in childhood: a double-blind study. Am Rev Respir Dis 1963; 88:189–198.
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Treatment is medical but sometimes it is necessary to drain the soft-tissue abscess.
OTHER UNUSUAL CLINICAL PICTURES Other unusual forms of TB have also been seen and include pleural effusion with a chest wall mass and TB of the thoracic vertebrae causing an unusual mediastinal mass and compression of the left main bronchus. Airway compression associated with spinal TB is rare in children. Rarely airway obstruction can be caused by extensive paravertebral mediastinal abscess in children with TB of the spine. 76
17. Nemir RL, Cardona J, Vaziri F, et al. Prednisone as an adjunct in the chemotherapy of lymph nodebronchial tuberculosis in childhood: a double-blind study. II. Further term observation. Am Rev Respir Dis 1967;95:402–410. 18. Toppet M, Malfroot A, Derde MP, et al. Corticosteroids in primary tuberculosis with bronchial obstruction. Arch Dis Child 1990;65:1222–1226. 19. Papagiannopoulos KA, Linegar AG, Harris DG, et al. Surgical management of airway obstruction in primary tuberculosis in children. Ann Thorac Surg 1999;68:1182–1186. 20. Hewitson JP, van Oppel UO. Role of thoracic surgery for childhood tuberculosis. World J Surg 1997;21:468–474. 21. Worthington MG, Brink JG, Odell JA, et al. Surgical relief of acute airway obstruction due to primary tuberculosis. Ann Thorac Surg 1993;56:1054–1062. 22. Seibert AF, Haynes J Jr, Middleton R, et al. Tuberculous pleural effusion. Twenty-year experience. Chest 1991;99:883–886. 23. Waagner DC. The clinical presentation of tuberculous disease in children. Pediatr Ann 1993; 22:622–628. 24. Merino JM, Carpintero I, Alvarez T, et al. Tuberculous pleural effusion in children. Chest 1999;115:26–30. 25. Moon WK, Kim WS, Kim IO, et al. Complicated pleural tuberculosis in children: CT evaluation. Pediatr Radiol 1999;29:153–157. 26. Segura RM. Useful clinical biological markers in the diagnosis of pleural effusions in children. Paediatr Respir Rev 2004;5(suppl A):S205–S212. 27. Ena J, Valls V, Perez de Oteyza C, et al. Utilidad y limitaciones de la adenosina desaminasa en el diagn’ ostico de la pleures’ia tuberculosa. Estudio metaanal’itico. Med Clin (Barc) 1990;95:333–335. 28. Aspin J, O’Hara H. Steroid-treated tuberculous pleural effusions. Br J Tuberc 1958;52:81–83. 29. Grewal KS, Dixit RP, Sil DR. A comparative study of therapeutic regimens with and without corticosteroids in the treatment of tuberculous pleural effusion. J Indian Med Assoc 1969;52:514–516. 30. Damany SJ, Shah KT. Treatment of pleural effusion with and without triamcinolone in addition to usual antituberculosis chemotherapy. J Indian Med Assoc 1968;51:391–393. 31. Mathur KS, Prasad R, Mathur JS. Intrapleural hydrocortisone in tuberculous pleural effusion. Tubercle 1960;41:358–362. 32. Lee CH, Wang WJ, Lan RS, et al. Corticosteroids in the treatment of tuberculous pleurisy. A double blind, placebo-controlled randomized study. Chest 1988;94:1256–1259. 33. Wyser C, Walzl G, Smedema JP, et al. Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebo-controlled, randomized study. Chest 1996;110:333–338. 34. Galarza I, Canete C, Granados A, et al. Randomised trial of corticosteroids in the treatment of tuberculous pleurisy. Thorax 1995;50:1305–1307. 35. Feldson B, Rosenberg L, Hamburger M. Roentgen findings in acute Friedlander’s pneumonia. Radiology 1949;46:559–565.
36. Korvick JA, Hackett AK, Yu VL, et al. Klebsiella pneumonia in the modern era: clinicoradiographic correlations. South Med J 1991;84:200–204. 37. Winer-Muram HT, Arheart KL, Jennings SG, et al. Pulmonary complications in children with hematological malignancies: accuracy of diagnosis with chest radiography and CT. Radiology 1997; 204:643–649. 38. Caillot D, Couaillier JF, Bernard A, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001; 19:253–259. 39. Eliasberg H, Neuland W. Zur Klinik der Epituberkulosen und gelatinosen Infiltration der kindlichen Lunge. Jahrb Kinderheilkd 1920;93:88. 40. Seal RME, Thomas DME. Endobronchial tuberculosis in children. Lancet 1956;271:995–996. 41. Jones EM, Rafferty TN, Willis HS. Primary tuberculosis complicated by bronchial tuberculosis with atelectasis (epituberculosis). Am Rev Tuberc 1942;46:392. 42. Beyers JA. Radiographic manifestations. In: Coovadia HM, Benatar SR (eds). A Century of Tuberculosis. Cape Town, South Africa: Oxford University Press, 1991:203–233. 43. Oppenheimer EH. Experimental studies on the pathogenesis of epituberculosis. Bull Johns Hopkins Hosp 1935;57:247. 44. Chauhan SS, Long JD. Management of tracheoesophageal fistulas in adults. Curr Treat Options Gastroenterol 2004;7:31–40. 45. Bhatia R, Mitra DK, Mukherjee S, et al. Bronchoesophageal fistula of tuberculosis origin in a child. Pediatr Radiol 1992;22:154. 46. Coleman FP, Bunch GH. Acquired non-malignant esophagotracheo-bronchial fistula. J Thorac Surg 1950;19:542–558. 47. Gie RP, Kling S, Schaaf HS, et al. Tuberculous broncho-esophageal fistula in children. Pediatr Pulmonol 1998;25:285–288. 48. Moersch HJ, Tinney WS. Fistula between the oesophagus and the tracheobronchial tree. Med Clin North Am 1944; July:1001–1007. 49. Wychulis AR, Ellis FH, Andersen HA. Acquired non-malignant esophageo-tracheobronchial fistula. JAMA 1966;196:103–108. 50. Danino EA, Evans CJ, Thomas JH. Tuberculous bronchoesophageal fistula in a child. Thorax 1955;10:351–353. 51. Lucaya J, Sole S, Badora J, et al. Bronchial perforation and broncho-esophageal fistulas: tuberculous origin in children. Am J Radiol 1980;135:525–528. 52. Goussard P, Sidler D, Kling S, et al. Esophageal stent improves ventilation in a child with a bronchoesophageal fistula caused by Mycobacterium tuberculosis. Pediatr Pulmonol 2007;42:93–97. 53. Radecke K, Gerken G, Treichel U. Impact of a selfexpanding, plastic esophageal stent on various esophageal stenoses, fistulas and leakages: a singlecenter experience in 39 patients. Gastrointest Endosc 2005;61:812–818.
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54. Kotanidou A, Andrianakis I, Mavrommatis A, et al. Mediastinal mass with dysphagia in an elderly patient. Infection 2003;31:178–180. 55. Sood A, Sood N, Kumar R, et al. Primary tuberculosis of esophagus. Indian J Gastroenterol 1996;15:75. 56. Gordon AH, Marshall JB. Esophageal tuberculosis: definitive diagnosis by endoscopy. Am J Gastroenterol 1990;85:174–177. 57. Ghandour Z, al Karawi MA, Mohamed AE. Spontaneous oesophageal perforation: unusual presentation of tuberculosis. Endoscopy 1997; 29:143–144. 58. Tucker LE, Aquino T, Sasser W. Mid-esophageal traction diverticulum: rare cause of massive upper gastrointestinal bleeding. Mo Med 1994; 91:140–142. 59. Adkins MS, Raccuia JS, Acinapura AJ. Esophageal perforation in a patient with acquired immunodeficiency syndrome. Ann Thorac Surg 1990;50:299–300.
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60. Sathiyasekaran M, Shivbalan S. Esophageal tuberculosis. Indian J Pediatr 2004;71:457–458. 61. Vennera M, Moreno R, Cot J, et al. Chylothorax and tuberculosis. Thorax 1983;38:694–695. 62. Anton PA, Rubio J, Casan P, et al. Chylothorax due to Mycobacterium tuberculosis. Thorax 1995;50:1019. 63. Gie RP, Goussard P, Kling S, et al. Unusual forms of intrathoracic tuberculosis in children and their management. Paediatr Respir Rev 2004;5(Suppl A): S139–S141. 66. Nishiike S, Irifune M, Doi K, et al. Laryngeal tuberculosis: a report of 15 cases. Ann Otol Rhinol Laryngol 2002;111:916–918. 67. Travis LW, Hybels RL, Newman MH, et al. Tuberculosis of the larynx. Laryngoscope 1976; 86:549–558. 68. Ramadan HH, Wax MK. Laryngeal tuberculosis. Arch Otolaryngol Head Neck Surg 1995;121:109–112. 69. Soda A, Rubio H, Salazar M, et al. Tuberculosis of the larynx: clinical aspects in 19 patients. Laryngoscope 1989;99:1147–1150.
70. Kim MD, Kim DI, Yune HY, et al. CT findings of laryngeal tuberculosis: comparison to laryngeal carcinoma. J Comput Assist Tomogr 1997;21:29–34. 71. Salazar GE, Schmitz TL, Cama R, et al. Pulmonary tuberculosis in children in a developing country. Pediatrics 2001;108:448–453. 72. Shields TW. Pulmonary tuberculosis and other mycobacterial infections of the lung. In: Shields TW (ed.). General Thoracic Surgery, 4th edn. Baltimore: Williams & Wilkins, 1994: 968–985. 73. Tatelman M, Drouillard EJP. Tuberculosis of the rib. Am J Roentgenol Radium Ther Nucl Med 1953;70:923–935. 74. Khalil A, Le Breton C, Tassart M, et al. Utility of CT scan for the diagnosis of chest wall tuberculosis. Eur Radiol 1999;9:1638–1642. 75. Mulloy EMT. Tuberculosis of the sternum presenting as metastatic disease. Thorax 1995;50:1223–1224. 76. Ochoa TJ, Rojas R, Gutierrez M, et al. Severe airway obstruction in a child with Pott’s disease. Pediatr Infect Dis J 2006;25:649–651.
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34
Overview of extrapulmonary tuberculosis in adults and children Helmuth Reuter, Robin Wood, H Simon Schaaf, and Peter R Donald
INTRODUCTION Tuberculosis is an ancient disease with evidence of spinal TB described in Neolithic man with clear evidence of TB bone lesions in mummified remains from Egypt. However, initial infection is usually respiratory following inhalation of an inoculum of organisms within tiny aerosol droplets, predominantly produced by adults with cavitary TB. Extrapulmonary TB, like pulmonary TB, is the result of infection with organisms of the Mycobacterium tuberculosis complex, which include M. tuberculosis, Mycobacterium bovis or Mycobacterium africanum. Extrapulmonary TB is defined as disease involving structures other than lung parenchyma and is less common than pulmonary TB. Extrapulmonary tuberculous disease occurs as result of contiguous spread of tubercle organisms to adjoining structures, such as pleura or pericardium, or by lymphohaematogenous spread during primary or chronic infection. Mucosal spread may occur by transfer of infected secretions, particularly by coughing and swallowing of infected respiratory secretions associated with cavitary pulmonary lesions entering the upper gastrointestinal tract. Cervical and gastrointestinal TB may also result from ingestion of M. bovis-infected milk products particularly in rural areas where pasteurization may not be readily available. The symptoms of extrapulmonary TB are protean and determined largely by local immune responses and resultant tissue injury within affected organs. The diagnosis of extrapulmonary TB may be elusive, particularly in the elderly and human immunodeficiency virus (HIV)-infected in whom the immune response may be blunted. Extrapulmonary TB is closely associated with weakened cellular immunity and is seen mainly in children younger than 3 years of age due to a greater frequency of lymphohaematogenous spread and immaturity of their immune system, the elderly whose immunodeficiency may be augmented by malnourishment and HIV-infected individuals whose CD4þ T-lymphocytes are selectively diminished. According to the World Health Organization (WHO) patients who are sputum smear-positive and also present with extrapulmonary tuberculous disease manifestations are categorized as pulmonary TB.1 According to current terminology, tuberculous intrathoracic lymphadenopathy (hilar or mediastinal), tuberculous pericarditis and pleural TB without radiographic abnormalities of the lung parenchyma constitute extrapulmonary TB. With the advent of computed tomographic imaging in association with postmortem studies,2 it is, however, clear that tuberculous pleural effusion, tuberculous pericarditis and thoracic lymph node TB are frequently associated with lung parenchymal lesions,2–4 warranting a change
in classification from pulmonary and extrapulmonary TB to intrathoracic and extrathoracic TB, respectively. In TB-endemic countries, TB control programmes focus on management of sputum smear-positive TB in an attempt to control the epidemic; extrapulmonary TB receives little public health emphasis as it tends to be paucibacillary. In endemic areas, extrapulmonary TB contributes significantly to disease burden and causes significant morbidity and mortality, especially in countries with a high HIV prevalence, where its significance has increased progressively over the past 20 years.5–8 The proportion of TB cases classified in the USA as extrapulmonary was 16% in 1991 and remained stable at approximately 20% of all TB notifications between 2001 and 2003.9 In developing countries the proportion of notifications classified as extrapulmonary disease has increased significantly in the wake of the HIV epidemic;1,5–7 however, the reported prevalence varies widely from 5% to more than 35% (Table 34.1).1 The uneven distribution of extrapulmonary TB may reflect a true difference in regional disease distribution due to factors such as race,10 gender,11 variable exposure to M. bovis and non-tuberculous mycobacteria (NTM) and differing HIV prevalence rates.12 High HIV prevalence leads to an increased TB case burden,13,14 and HIV-associated immunosuppression modifies the clinical presentation of TB with more frequent dissemination of infection and subsequent development of extrapulmonary manifestations.15 The profound differences in notification rates probably also reflect ascertainment biases in identifying extrapulmonary TB because it is generally more difficult to diagnose than pulmonary TB. Clinical case definitions of extrapulmonary disease may also differ from surveillance definitions. Individuals with extrapulmonary disease together with pulmonary infection are classified in WHO surveillance reporting as pulmonary TB.1 A confirmed diagnosis of extrapulmonary TB requires a combination of mycobacterial culture, histological examination and strong clinical evidence of active disease. However, the availability and quality of diagnostic laboratory services vary markedly.1 Extrapulmonary involvement may also be commoner than reported; once M. tuberculosis is identified in a sputum specimen, infection involving other sites is not pursued because it will not influence the initiation of chemotherapy. Recent reports suggest an increased risk for active TB, including miliary, lymphatic and peritoneal TB, in association with tumour necrosis factor (TNF)-a antagonist use.16 Although increased TB risk appears to be a drug class effect associated with TNF-a blockade, it varies between specific antagonists, which may be related to the different ways in which TNF-a is neutralized.17
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Table 34.1 The proportion of adult tuberculosis cases classified as extrapulmonary tuberculosis Study
Country
Period
Proportion classified as extrapulmonary TB (%)
CDC, 2004 CDC, 2004 WHO report, 2006 WHO report, 2006 WHO report, 2006 WHO report, 2006
USA USA Nigeria, Gambia
1991 2001–2003 2004
16 20 5
Uganda, Senegal, Ghana Zambia, South Africa, Kenya Tanzania, Malawi, Cote d’Ivoire, Congo Burundi, Algeria, Ethiopia
2004
5–10
2004
10–20
2004
20–30
2004
>30
WHO report, 2006
Adapted from American Thoracic Society, Centers for Disease Control (CDC)9 and World Health Organization (WHO).1
PATHOGENESIS OF EXTRAPULMONARY TUBERCULOSIS Extrapulmonary TB arises from organ seeding with M. tuberculosis following mucosal or lymphohaematogenous spread. Mucosal spread usually arises in those pulmonary TB patients with high bacillary loads, typically in long-standing, untreated cavitary disease, as the result of highly infectious respiratory secretions that bathe the upper respiratory mucosa and gastrointestinal tract, leading to laryngeal or gastrointestinal TB, respectively. Tuberculous pleurisy is the result of a delayed hypersensitivity response to M. tuberculosis organisms that gain access to the pleural space after rupture of a subpleural caseous focus and accompanying discharge of tubercle bacilli into the pleural cavity.2,18 For most forms of extrathoracic TB, spread occurs through blood and lymphatics from an established primary or chronic focus. Laryngeal disease is uncommon in HIV-infected persons, in whom extrapulmonary disease arising from haematogenous and lymphatic dissemination is the rule. Presumably, the basis for the high frequency of extrapulmonary TB among HIV-infected patients and young children is the failure of the immune response to contain M. tuberculosis, thereby enabling lymphohaematogenous spread to single or multiple extrathoracic sites where it is not controlled.
HIV AND EXTRAPULMONARY TUBERCULOSIS HIV infection has transformed TB from an endemic disease into a global epidemic. HIV infection increases the frequency of reactivation of latent M. tuberculosis infection, of rapid progression after initial infection with M. tuberculosis and dissemination of TB organisms to tissues other than lung parenchyma.15 The frequency of extrapulmonary TB in HIV-infected individuals is related to many factors including the degree of immunosuppression and the background prevalence of TB in the community. In industrialized countries where TB prevalence is low, the predominant HIV-associated
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disseminated mycobacterial infection is due to Mycobacterium avium complex (MAC). Disseminated MAC infection was rare prior to the HIV epidemic and its association with profound HIV immune suppression was recognized in the earliest phase of the US epidemic, allowing incorporation of the diagnosis into the earliest acquired immunodeficiency syndrome (AIDS) case definitions.19,20 In contrast, TB was endemic prior to the HIV epidemic and, although there is a similar strong positive association with CD4 cell depletion, the HIV attributable fraction of TB (both pulmonary and extrapulmonary) is lower than that for MAC. The relationship between pulmonary and extrapulmonary TB and HIV infection is further complicated by increasing difficulty in separating these diagnoses when profound immune suppression is present. Immune restoration disease (IRD) following initiation of antiretroviral therapy (ART) may frequently unmask previously unapparent extrapulmonary foci, especially in those with low nadir CD4 cell counts. In a review of reported IRD associated with M. tuberculosis, 12 of 13 cases classified as pulmonary disease prior to starting ART developed extrapulmonary manifestations as part of their IRD.21 The combination of a variable attributable fraction of TB to HIV together with diagnostic imprecision have been reflected by an uncertain role of TB in both AIDS surveillance and case definitions. In 1987 extrapulmonary TB, regardless of concurrent pulmonary disease, was added to the Centers for Disease Control (CDC) AIDS surveillance definition,22 and later that year was incorporated into the WHO surveillance definition of AIDS. In 1989 non-cavitary pulmonary TB was added to AIDS case definition for surveillance by the Pan American Health Organization, its diagnosis given equal scoring with extrapulmonary TB.23 In 1993, pulmonary TB was added to expanded CDC surveillance AIDS case definition;24 the next year it was added to the WHO AIDS surveillance definition.25 While pulmonary and extrapulmonary TB now have equal status in AIDS surveillance definitions, WHO clinical case definitions used for patient management continue to classify pulmonary disease as a WHO stage 3, a pre-AIDS diagnosis and extrapulmonary TB as an AIDS defining condition. HIV infection increases TB dissemination particularly as the CD4 cell count declines below 200 cells/mL. Extrapulmonary involvement has been reported in more than 50% of those patients with concurrent AIDS and TB.15 The clinical manifestations of extrapulmonary TB are also modified by late-stage HIV infection, resulting in increased involvement of multiple foci, frequent concurrent pulmonary and extrapulmonary disease, rapid progression of haematogenous disease and frequent development of abscesses of the liver, spleen and other intra-abdominal organs.15 Although there is a marked antibody response to M. tuberculosis infection, cellular immunity is the predominant mechanism for host defence and T-lymphocytes are central for control of M. tuberculosis infection.26 CD4þ T cells with ab T-cell receptors recognize mycobacterial antigens processed and presented by macrophages in conjunction with major histocompatibility complex (MHC) II molecules, leading to T-cell transformation and further clonal expansion of activated T cells.27 Expansion of transformed CD4þ T cells together with macrophage activation and cytokine secretion leads to inhibition of intracellular growth and development of tissue hypersensitivity. CD8þ T-lymphocytes and CD4þ Tgd-lymphocytes also play a role in tissue hypersensitivity and cellular immunity to M. tuberculosis. The pathological features of M. tuberculosis infection are determined by the interaction between tissue hypersensitivity and local mycobacterial antigen load. Where tissue hypersensitivity is high and antigen load sparse, well-formed granulomata represent a successful immunological containment of infection. The morphology of a
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Overview of extrapulmonary tuberculosis in adults and children
well-formed granuloma is characterized by a central necrotic core surrounded by concentric layers of macrophages, epithelioid cells, multinucleated Langhans giant cells and lymphocytes.28 The cellular wall and outer fibrosis restricts M. tuberculosis to the site of infection and prevents dissemination. Where both antigen load and hypersensitivity are high, the granuloma is less well organized and caseating necrosis may be present. With low hypersensitivity the tissue reaction may be non-specific with large numbers of organisms and scanty lymphocytes and macrophages.29 Quantitative and qualitative deficiencies of components of the TB immune response result in decreased containment of M. tuberculosis and increased dissemination. Tuberculous bacteraemia confirmed by positive blood culture has been documented in HIV-infected patients but is extremely rare in HIV-seronegative patients.30 The extent of mycobacterial dissemination is often unsuspected, as shown by West African autopsy data.31 Because of the high frequency of extrapulmonary TB among HIV-infected patients, diagnostic specimens from any suspected site of disease should be examined for mycobacteria. Moreover, cultures of urine, blood and bone marrow may reveal M. tuberculosis in patients without an obvious localized site of disease but who are febrile.
TREATMENT OF EXTRAPULMONARY TUBERCULOSIS IN ADULTS There have been fewer treatment studies evaluating duration and treatment response of extrapulmonary TB than of pulmonary TB. Treatment response is also frequently assessed by indirect clinical and radiological response because follow-up biopsy specimens, necessary to show bacterial treatment response, may be lacking. However, extrapulmonary foci with the exception of bone, joint and central nervous system (CNS) infections generally appear to respond to standard 6- to 9-month regimens including isoniazid (INH) and rifampicin (RMP), in a fashion similar to that of pulmonary TB.32–40 Therefore among patients with extrapulmonary TB a regimen of 2 months of INH, RMP, pyrazinamide (PZA) and ethambutol (EMB) followed by 4–7 months of INH and RMP is recommended as initial therapy unless the organisms are strongly suspected of being resistant to first-line drugs.40 The duration of therapy for extrapulmonary TB caused by drug-resistant organisms is not known. In the treatment of bone and joint TB, some studies have shown that 6- to 9-month RMP-containing regimens are as effective as 18-month non-RMP-containing regimens.39 However, because of the difficulties in assessing response to therapy some experts favour a 9-month or longer duration of treatment.40 Tuberculous meningitis has a particularly high morbidity and mortality even with prompt and adequate chemotherapy.41–43 There is a lack of randomized controlled trial data to guide optimal duration of chemotherapy for tuberculous meningitis; however, present recommendations based on expert opinion are for 2 months of four-drug therapy followed by 7–10 months of INH and RMP.40 Some recommendations suggest prolonged therapy for up to 2 years.42,43 Monitoring of cell, glucose and protein concentrations by repeat lumbar punctures is recommended to establish initial response to chemotherapy; however, these parameters may be difficult to interpret as cell count and protein may remain abnormal in patients chronically infected with HIV. A number of studies have explored the role of adjunctive corticosteroid therapy.44–46 Several smaller studies showed improvement in survival and decreased neurological sequelae with corticosteroid therapy with the greatest benefit for those with decreased level of consciousness but not coma.42,45 A large prospective
34
randomized placebo-controlled study of corticosteroid adjunctive therapy performed in Vietnamese adults demonstrated improved survival but not a decreased incidence of severe disability.46 Dexamethasone is presently recommended for all patients with tuberculous meningitis, particularly those with decreased level of consciousness.40 Expert opinion recommends adjunctive corticosteroid therapy also for patients with tuberculous respiratory failure associated with disseminated or miliary TB.40 The role of adjunctive corticosteroid therapy in the management of tuberculous pericarditis is unclear.33,47 Clinical benefit, including decreased mortality and need for pericardiectomy, has been reported in HIV-seronegative patients in South Africa,34 and in HIV-infected tuberculous pericarditis patients in Zimbabwe,35 respectively, but was not observed in other studies.33,47
TREATMENT OF EXTRAPULMONARY TUBERCULOSIS IN CHILDREN Sputum smear-negative disease is usually paucibacillary and therefore the risk of acquired drug resistance is low. Drug penetration into the anatomical sites involved is good and the success of three drugs (INH, RMP, PZA) during the 2-month intensive phase and two drugs (INH, RMP) during the 4-month continuation phase is well established.48 Disseminated tuberculous disease is frequently associated with CNS involvement.48 It is therefore essential to consider the cerebrospinal fluid (CSF) penetration of drugs used in the treatment of disseminated disease. INH and PZA penetrate the CSF well.49 RMP and streptomycin (SM) penetrate the CSF poorly, but may achieve therapeutic levels in the presence of meningeal inflammation.49 The value of streptomycin is limited by poor CSF penetration and intramuscular administration. EMB hardly penetrates the CSF, even in the presence of meningeal inflammation and has no demonstrated efficacy in the treatment of tuberculous meningitis.48,49 The recommended treatment for lymph node, pleural and pericardial TB in children is 6 months of directly observed therapy (DOT); 2 months of three drugs (INH, RMP, PZA) followed by 4 months of two drugs (INH,RMP).40,50 The cellular immune response assists with organism containment and eradication. Because immunocompromised children lack this important immune contribution, they are at increased risk of disease relapse following standard short-course therapy.51 It seems prudent to prolong treatment in immunocompromised children, although this has not been verified in randomized controlled trials. In the absence of sufficient evidence current recommendations are to consider prolonging treatment to 9 months.40,48
PARADOXICAL REACTIONS AND IMMUNE RESTORATION DISEASE Clinical or radiological deterioration of TB after commencing effective anti-TB therapy is reported to occur in 2–23% of HIV-seronegative individuals.52 These paradoxical reactions may manifest mildly as exacerbation of systemic symptoms or more significantly as respiratory failure or neurological deterioration. Extrapulmonary TB, especially involvement of the CNS, is a strong risk factor for paradoxical reactions.52 Paradoxical reactions following initiation of effective chemotherapy have been associated with conversion of cutaneous response to purified protein derivative from anergy to a positive response,53 and with a rise in serum concentration of TNF-a, which may result from release of mycobacterial wall antigens liberated by mycobacterial killing.54
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Immune restoration disease in those HIV-infected patients is an adverse consequence of restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral therapy (HAART). IRD, also known as immune reconstitution inflammatory syndrome (IRIS), occurs in 29–36% of TB/HIV coinfected patients receiving newly commenced anti-TB therapy and HAART.55 A temporal association between HAART commencement and worsening existing symptoms, or new clinical findings, is a strong clue to the diagnosis of IRD. A positive response to HAART, manifested by a decrease in plasma viral load, is a necessary component for the diagnosis of IRD. However, although a brisk rise in blood CD4 lymphocyte count is frequent, it is not essential for the diagnosis of IRD. There is a strong association between IRD and extrapulmonary TB; a review of 27 papers described 86 cases of M. tuberculosisassociated IRD, 82 of which reported extrapulmonary manifestations.55 Progressive HIV-associated immunodeficiency results in impaired granuloma formation and decreased immune-mediated tissue damage. Thus patients with advanced HIV infection have a propensity to develop extrapulmonary TB with very high bacterial burdens, but without specific organ-related symptoms. IRD frequently results in worsening of existing symptoms but also in new manifestations of previously unrecognized extrapulmonary TB. The unrecognized dissemination of TB in advanced HIV disease was illustrated by the development of a new extrapulmonary manifestation of IRD in 18 of 19 reported cases where the pre-ART site of involvement was pulmonary.55 The commonest reported site for extrapulmonary IRD was lymphadenopathy, which occurred in 71% of patients; 80% was extrathoracic and 20% intrathoracic.55 Other organ involvement included hepatosplenomegaly, psoas abscess, splenic abscess, other intra-abdominal abscesses, ileocaecal disease and skin lesions. Although some manifestations of M. tuberculosis-associated IRD were life-threatening, such as respiratory failure, perforated bowel, splenic rupture and expanding intracranial lesions, no deaths were reported, but this may reflect a reporting bias. Immune reconstitution is also seen in children with TB and may follow nutritional supplementation, anti-TB therapy or initiation of HAART. In a recent prospective survey of 152 Thai children with low CD4 percentages (< 15%), IRD was documented in 14 (19%), usually within 4 weeks of HAART initiation.56 The majority of IRD cases (n ¼ 9) were due to atypical mycobacteria; three were due to M. tuberculosis and due to 2 M. bovis Bacillus Calmette–Gue´rin (BCG). HAART is now increasingly accessible in resource-poor regions where TB is prevalent. In sub-Saharan Africa individuals accessing HAART with advanced immune suppression, many of whom would have previously died without a pre-mortem diagnosis of disseminated TB being made, are developing extrapulmonary IRD after initiating HAART.21 The burden of investigating and treating large numbers of patients with TB who present with pulmonary and extrapulmonary symptoms soon after initiating HAART is a major constraint on further rapid ART rollout.57
EXTRAPULMONARY MANIFESTATIONS OF TUBERCULOSIS TUBERCULOUS LYMPHADENITIS Tuberculous lymphadenitis is the most common manifestation of extrapulmonary TB with cervical nodes most commonly involved, although inguinal, mesenteric, and mediastinal nodes may also be involved.58,59 Tuberculous lymphadenitis often
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affects HIV-seronegative children and young adults,60,61 but in countries with high HIV prevalence is most commonly seen in HIV-infected patients, and is characterized by rapidly enlarging nodes, tenderness or marked asymmetry, features inconsistent with a diagnosis of persistent generalized lymphadenopathy. The differential diagnosis includes NTM infection, Kaposi’s sarcoma and lymphoma. NTM lymphadenitis is relatively common in children and HIV-infected adults,62 but is rare in HIV-seronegative adults. The disease generally remains localized to the cervical region and usually unaccompanied by constitutional symptoms.59 NTM lymphadenitis generally remains localized to the cervical region and can be managed by excision biopsy; if left untreated, the nodes often progress to softening, rupture, sinus formation, healing with fibrosis and calcification.62 In children cervical lymphadenitis is the most common extrathoracic manifestation of TB. Disease pathology within the lymph node is similar to that in other organs, with initial tubercle formation and lymphoid hyperplasia that may progress to caseation and necrosis. Isolated involvement of a single node is rare and nodes are usually matted due to considerable periadenitis.61 A cold abscess results when caseous material liquefies and leads to a soft fluctuant node with discoloration of the overlying skin; spontaneous drainage and sinus formation may follow. Untreated, the natural course of TB lymphadenitis in an immune competent host follows a prolonged and relapsing course, often interrupted by transient lymph node enlargement, fluctuation and/or sinus formation.61 In adults tuberculous lymphadenitis is characteristically indolent and usually presents as a unilateral painless mass along the upper border of the sternocleidomastoid muscle, although more than one site may be involved in up to 35% of cases.63 Constitutional symptoms are usually mild or absent,59,60 and tuberculin skin tests (TST) positive in 75–100% of HIV-uninfected individuals.58,59,63,64 Fine needle aspiration (FNA) is the diagnostic procedure of choice with a reported diagnostic yield varying from 42% to 83%.58–61,64 In some cases an excision biopsy is required, and may result in higher yields, especially if both histology and mycobacterial culture are obtained.59,64 Excision may also be a treatment option, particularly in NTM disease where the therapeutic response to chemotherapy is frequently suboptimal.60 Incisional biopsy should be avoided because it tends to result in sinus formation, a complication not seen with FNA.61 The prevalence of associated chest radiographic abnormalities varies considerably between reported series, probably reflecting differing age distributions. Patients with mediastinal lymphadenopathy may present with cough and dysphagia.65 The diagnosis is usually confirmed by CT scan, and as CT becomes more widely available more cases of intrathoracic and intra-abdominal lymphadenopathy will probably be reported. Involvement of intrathoracic lymph nodes (perihilar and/or paratracheal) is considered the radiological hallmark of primary infection.48,50 Both anteroposterior (AP) and lateral views are required for optimal lymph node visualization. Transient hilar adenopathy is not uncommon following recent primary infection and particular care should be exercised when interpreting results of very sensitive tests such as high-resolution CT (HRCT) of the lung, in the absence of clinical data.48,50 Upper abdominal and mediastinal lymph node TB rarely causes thoracic duct obstruction and chylothorax, chylous ascites or chyluria.66 Swollen glands in the porta hepatis may compress the bile duct and result in obstructive jaundice.67
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Overview of extrapulmonary tuberculosis in adults and children
TUBERCULOUS PLEURAL EFFUSION Tuberculous pleurisy is categorized as extrapulmonary TB despite an intimate anatomic relationship between the pleural membranes and lungs.18 Pleural effusion is a common form of extrapulmonary TB, exceeding 20% of all extrapulmonary TB cases in adults.68,69 Tubercle bacilli enter the pleural space where a delayed hypersensitivity immune response is induced. High interferon-gamma (IFN-g) levels in the pleural fluid are in keeping with a Th1-type response. Tuberculous effusions can follow postprimary, chronic pulmonary and disseminated tuberculous disease. Postprimary effusions frequently develop in young adults due to rupture of subpleural collections of mycobacteria into the pleural space, and pleural fluid typically obliterates 30–60% of the affected hemithorax, although massive effusions may occur. Postprimary effusions frequently resolve spontaneously. However, in the prechemotherapy era more than 60% relapsed within 5 years.70 Effusions complicating chronic pulmonary TB occur in older individuals and may be associated with complicating cardiac or liver disease. Rupture of caseous material from a pulmonary cavity or an adjacent parenchymal focus via a bronchopleural fistula can lead to tuberculous empyema, which is much less common than tuberculous pleurisy with effusion and is associated with a large number of organisms spilling into the pleural space and multiplying there.71 Tuberculous empyema is usually accompanied by radiographic evidence of pulmonary parenchymal disease and air may be seen in the pleural space. The pleural effusion may be loculated and the aspirate is usually thick and resembles pus. Acid-fast smears and mycobacterial cultures are usually positive, making pleural biopsy unnecessary. Tuberculous empyema may burrow through soft tissues and drain spontaneously through the chest wall. Pleural effusions frequently complicate miliary TB (10–30%) where they may be bilateral and associated with pericardial and or peritoneal effusions.72,73 Pleural effusions were radiographically diagnosed in 21% of 150 HIV/TB coinfected individuals presenting sequentially to a South African HIV clinic.74 Tuberculous effusions were less strongly associated with low CD4 cell counts than disseminated or miliary TB.75 Two-year survival of those with effusions was 63%, which was also intermediate between typical pulmonary TB and other WHO stage 4 conditions.75 Clinical presentation may be acute or subacute with the main symptoms being non-productive cough, pleuritic chest pain, fever and dyspnoea, a symptom complex easily confused with bacterial pneumonia. If the effusion is large enough, dyspnoea may occur, although effusions generally are small and rarely bilateral. Chest radiography usually demonstrates a small to moderate unilateral effusion of which 20% are associated with pulmonary lesions.76 CT scan is more sensitive than chest radiograph and evidence of parenchymal infiltrates, cavitation and pleural thickening is more frequently demonstrated.3 In patients with tuberculous pleurisy the pleural fluid is an exudate with a protein content > 30 g/L, pH < 7.3 and lactate dehyrogenase (LDH) > 200 U/L. Lymphocytosis is typical, but a minority of patients have a predominantly polymorphonuclear cellular infiltrate. Direct examination of pleural fluid by Ziehl–Neelsen staining requires a bacillary density of 10,000/mL, and in the absence of empyema has low sensitivity. Pleural fluid mycobacterial culture is positive in 25–30% of cases.76 Granulomata can be identified in 80% of needle biopsies and culture of biopsy material increases the yield by a further 12%.76 Polymerase chain reaction (PCR) of pleural
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biopsy has sensitivity of 90% and specificity of 100%, similar to combined histology and mycobacterial culture; however, a definitive diagnosis can be achieved more rapidly.77 Biochemical markers such as adenosine deaminase activity (ADA), IFN-g, immunosuppressive acidic protein and soluble interleukin-2 receptor (sIL-2R) have been used to distinguish between tuberculous and non-tuberculous aetiologies. In a direct comparison, receiver operating characteristic (ROC) analysis demonstrated that pleural fluid IFN-g was the best indicator among these four biological markers. In high-TB-prevalence settings an ADA > 47 U/L is reported in 99% of tuberculous effusions and in low-prevalence settings a normal ADA has a high negative predictive value and can be used to exclude a tuberculous aetiology.76 Tuberculous pleural effusion responds well to medical therapy with resorption of pleural fluid in 6–12 weeks. Although early postprimary pleural effusions may resolve spontaneously, chemotherapy prevents recurrent disease elsewhere, which occurs in approximately 60% of untreated cases.70 In children, especially those younger than 3 years of age, small effusions often constitute part of the primary complex forming adjacent to the primary focus. Isolated larger pleural effusions are unusual in young children, occur typically in adolescence and tend to develop soon (within the first 3–9 months) after primary infection.78 The pleural fluid typically obliterates 30–60% of the affected hemithorax, although massive fluid collections may cause mediastinal shift and cardiovascular compromise.79 The pleural fluid is characteristically lymphocyte-rich, straw-coloured and represents a cell-mediated hypersensitivity response. Loculated fluid collections may indicate TB empyema that arises when bacilli actively multiply within the pleural space. This is not common, but immune compromised children may be at increased risk.
TUBERCULOUS PERICARDITIS Tuberculosis was the cause of acute pericarditis in 4% of patients in industrialized countries,80 and in 60–80% of patients in resourcepoor settings.8,34 Pericardial effusion is a frequent clinical finding in HIV-infected patients coinfected with TB.8,35 However, asymptomatic pericardial effusions are also frequently found in HIVinfected individuals and may be due to a variety of neoplastic and infective aetiologies including TB.81 While small effusions are a frequent but not considered relevant finding, moderate to severe effusions were found in 13% of 181 consecutive patients presenting to a university HIV clinic in Portugal.81 These effusions were more frequent in patients at more advanced stages of HIV infection. Tuberculous pericarditis occurs most commonly in the third to fifth decades of life although HIV infection is associated with a lower age at presentation.8,81 Tuberculous pericarditis most commonly results from direct extension from contiguous mediastinal and hilar lymph nodes or by lymphohaematogenous spread. The clinical presentation of tuberculous pericarditis is variable and includes acute pericarditis with or without effusion, cardiac tamponade, silent large pericardial effusion with a relapsing course, toxic symptoms with persistent fever, acute constrictive pericarditis, subacute constriction, effusive–constrictive or chronic constrictive pericarditis.80,82 The predominant clinical features of tuberculous pericarditis include dyspnoea, cough, chest pain, night sweats, orthopnoea, weight loss, ankle oedema, cardiomegaly, hepatomegaly, fever and tachycardia. Other findings include pericardial rub, pulsus paradoxus, distended neck veins, pleural effusion and soft heart sounds.33,82 Tuberculous pericarditis with HIV infection presents more frequently with
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fever, generalized lymphadenopathy and concomitant pulmonary infiltrates.82 Chest radiography demonstrates cardiomegaly; echocardiography or chest CT (Fig. 34.1) confirms pericardial effusion as the cause. Constrictive pericarditis may clinically resemble cirrhosis, as the associated ascites may be disproportionately large compared with the peripheral oedema present (ascites praecox). Rarely, patients may present with clinical features suggestive of constriction in the presence of pericardial effusion, a condition referred to as effusive–constrictive pericarditis. The echocardiographic visualization of fibrinous strands in pericardial fluid is suggestive of tuberculous aetiology,82 but pericardiocentesis or pericardiectomy may nevertheless be required to establish a definitive diagnosis. Concomitant pleural effusion may be present in 39–50% of cases and frequently provides an alternative source of diagnostic material.34,82,83 Tuberculous pericardial fluid shares many characteristics of tuberculous pleural fluid with low sensitivity of Ziehl–Neelsen staining and moderate sensitivity of mycobacterial culture.34,35,82 Pericardial biopsy may have a better diagnostic yield than pericardial fluid culture, but is invasive, requires surgical expertise and has a mortality risk. Typical granulomata cannot always be demonstrated and pericardial biopsy may show non-specific findings, even when M. tuberculosis is found in the pericardial fluid.4,34,84 ADA and IFN-g levels are elevated and the cellular component is predominantly lymphocytic in effusions from both HIV-infected and -uninfected individuals.82,85,86 Whereas CD4þ lymphocytes predominate in HIV-seronegative cases, CD8þ cells predominate in HIV-infected cases.86 The tuberculin skin test is usually positive in immunocompetent patients with pericardial TB.34,82 The goal of therapy for tuberculous pericarditis is to treat the acute symptoms of cardiac compression and prevent progression from the effusive to the constrictive stage, in which a fibrotic and
Fig. 34.1 Chest CT demonstrating tuberculous pericarditis. A 48-year-old man known to have tuberculous pericarditis presented with progressively worsening abdominal distension and ankle oedema following closed pericardiocentesis and 6 weeks of antituberculous therapy with adjunctive oral prednisone. Echocardiography and chest CT demonstrated large pericardial effusion with prominent pericardial thickening. In addition, echocardiography demonstrated septal ‘knocking’ and transvalvular flow patterns suggestive of effusive–constrictive pericarditis.
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calcified pericardium entraps the heart.33,87 The mortality rate in untreated acute effusive tuberculous pericarditis approaches 85%.80 Standard management of pericardial effusion includes pericardiocentesis by either echocardiographically guided closed pericardiocentesis33,87 or surgical fenestration.34,35 The open procedure has the advantage that pericardial tissue is obtained for mycobacterial culture and histopathological diagnosis, but it has the disadvantage of anaesthesia and potential surgical mortality.34,87 Recommended antituberculous chemotherapy of pericardial TB is the same as for pulmonary TB.33,84 In a large randomized, doubleblind, placebo-controlled trial, adjunctive corticosteroid therapy (prednisone) for the first 11 weeks of chemotherapy resulted in significant clinical benefit;34 significant survival benefit was maintained in those randomized to corticosteroid therapy over 10 years of follow-up.88 The same benefits have not been demonstrated elsewhere and there is currently no convincing evidence for routine corticosteroid administration in patients who have undergone successful pericardiocentesis.33,47,87 In children pericardial effusion usually develops when a subcarinal lymph node erupts into the pericardial space.78 On chest radiography the heart shadow may be enlarged with a suggestive globular appearance, but cardiac ultrasound is the most sensitive test to confirm or exclude a pericardial effusion. Long-term sequelae include constrictive pericarditis; therefore in children pericardial effusion is an indication for the use of corticosteroids together with antituberculous treatment.79
ABDOMINAL TUBERCULOSIS The term abdominal TB encompasses tuberculous involvement of any of the intra-abdominal organs including any part of the gastrointestinal tract from mouth to anus, omentum, peritoneum, mesentery and its nodes and other solid intra-abdominal organs such as liver, spleen and pancreas. Infection is primarily due to either swallowing of infected material from pulmonary disease or haematogenous spread to abdominal organs with subsequent involvement of contiguous structures. The clinical presentations are protean and mimic many other diseases. The most frequent presenting symptoms are abdominal distension and/or pain, fever and weight loss but may vary with the site of tuberculous involvement.89–92 The oropharynx may be affected with chronic ulceration. Oesophageal involvement may present with stricture or tracheo- or broncho-oesophageal fistula, as a result of erosion of mediastinal caseating nodes into the oesophagus. Gastric and duodenal disease may cause ulceration or obstruction. Fistulae, perforation or malabsorption may result from small bowel involvement. The ileocaecum and jejunoileum are the most frequent sites of involvement. Complications include a palpable mass, obstruction, perforation and fistula formation. Massive rectal bleeding can complicate colonic involvement and rectal lesions present as fissures, fistulas and perirectal abscesses.93 Solid organ involvement occurs in approximately 20% of cases of abdominal TB.92 Hepatic involvement may present with abdominal distension, right hypochondrial pain and jaundice,94 and splenic disease with moderate splenomegaly; pancreatic TB may mimic pancreatitis or carcinoma. Tuberculous hepatitis, rarely with jaundice, is usually seen in patients with disseminated disease and should be suspected if liver enzymes are elevated. Abdominal ultrasonography is indicated to look for intra-abdominal lymphadenopathy and detect hepatic enlargement, a granular infiltrate suggesting granulomatous inflammation and to exclude tuberculous abscesses. The histological abnormalities may
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Overview of extrapulmonary tuberculosis in adults and children
vary from non-specific inflammatory changes to very specific granulomatous lesions and the presence of M. tuberculosis. The diagnostic yield may improve by mycobacterial culture of biopsy specimens. The biliary ducts and the pancreas are rarely involved, although this has been described as part of miliary TB in immunocompromised patients.95 The clinical manifestations depend on the site and extent of disease and may include anorexia, malaise, lowgrade fever, weight loss, night sweats, abdominal pain, bloody stools, obstructive jaundice and acute or chronic pancreatitis.96,97 Pancreatic TB may mimic malignancy and present as a pancreatic mass or abscess.95,96 The spleen is commonly involved in patients with disseminated TB, but isolated splenic TB presenting with splenomegaly, hypersplenism, solitary splenic lesions or splenic abscesses is rare.98 Tuberculous peritonitis usually presents with pain and abdominal distension accompanied by fever, weight loss and anorexia.91 Confirmation of abdominal involvement requires a combination of endoscopic, microbiological, histological and molecular techniques. Tuberculous ascites has biochemical characteristics similar to those of tuberculous pleural and pericardial exudates. Cellular content is predominantly lymphocytic, ADA levels are elevated and the acidfast bacilli and mycobacterial culture yields are low. Isolation of M. tuberculosis is enhanced by centrifugation of large samples of peritoneal fluid, bedside inoculation of peritoneal fluid into liquid culture media and when peritoneal biopsy material can be examined and cultured. The difficulty of making a diagnosis of abdominal TB is illustrated by many autopsy-proven cases unsuspected during life94,99 and considerable diagnostic delay even in well-resourced settings.99 A strong association between untreated cavitary lung disease and gastrointestinal involvement, consistent with prolonged exposure to swallowed infected secretions, was demonstrated in autopsies performed in the prechemotherapy era. In Los Angeles, California, gastrointestinal lesions were present in 25% of 6,085 autopsies in which TB was identified,100 and more recently a continued relationship between smear-positive cavitary lung and gastrointestinal disease has been demonstrated in a South African hospital cohort, in whom the prevalence of proven gastrointestinal TB was 28%.101 The lesions were predominantly superficial mucosal lesions of the caecum, which appeared to be related to the severity of pulmonary disease.101 Conversely, pulmonary TB has been recognized in between 1% and 64% of reported series of abdominal TB in HIV-seronegative populations.90–92,102 This wide variability in the association between abdominal and pulmonary involvement may be due to selection biases due to variable sensitivities of the diagnostic modalities for defining pulmonary and abdominal involvement, the type and chronicity of abdominal involvement at presentation and the variable access of each population to diagnosis and effective chemotherapy of early pulmonary TB. Abdominal TB occurs more frequently in HIV-infected than in HIV-seronegative individuals, due to both an overall increased incidence of TB together with an increased propensity for dissemination as the CD4 cell count declines.103,104 M. tuberculosis infection in AIDS patients more frequently involves the solid abdominal organs in keeping with lymphohaematogenous spread. The liver, spleen and pancreas as well as the peritoneum and gastrointestinal tract are frequently involved. Fistulae are more frequent in AIDS and may occur from any segment of bowel. Conventional short-course chemotherapy, as for pulmonary TB, appears to be effective, although surgery is occasionally required for complications.
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GENITOURINARY TUBERCULOSIS Genitourinary TB results from seeding of the genital organs or kidney at the time of initial tuberculous infection and bacteraemia. Genitourinary symptoms, including dysuria, haematuria and flank pain, are more frequent than constitutional symptoms in patients with renal TB. Many individuals are asymptomatic and finding sterile pyuria, with or without accompanying haematuria or albuminuria, is the clinical trigger for investigation of possible renal TB, especially in those with evidence of prior TB or other active organ involvement.105–107 Diagnosis is usually established by culture of repeated early morning urine collections.105,106 Three early morning cultures are sufficient to confirm the diagnosis in 80–90% of cases. Intravenous pyelograms are usually abnormal. Supportive clinical findings include papillary necrosis, ureteral strictures with or without hydronephrosis and focal calcification. Approximately 40–75% of patients have chest radiographic abnormalities suggesting previous or current pulmonary TB.105,106 Asymptomatic renal involvement, manifested by positive urinary mycobacterial culture in the absence of renal signs or symptoms, is present in 5% of HIVseronegative cases with active pulmonary TB and 21% of those with extrapulmonary TB.108 The frequency of renal involvement is even higher in those with TB/HIV coinfection. Urine mycobacterial culture was positive in 15% of HIV-infected pulmonary TB cases and in 29–77% of those HIV-infected known to have extrapulmonary TB.109–111 Histological evidence of renal TB was found in 23% of a series of autopsies of AIDS patients in Brazil.112 Standard antituberculous chemotherapy is indicated for renal TB, although some prefer prolonged therapy.113 If left untreated, renal TB may result in obstructive nephropathy, renal stone disease, recurrent bacterial infections and ultimately renal failure. Ureteric obstruction may also develop during chemotherapy and repeated imaging may be required to exclude development of hydronephrosis.
Male genitourinary tuberculosis Male genital TB is strongly associated with concomitant renal TB and may involve prostate, seminal vesicles, epididymis and testes with decreasing incidence.105,106 The diagnosis is usually entertained in those presenting with a scrotal mass and confirmed by biopsy. Prostate TB is rare but has been increasingly reported in AIDS and may be associated with only mild urinary symptoms.114 A substantial number of patients with any form of genitourinary TB are asymptomatic and are detected because of an evaluation for an abnormal routine urinalysis. In more than 90% of patients with renal or genital TB, urinalyses are abnormal, the main finding being pyuria and/or haematuria with no organisms isolated from routine urine culture.105,106 Diagnosis of isolated genital lesions usually requires biopsy, because the differential diagnosis often includes neoplasia or other chronic infectious processes. Female genitourinary tuberculosis Symptomatic female genital tract TB accounts for less than 2% of TB and usually presents with abnormal vaginal bleeding, menstrual irregularities, abdominal pain and constitutional symptoms.107 The primary focus is the endosalpinx from which spread takes place to the endometrium, ovaries, cervix and more rarely to the vagina. The clinical presentation of disease involving the ovaries and endosalpinx may suggest pelvic inflammatory disease or mass unresponsive to antimicrobial therapy. Involvement of the cervix may mimic a neoplasm and vaginal lesions present as indolent ulceration. The diagnosis may be made as a result of investigations for
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infertility and return to fertility after treatment is not encouraging. Involvement of the endosalpinx predisposes to both subsequent ectopic pregnancies and infertility.115 Diagnosis is by culture and histology of surgical specimens such as endometrial scrapings, ulcerative lesions and cervical biopsy. Drug treatment follows standard TB regimens, although criteria for assessing treatment efficacy are lacking. Surgery is usually reserved for large residual tubo-ovarian abscesses.
TUBERCULOSIS OF THE CENTRAL NERVOUS SYSTEM Tuberculous meningitis is the most common form of CNS TB, being responsible for between 70% and 80% of cases followed in decreasing incidence by intracranial tuberculomata and spinal arachnoiditis. Neurological TB is invariably secondary to TB elsewhere in the body. Meningitis results from intense inflammation initiated by the rupture of a subependymal tubercle (Rich focus) rather than from direct haematogenous seeding, but whether the subependymal tubercle develops during primary haematogenous dissemination or secondary spread from extracranial TB is not clear.116,117 In children, tuberculous meningitis is an early postprimary event; however, subependymal foci may remain quiescent for prolonged periods, resulting in delayed presentation. Tuberculous meningitis is the most severe manifestation of childhood TB. BCG vaccination provides some degree of protection against severe forms of TB (disseminated TB and tuberculous meningitis), but despite universal BCG vaccination severe disease manifestations still occur, mainly affecting very young (immune immature) and/ or immunocompromised children in endemic areas. In tuberculous meningitis meningeal involvement is most pronounced at the base of the brain where ensuing arachnoiditis encases cranial nerves and penetrating vessels with associated cranial nerve palsies. Cerebral vasculitis may lead to thrombosis and focal infarction of the basal ganglia and pons, resulting in movement disorders or lacunar infarcts. Associated cerebral oedema or hydrocephalus (Fig. 34.2) causes decreased level of consciousness, seizures and raised intracranial pressure. A prodrome of malaise, low-grade fever, apathy, anorexia and behaviour changes lasting for 2–3 weeks is followed by protracted headache, progressive meningism, vomiting, increasing drowsiness and focal neurological signs.116 The initial clinical spectrum is broad, ranging from subtle mental status changes to rapid progression mimicking pyogenic meningitis and consequences of acute hydrocephalus as demonstrable by CT scan (Fig. 34.2). Without early treatment, stupor and coma inevitably ensue and death follows in 5–8 weeks.116 Focal or generalized seizures and cranial nerve palsies are frequent,117 and evidence of concomitant extrapulmonary TB, including miliary shadowing on chest radiograph, is present in 75% of cases.116 A high index of clinical suspicion for the early diagnosis and prompt initiation of treatment for tuberculous meningitis should be maintained, as the long-term prognosis is influenced by the duration and level of neurological impairment at commencement of therapy. Diagnosis is largely based on an index of suspicion and examination of the CSF, which is characterized by increased opening pressure, a raised protein, a preponderate mononuclear cellular response and hypoglycorrhachia. CSF leucocyte counts vary from 100 to 1,000 leukocytes/L with lymphocytes predominating in 65–75% of patients.46 Atypical findings are common, including predominance of polymorphonuclear cells and a normal glucose. On repeated testing there is usually an evolution to the
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Fig. 34.2 Tuberculous meningitis causing acute hydrocephalus. An 11-year-old boy presented with a 1-week history of headaches and daily vomiting. His aunt had died of pulmonary TB during the previous year. A brain CT scan demonstrated acute hydrocephalus (black arrows) and basal enhancement (white arrows). He had a sudden neurological deterioration and was treated with mannitol, emergency insertion of ventriculoperitoneal (VP) shunt, four-drug antituberculous chemotherapy and adjunctive dexamethasone.
more typical picture. In adults, the yield of acid-fast bacilli on direct smear of CSF is 10–20%, but is improved when a large quantity of CSF is centrifuged and there is an incremental yield with repeat investigations. The yield of CSF culture is similarly volume dependent and is typically positive in 45–90% of cases but culture takes up to 4 weeks. CSF PCR for M. tuberculosis has been explored in order to expedite the diagnosis but lacks sensitivity and cannot be used to exclude the diagnosis of tuberculous meningitis.118 A substantial number of patients will have M. tuberculosis isolated from other sources, and, in the presence of compatible CSF findings, such isolation is sufficient to diagnose tuberculous meningitis. Given the severity of tuberculous meningitis, a presumptive diagnosis justifies empiric treatment. The combination of a suggestive clinical presentation, including a history of household contact with an infectious pulmonary TB case, and compatible laboratory and imaging findings is frequently used to initiate chemotherapy before a definitive diagnosis is made. The demonstration of basal inflammation on CT and magnetic resonance imaging (MRI) supports the diagnosis (Fig. 34.2). HIV infection increases the incidence of tuberculous meningitis several-fold but does not fundamentally alter the clinical and laboratory manifestations.119,120 The mononuclear cell preponderance and raised protein in the CSF of those with chronic HIV infection may, however, mimic the diagnosis of tuberculous meningitis. There should be a low threshold for initiation of empiric antiTB therapy and treatment is with a standard course of INH,
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Overview of extrapulmonary tuberculosis in adults and children
RMP, PZA and SM or ethionamide continued for 9–12 months together with adjunctive corticosteroids.40,44–46
INTRACRANIAL TUBERCULOMATA Tuberculomata are space-occupying lesions that may manifest with seizures. They vary in size from a few millimetres up to 3–4 cm in diameter and appear on imaging studies usually as solitary avascular structures with considerable surrounding cerebral oedema. Although definitive diagnosis is dependent on biopsy this is frequently impracticable in resource-poor settings where these lesions are more common. Treatment is with corticosteroids to reduce the oedema and symptoms, and chemotherapy results in slow resolution of the tuberculoma. In HIV-infected individuals tuberculomata occur more frequently and may become apparent as part of IRD. The main differential diagnoses include neurocysticercosis and cerebral lymphoma. In resource-poor settings where neurosurgical facilities are limited, empiric therapy for both toxoplasmosis and tuberculomata may need to be initiated for ring-enhancing intracranial lesions.
TUBERCULOUS SPINAL MENINGITIS Rarely, spinal meningitis or an intramedullary tuberculoma occurs without intracranial involvement. Symptoms result from cord or nerve root compression and are determined by the level of cord involvement but include a level of loss of sensory sensation, root pain, bladder and sphincter weakness or paralysis.
BONE AND JOINT TUBERCULOSIS Skeletal TB is predominantly caused by haematogenous spread, although spread from contiguous structures may infrequently occur. The spine is most commonly involved, followed by tuberculous arthritis of the weight-bearing joints and less commonly tuberculous osteomyelitis.121–123 Usually only one bone or joint is involved, but occasionally the process is multifocal.124,125 Evidence of either previous or current pulmonary TB is found in approximately 50% of reported patients, and other extrathoracic sites may also be involved.
SPINAL TUBERCULOSIS Archaeological skeletal evidence shows spinal TB has been with humans for millennia. However, Percival Pott (1714–1788), an eminent surgeon, has given his name to the spinal pathology and accompanying deformity; he was the first to show that it caused paraplegia and was responsive to surgery. The incidence of osteoarticular TB increases with age and is equally frequent among men and women, overall making up approximately 9% of cases of extrapulmonary TB.126 Most skeletal TB results from endogenous reactivation of foci of infection seeded during the initial bacteraemia, although spread from paravertebral lymph nodes has been postulated to account for the common localization of spinal TB to the lower thoracic and upper lumbar vertebrae.127 Spinal TB less frequently involves middle thoracic or cervical vertebrae. Usually two adjacent vertebrae are involved, although skip lesions may occur.128 The infection begins in the anterior inferior or anterior superior aspect of the vertebrae, leading to bony collapse and the classical radiological appearance of anterior wedging of two vertebrae with intervening disc destruction. The early changes of spinal
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TB are difficult to detect by standard films, and CT scans or MRI may be needed to visualize disease process. Bone is replaced by granulomatous tissue with or without caseation necrosis and mycobacteria are scanty. While a disease of children and young adults in endemic regions it is a disease of the elderly in developed countries.129 The presentation may be cryptic with local back pain accompanied by few systemic symptoms leading to delayed diagnosis which may eventually be precipitated by signs of advancing bony destruction, deformity and neurological weakness or paraplegia secondary to spinal compression. Pus at high pressure due to confinement within tight ligaments follows the path of least resistance along fascial planes and can present with abscesses and sinuses distant from the original bony lesion before or after the initiation of chemotherapy. Involved anatomical regions may range from retropharyngeal abscess in the neck to psoas abscess presenting with a femoral triangle mass in the groin. Weakness and paralysis is the most serious complication, occurring in 30–50% of cases and can present or worsen after initiation of therapy.129 Long spinal tracts may be affected by a combination of local pressure, vasculitis and arachnoiditis.129 Treatment is predominantly medical although surgery may be indicated for those with instability of the spine at risk of progressive deformity.130,131 Medical treatment consists of standard TB chemotherapy, but is usually prolonged.40
PERIPHERAL OSTEOARTICULAR TUBERCULOSIS Tuberculous arthritis usually presents as a slowly progressive monarthritis affecting predominantly, although not exclusively, the major weight-bearing joints such as knee and hip. Systemic symptoms are frequently absent or mild and the main signs and symptoms are joint swelling, pain and diminished range of movement. Evidence of prior pulmonary TB on chest radiograph is present in approximately 50% of cases.121 Radiological findings vary with the chronicity of infection and range from soft-tissue swelling, juxta-articular osteopenia, joint-space narrowing with subchondral erosions to joint destruction.122 The diagnosis may be delayed or more difficult when TB infects joints previously damaged by other arthritic processes. The diagnosis is confirmed by demonstration of histological changes compatible with TB on synovial or bone biopsy and/or positive mycobacterial culture of synovial fluid or periarticular abscess.122,123 Acid-fast stains of joint fluid are usually negative, and culture for M. tuberculosis positive in approximately 60–80% of patients with osteoarticular TB.132 Treatment is with chemotherapy with surgical joint fusion reserved for serious joint instability present after failed prolonged medical therapy.40 Tuberculous osteomyelitis presents as a cold abscess with swelling and/or sinus formation overlying the involved bone. Lesions may be single or multiple, involving ribs, skull, pelvis or the long bones.124 Diagnosis is confirmed by bone biopsy and mycobacterial culture. Treatment is medical with adjunctive surgical debridement if necessary.121,122,124
DISSEMINATED TUBERCULOSIS The term disseminated TB refers to TB that involves two or more non-contiguous sites. It can occur during primary TB infection, after reactivation of latent infection or after reinfection, depending on the efficacy of the cellular immune response to contain the disease. Dissemination occurs when tubercle bacilli enter the blood
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circulation via the lymphatics and spread to visceral sites that have a rich vascular supply such as the liver, spleen, brain and the bone marrow. Miliary TB is a pathological name describing miliary (millet seed)-sized granulomata in various organs affected by haematogenous dissemination of tubercle bacilli. While miliary TB can be recognized in histological specimens from tissues other than the lung,133 the majority (86–91%) of published clinical papers rely on recognition of miliary shadows on chest radiograph (Fig. 34.3). In order to clarify the difference between clinical and pathological diagnoses, it has been proposed that the term miliary TB should be restricted to disseminated TB with miliary shadows on chest radiograph and those cases not showing miliary shadows on chest radiograph be called disseminated TB.134 Disseminated TB is a life-threatening disease resulting from haematogenous spread of M. tuberculosis to a variety of tissues and may lead to a wide range of manifestations, from an acute fulminant illness to a prolonged cryptic illness with subtle clinical findings. The presenting symptoms and signs are generally non-specific and are dominated by systemic effects, particularly fever, weight loss, anorexia and weakness.73 Other symptoms depend on the relative severity of disease in the organs involved. Fever, wasting, hepatomegaly, pulmonary findings, lymphadenopathy and splenomegaly occur in descending order of frequency. Physical findings may include choroidal tubercles, with granulomata located in the choroid of the retina, and cutis miliaris disseminata, a rare cutaneous manifestation of miliary TB.135,136 In HIV-seronegative patients with disseminated TB underlying predisposing conditions such as diabetes mellitus, organ failure and autoimmune conditions are present in 41–47% of cases.73,136,137 The disease is characterized by high mortality, reported to be 18–30%. Mortality is strongly associated with age, mycobacterial burden, delayed chemotherapy and laboratory markers indicative of severity of disease such as lymphopenia, thrombocytopenia, hypoalbuminaemia and elevated hepatic transaminases.73,133,134 Diagnosis can be made by isolation of M. tuberculosis from sputum and gastric washings but is frequently missed and more invasive investigations are required. In retrospective series the diagnostic yield of bronchoscopy, bone marrow biopsy and liver biopsy were high.73,133,134 Identification of typical granulomata and/or acid-fast
bacilli in histological specimens allows for rapid diagnosis of disseminated TB; however, mycobacterial culture, while enabling a definitive diagnosis to be made, results in increased delay in confirming the diagnosis. Adult respiratory distress syndrome (ARDS) is a serious complication of miliary TB, occurring in approximately 1% of cases. ARDS is increased in those with the same disease risk factors associated with increased mortality.137 The incidence of disseminated TB is increased in patients coinfected with HIV with miliary shadowing identified in up to 38% of AIDS patients with extrapulmonary TB.24 Constitutional symptoms predominate and the disease is characterized by a high mycobacterial burden, diffusely spread throughout multiple organs in individuals with anergic or poor immunological reactivity. Complications such as ARDS, skin lesions and abscess formation occur more frequently in those who are HIV-infected. IRD is frequent in those with disseminated TB commencing antiretroviral therapy.55 Diagnosis can be confirmed by histological examination of organ and lymph node biopsies, and culture of respiratory secretions, CSF, urine and blood. In children dissemination represents as a condition of infinite gradation. Occult dissemination is common following primary infection; however, it rarely progresses to disseminated disease except in very young (< 3 years of age) and immunocompromised children.48,78 Typical radiological signs include the presence of even-sized miliary lesions (< 2 mm) distributed bilaterally into the very periphery of the lung.79 Diagnostic confusion often exists in HIV-infected children in whom lymphocytic interstitial pneumonitis, malignancies and opportunistic infections such as Pneumocystis jiroveci pneumonia may present with a similar radiological picture.138 In these instances, response to treatment and/or bacteriological confirmation may be the only way to establish a definitive diagnosis and treatment should not be delayed while awaiting diagnostic confirmation.
CUTANEOUS TUBERCULOSIS Cutaneous responses to M. tuberculosis infection are highly varied and reflect diverse pathological responses to mycobacterial organisms and antigens. Tuberculids are the commonest skin
Fig. 34.3 Disseminated (miliary) TB. A 15-month-old HIV-infected, underweight infant presented with intermittent fever and coughing. His chest radiograph (A) and CT scan (B) demonstrated diffuse granular shadowing suggestive of disseminated (miliary) TB.
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Overview of extrapulmonary tuberculosis in adults and children
manifestations of tuberculous infection although mycobacteria are not isolated from the lesions. Erythema induratum was the commonest tuberculid (93%) followed by papulonecrotic tuberculid and together they constituted 85% of cutaneous TB cases seen over a 10-year period in Hong Kong.139 Erythema nodosum is not a form of cutaneous TB, but a hypersensitivity reaction attributed to primary TB, many other infections and some drugs. True cutaneous TB includes lupus vulgaris, scrofuloderma and verrucosa cutis and are characterized by the presence of granulomata with caseating necrosis and a relative paucity of mycobacterial organisms. Lupus vulgaris is seen mainly on the extremities; cervical and axillary regions are the commonest sites for scrofuloderma and verrucosa cutis occurs predominantly on the sole and foot.140 The diagnosis of cutaneous TB can be confirmed by demonstration of epithelioid cell granulomata and caseation necrosis on cytology or biopsy.141 In a series of fine needle aspirations from cutaneous TB lesions, acid-fast bacilli were identified in 79% of scrofulodermatous lesions and 22% of lupus vulgaris lesions.141 There is a good response to anti-TB chemotherapy with a resolution of lesions within 6 months in 92% of patients receiving RMP-containing combination chemotherapy.139 Cutis miliaris disseminate, previously recognized as a rare complication of miliary TB, is now more frequently recognized in patients with advanced HIV infection together with dissemination of M. tuberculosis organisms and is manifested by the presence of miliary tubercles within the dermis.142
OCULAR TUBERCULOSIS Besides cranial nerve involvement TB may affect all parts of the eye, most commonly the choroids.143 In children papulonecrotic TB and phlyctenular conjunctivitis are hypersensitivity reactions due to primary TB disease. Tuberculous uveitis may present as panuveitis or as chronic granulomatous iridocyclitis.143 Patients with miliary TB may present with choroidal tubercles, which can be single or multiple and vary in size.143 Rarely, lupus vulgaris may affect the eyelids.
TUBERCULOSIS OF LARYNX, PHARYNX, ORAL CAVITY AND SALIVARY GLANDS Before the advent of anti-TB treatment patients often developed laryngeal TB, which is a highly infectious form of extrapulmonary TB. Although now rare, laryngeal TB still occurs in areas with high prevalence of pulmonary TB. The clinical manifestations of laryngeal TB have changed and are different from those of classic reports.144 It can occur without pulmonary TB, and the characteristics of lesions can be granulomatous, ulcerative, polypoid or nonspecific. The main presenting symptoms are hoarseness and pain, which may radiate to one or both ears and may lead to odynophagia. Active pulmonary disease is present in approximately half of cases and inactive pulmonary TB in a third. Depending on the presentation, tuberculous laryngitis may resemble acute viral laryngitis or carcinoma of the larynx. Clinical features of these conditions may overlap and the granulomatous and ulcerative lesions may resemble laryngeal carcinoma.144 Laryngeal TB responds readily to standard TB chemotherapy. Tuberculous involvement of the tonsils, pharynx and oral cavity is uncommon. The presenting features may include ulceration of the tonsil or oropharyngeal wall, granulomatous inflammation of the nasopharynx or cervical abscess.144 Infection in the oral cavity
34
is usually acquired through infected sputum coughed out by a patient with pulmonary TB or by haematogenous spread. The tongue is the most common site of involvement and accounts for nearly half the cases. Other sites of involvement include floor of mouth, soft palate, anterior pillars and uvula.145,146 Tuberculous sialitis is usually secondary to TB of the oral cavity or pulmonary TB.146 The parotid glands are most commonly involved and clinical presentation can be acute or chronic. Acute presentation may resemble acute bacterial sialitis and clinical differentiation may be difficult. In other situations, the clinical presentation may resemble that of a salivary gland tumour.146 Unsuspected tuberculous parotid abscess may be mistaken for a pyogenic abscess and inappropriately drained, leading to formation of a persistent sinus.145
TUBERCULOSIS OF THE EAR, PARANASAL SINUSES, NOSE AND NASOPHARYNX Tuberculosis of the ear rarely involves the external ear and usually develops when the tubercle bacilli invade the Eustachian tube or by haematogenous spread to the mastoid process.137 Tuberculous otitis media may present as painless otorrhoea. Otoscopy may reveal pale granulation tissue in the middle ear with dilatation of vessels in the anterior part of the tympanic membrane. Multiple perforations of the tympanic membrane may occur as a result of caseating necrosis. Facial nerve palsy may sometimes develop.145 Tuberculous involvement of the ear appears to be particularly common in HIV-infected children. Tuberculosis of the nose, paranasal sinuses and nasopharynx is uncommon. Tuberculosis of the nasal mucosa may present with nasal discharge, mild pain and partial nasal obstruction and may be complicated by septal perforation, atrophic rhinitis and scarring of the nasal vestibule.145 Tuberculous involvement of the nasal mucosa may present with granulomatous lesions resembling Wegener’s granulomatosis.147
TUBERCULOSIS OF THE BREAST Tuberculous mastitis can occur as primary disease or can be secondary to TB elsewhere in the body. Secondary involvement of the breast is more common than primary involvement and tubercle bacilli may reach the breast through lymphatic or haematogenous routes, or by contiguous spread from the ribs or pleural space. Lymphatic spread by retrograde extension from the axillary lymph nodes is considered to be the most common mode of spread though spread from cervical and mediastinal lymph nodes has been occasionally reported.145 Primary TB mastitis is extremely rare and is thought to occur due to direct inoculation of the breast by M. tuberculosis through skin abrasions or duct openings in the nipple.145 Clinical presentation is atypical and histopathological evidence suggests the diagnosis.
MISCELLANEOUS CONDITIONS Extrapulmonary TB may involve almost any body organ system and like syphilis is a great mimic of many other diseases (Tables 34.2 and 34.3). This is mostly the result of disease progression that occurs at sites where the TB bacillus was deposited during the initial phase of occult dissemination.145,148 In some individuals a few mycobacteria may provoke intense immunological responses with local tissue injury, while in contrast there may be a non-reactive
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Table 34.2 The distribution of tuberculosis cases by anatomical site comparing HIV-seronegative with HIV-infected patients
Pulmonary TB only Extrapulmonary TB only Both pulmonary and extrapulmonary TB Pleural TB Lymph node TB Genitourinary TB Disseminated TB TB meningitis Abdominal TB Other TB
HIV-seronegative (%)
HIV-infected (%)
75 15 5
30 20 50
20 35 9 8 5 3 10
20 35
45
Adapted from Sharma and Mohan.145
pattern of response to a widespread organism burden in anergic individuals. Tuberculosis is capable of producing rare and unusual presentations, such as tuberculous adrenal involvement presenting as an Addisonian crisis or tuberculous infection of the craniovertebral junction presenting as torticollis.149 Newborn babies may acquire congenital TB via the placenta, if the mother develops active TB and haematogenous dissemination, in which case the primary (Ghon) focus is usually located in the liver. Cases of congenital TB are on the rise in countries where TB/HIV coinfection rates among expectant mothers are high. The incidence and prevalence of extrapulmonary TB varies profoundly and is closely linked to global resource inequalities. Consequently in industrialized settings where extrapulmonary TB is less common, a high index of clinical suspicion for a possible tuberculous aetiology needs to be maintained. In contrast, in resourcepoor settings where the prevalence of TB is high together with its recognized ability to produce protean manifestations many patients receive prolonged empiric courses of anti-TB treatment for non-tuberculous conditions.
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388
Table 34.3 Disease spectrum documented in a prospective community-based survey of all children < 13 years of age, treated for tuberculosis in a highly endemic area TB manifestation
Total (%) n ¼ 439
Not TB
85 (19.4)
Intrathoracic TB Ghon focus Uncomplicated Complicated Lymph node disease Uncomplicated Complicated Compression Consolidation Pleurisy Pericarditis Miliary disease Adult-type disease
307 (69.9)
Extrathoracic TB Peripheral lymphadenitis Cervical Other Central nervous system TB Meningitis Tuberculoma Abdominal TB Osteoarticular TB Spinal TB Other Skin
72 (16.4)
[Intra þ Extrathoracic TB]
[25 (5.7)]
16/307 (5.2) 3/307 (1.0) 147/307 (47.9) 25/307 (8.1) 62/307 (20.6) 24/307 (7.8) 1/307 (0.3) 15/307 (4.9) 14/307 (4.6)
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107. Garcia-Rodriquez JA, Garcia SJE, Munoz BJL, et al. Genitourinary tuberculosis in Spain: a review of 81 cases. Clin Infect Dis 1994;18:557–561. 108. Bentz RR, Dimvheff DG, Nemiroff MJ, et al. The incidence of urine cultures positive for Mycobacterium tuberculosis in the general tuberculosis patient population. Am Rev Respir Dis 1975;111:647–650. 109. Aceti A, Zanetti S, Mura MS, et al. Identification of HIV patients with active pulmonary tuberculosis using urine based polymerase chain reaction assay. Thorax 1999;54:145–146. 110. Wilson D, Nachega JB, Chaisson RE, et al. Diagnostic yield of peripheral lymph node needlecore biopsies in HIV-infected adults with suspected smear-negative tuberculosis. Int J Tuberc Lung Dis 2005;9:220–222. 111. Moreno S, Hermida JM, Buzon L, et al. Tuberculosis presenting as diffuse pulmonary infiltrates in AIDS patients: diagnostic performance of clinical samples. Enferm Infect Microbiol Clin 1995;13:297–300. 112. Marques LP, Rioja LS, Oliviera CA, et al. AIDSassociated renal tuberculosis. Nephron 1996; 74:701–704. 113. Gokce G, Kilicarsian H, Ayan S, et al. Genitourinary tuberculosis: a review of 174 cases. Scand J Infect Dis 2002;34:338–340. 114. Lanjewar DN, Maheshwari MB. Prostatic tuberculosis and AIDS. Natl Med J India 1994;7:166–167. 115. Namavar JB, Parsanezhad ME, Ghane-Shirazi R. Female genital tuberculosis and infertility. Int J Gynaecol Obstet 2001;75:269–272. 116. Thomas MD, Chopra JS, Walia BNS. Tuberculous meningitis. A clinical study of 232 cases. J Assoc Physicians India 1977;25:633–639. 117. Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and miliary tuberculosis: the Rich focus revisited. J Infect 2005;50:193–195. 118. Pai M, Flores LL, Pai N, et al. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003;3:633–643. 119. Berenguer J, Moreno S, Laguna F, et al. Tuberculous meningitis in patients with human immunodeficiency virus. N Engl J Med 1992;326:668–672. 120. Dube MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992;93:520–524. 121. Grosskopf I, Ben David A, Charach G, et al. Bone and joint tuberculosis—a 10-year review. Isr J Med Sci 1994;30:278–283. 122. Watts HG, Lifeso RM. Tuberculosis of bones and joints. J Bone Joint Surg Am 1996;78:288–298. 123. Lifeso RM, Weaver P, Harder EH. Tuberculous spondylitis in adults. J Bone Joint Surg Am 1996;67:1405–1413. 124. Muradali D, Gold WL, Vellend H, et al. Multifocal osteoarticular tuberculosis: Report of four cases and review of management. Clin Infect Dis 1993;17: 204–209. 125. Schaaf HS, Donald PR. Multiple bone tuberculosis and dactylitis. (Radiological case of the month). Arch Pediatr Adolesc Med 2000;154:1059–1060. 126. Farer LS, Lowell LM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979;109:205–217. 127. Burke HR. The pathogenesis of certain forms of extrapulmonary tuberculosis. Am Rev Tuberc 1950;62:48–67. 128. Emel EW, Guzey FK, Guzey D, et al. Non contiguous multifocal spinal tuberculosis involving cervical, thoracic, lumbar and sacral segments. A case report. Eur Spine 2006;15:1019–1024.
129. Janssens JP, De Haller R. Spinal tuberculosis in a developed country. A review of 26 cases with special emphasis on abscesses and neurologic complications. Clin Orthop 1990;257:67–75. 130. Rajasekaran S, Shanmugasundaram TK, Prabhaker R, et al. Tuberculous lesions of the lumbosacral region. A 15-year follow-up of patients treated by ambulant chemotherapy. Spine 1998;23:1163–1167. 131. Park DW, Sohn JW, Kim EH, et al. Outcome and management of spinal tuberculosis according to the severity of disease: a retrospective study of 137 adult patients at Korean teaching hospitals. Spine 2007;32:E130–135. 132. Berney S, Goldstein M, Bishko F. Clinical and diagnostic features of tuberculous arthritis. Am J Med 1972;53:36–42. 133. Miyoshi I, Daibata M, Kuroda N, et al. Miliary tuberculosis not affecting the lungs but complicated by acute respiratory distress syndrome. Intern Med 2005;44:622–624. 134. Matsumshima T. Miliary tuberculosis or disseminated tuberculosis. Int Med 2005;44:687. 135. Massaro D, Katz S, Sachs M. Choroidal tubercles: a clue to hematogenous tuberculosis. Ann Intern Med 1964;60:231–241. 136. Hussain SF, Irfan M, Abbasi M, et al. Clinical characteristics of 110 miliary tuberculosis patients from a low HIV prevalence country. Int J Tuberc Lung Dis 2004;8:493–499. 137. Kim J-Y, Park YB, Kim YS, et al. Miliary tuberculosis and acute respiratory distress syndrome. Int J Tuberc Lung Dis 2003;7:359–364. 138. Graham SM, Coulter JBS, Gilks CF. Pulmonary disease in HIV-infected children. Int J Tuberc Lung Dis 2001;5:12–23. 139. Chong LY, Lo KK. Cutaneous tuberculosis in Hong Kong: a 10-year retrospective study. Int J Dermatol 1995;34:26–29. 140. Umpathy KC, Begum R, Ravichandran G, et al. Comprehensive findings on clinical, bacteriological, histopathological and therapeutic aspects of cutaneous tuberculosis. Trop Med Int Health 2006;11:1521–1528. 141. Kathuria P, Agarwal K, Koranne RV. The role of fine-needle aspiration cytology and Ziehl Neelsen staining in the diagnosis of cutaneous tuberculosis. Diagn Cytopathol 2006;34:826–829. 142. Libraty DH, Byrd TF. Cutaneous military tuberculosis in the AIDS era: case report and review. Clin Infect Dis 1996;23:706–710. 143. Bouza E, Merino P, Munoz P, et al. Ocular tuberculosis. A prospective study in a general hospital. Medicine 1997;76:53–61. 144. Lim JY, Kim KM, Choi EC, et al. Current clinical propensity of laryngeal tuberculosis: a review of 60 cases. Eur Arch Otorhinolaryngol 2006;263: 838–842. 145. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316–353. 146. Weaver RA. Tuberculosis of the tongue. JAMA 1976;235:2418. 147. Harrison NK, Knight RK. Tuberculosis of the nasopharynx misdiagnosed as Wegener’s granulomatosis. Thorax 1986;41:219–220. 148. Marais BJ, Donald PR, Gie RP, et al. Diversity of disease manifestations in childhood pulmonary tuberculosis. Ann Trop Paediatr 2005;25: 79–86. 149. Mohindra S, Gupta SK, Gupta R. Unusual presentations of craniovertebral junction tuberculosis: a report of 2 cases and literature review. Surg Neurol 2006;66:94–99.
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35
Tuberculosis lymphadenitis and involvement of the reticuloendothelial system in children Ben J Marais and Stephen M Graham
TUBERCULOSIS LYMPHADENITIS Tuberculosis lymphadenitis (historically referred to as scrofula) is the commonest form of extrapulmonary TB recorded in children from TB-endemic areas, present in 8–10% of children diagnosed with TB in India and South Africa.1,2 Lymph nodes become infected with Mycobacterium tuberculosis following lymphatic drainage from a local disease site or after haematogenous dissemination. The cervical lymph nodes are the commonest site of clinical presentation and TB lymphadenitis is a common cause of persistent cervical adenopathy in children living in TB-endemic regions. Tuberculosis lymphadenitis was diagnosed in 22% of South African children who presented to a primary health centre with persistent cervical adenopathy (> 1 1 cm and not responding to a course of oral antibiotics) and this increased to 64% once a visible local cause was excluded.3 Figure 35.1 presents a flow diagram of all 167 children referred with persistent cervical adenopathy. Table 35.1 demonstrates the demographics and aetiology of persistent cervical adenopathy in the 158 children who were evaluated.
EPIDEMIOLOGY The mycobacteria that cause cervical lymphadenitis are highly variable depending on the setting. In areas where TB is endemic and bovine TB is well controlled, M. tuberculosis is the commonest cause.3,4Mycobacterium bovis may be a frequent cause in areas where the control of bovine TB is poor and milk is not routinely pasteurized.5 In developed countries with low rates of TB transmission, environmental mycobacteria, also referred to as non-tuberculous mycobacteria (NTM), are mainly responsible for peripheral lymphadenitis, particularly Mycobacterium avium complex (MAC).6 The aetiological agent may be determined by different environmental conditions. For example, the decrease in Mycobacterium scrofulaceum (historically associated with scrofula) and the concurrent increase in MAC as a cause of chronic cervical lymphadenopathy has been attributed to the chlorination of potable water supplies.7 In the context of these shifting epidemiological patterns it is interesting to note that the stoppage of Bacillus Calmette–Gue´rin (BCG) immunization in certain developed countries has led to a marked increase in the incidence of lymphadenitis caused by environmental mycobacteria, suggesting that BCG immunization provides protection against disease caused by these organisms.8 A similar protective effect provided by natural infection with M. tuberculosis, which may also enhance the protection provided
by universal BCG vaccination, probably explains why lymphadenitis due to M. avium complex or other environmental mycobacteria is rare in countries with a high burden of TB, despite the fact that 10% of rural children react to avian purified protein derivative (PPD) tuberculin.9 M. bovis BCG itself may cause regional lymphadenitis and even disseminated disease in severely immune compromised children. The simultaneous change of the M. bovis BCG strain (from Japanese to Danish) and the application route (from transcutaneous to intradermal) used for neonatal BCG vaccination in South Africa resulted in a marked increase in the number of infants who developed right-sided axillary lymphadenitis.10 This sudden increase in regional BCG-related complications was partly explained by previous inadequate delivery methods and initial unfamiliarity with the new intradermal technique. However, of particular concern was a number of human immunodeficiency virus (HIV)-infected infants who developed both regional, defined as axillary lymphadenitis on the side of the BCG vaccination scar, and/or disseminated BCG disease following neonatal vaccination.11 Axillary BCG lymphadenitis may also be a manifestation of the immune reconstitution inflammatory syndrome (IRIS), mostly seen in severely immunocompromised HIV-infected children within the first 3 months of starting antiretroviral therapy (ART).11 In a Thai study, IRIS was documented in 19% of children with low CD4 T-helper cell percentages (< 15%) newly started on ART; the majority of cases (nine) were caused by environmental mycobacteria, three by M. tuberculosis, and two by M. bovis BCG.12
PATHOGENESIS Tuberculosis lymphadenitis in the majority of cases represents the glandular component of a primary complex, which consists of the Ghon focus (or site of primary infection) and the regional lymph nodes. This was concluded from clinical experience during the prechemotherapy era. Peripheral lymphadenitis frequently occurred in complete isolation but in a substantial number of cases traces of a primary focus could be found after careful scrutiny.13 These cases suggested that the lymph nodes involved also reflect the most likely site of the Ghon focus. The submandibular group of nodes was most frequently affected and was associated with visible calcification of the intrathoracic lymph nodes, suggesting a primary focus in the lung. Similarly involvement of the supraclavicular nodes was associated with a primary focus in the apex of the lung.13 However, in a minority of cases cervical lymph
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SECTION
5
CLINICAL PRESENTATIONS OF TUBERCLOSIS NOT TB
TB Persistent cervical adenopathy >1¥1 cm 167
Not evaluated 9 Visible local cause 105
Evaluated 158 No visible local cause 53 < 2 ¥2 cm 20
TST negative 13
TST positive 7 FNA 7
Not TB 3
<-2 ¥ 2 cm 33 FNA 17 TB 17 TB 4
Biopsy Rx response 8 8 TB 6 (2# )
TB 8
NOT TB Symptom resolution in the absence of antituberculosis chemotherapy TB bacteriologic confirmation; isolation of M. tuberculosis from a lymph node, or microscopically visible acid-fast or autofluorescent bacilli associated with caseating necrosis on cytology, or clinical diagnosis; significant therapeutic response (lymph node size decreased from <-2 ¥ 2 cm to <1¥1 cm after 3 months of standard antituberculosis treatment) Not evaluated significant therapeutic response as for clinical diagnosis # 1 chronic inflammatory process diagnosed after excision biopsy, 1 non-acute bacterial abscess diagnosed after incision and drainage
Fig. 35.1 Flow diagram of children who presented to primary healthcare facilities with persistent cervical adenopathy in a TB-endemic area.
Table 35.1 Demographics and aetiology of persistent cervical adenopathy in children presenting to primary healthcare facilities in a TB-endemic area (n = 158) Number (%) Demographics Gender Male Female Age groups < 5 years 5–9 years 10 years
69 (43.7) 89 (56.3) 93 (58.9) 51 (32.2) 14 ( 8.9)
Aetiology Visible local cause Bacterial infection (crusted impetigo) Tinea capitis (with secondary infection) Traction folliculitis Otitis externa No visible local cause Tuberculous lymphadenitis Reactive nodes Non-specific inflammation Non-acute bacterial abscess Malignancy
node involvement may originate from a Ghon focus in the tonsils, oropharynx, or tissues of the head and neck. Tuberculosis lymphadenitis involving axillary or inguinal nodes is uncommon but if present is usually associated with a local Ghon focus and a diligent search may be rewarded by finding a tuberculous skin lesion at some distal point.13,14 Tuberculosis lymphadenitis usually develops within the first 6–12 months after primary infection with M. tuberculosis. In rare cases, generalized TB lymphadenitis may be associated with haematogenous dissemination and this may occur in the absence of overt miliary disease.15 Disease pathology within the lymph node is similar to that seen in other organs, with initial tubercle formation and lymphoid hyperplasia that may progress to caseation and necrosis. Isolated involvement of a single node is rare and nodes are usually matted due to considerable periadenitis, although one node is frequently more prominent than others within a matted group of nodes.16 A cold abscess results when the caseous material liquefies and this is signified by a soft fluctuant node with violaceous discoloration of the overlying skin (Fig. 35.2); spontaneous drainage and sinus formation may follow.13 Untreated, the natural course of TB lymphadenitis in an immunocompetent host follows a prolonged and relapsing course often interrupted by transient lymph node enlargement, fluctuation, and/or sinus formation before ultimately healing with associated scarring and/or calcification.13,14
CLINICAL FINDINGS AND DIAGNOSIS 105 (66.5) 26 (16.5) 34 (21.5) 44 (27.8) 1 ( 0.6) 53 (33.5) 35 (22.2) 13 ( 8.2) 4 ( 2.5) 1 ( 0.6) 0
Reactive nodes, cervical mass < 2 2 cm, tuberculin skin test negative, and natural symptom resolution. Adapted from Marais et al.3
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Fig. 35.2 A supraclavicular lymph node with involvement of overlying skin.
The various conditions that should be considered in the differential diagnosis of a child with chronic cervical adenopathy are listed in Table 35.2. Table 35.3 reflects the clinical findings in 35 children with confirmed TB cervical lymphadenitis when they presented to the primary healthcare facility. A history of close contact with an adult index case remains important and is documented in approximately 50% of children with TB lymphadenitis.3,16 The condition seems to occur with equal frequency in all age groups, except infancy when it is rarely seen.3 Tuberculosis lymphadenitis is characteristically painless and not tender to palpation; nodes are large (> 2 2 cm) and frequently matted.3,16 The lymph nodes are initially firm but may become fluctuant and sinus formation may be present.16,17 If secondary infection complicates the picture the affected nodes become red, warm, and painful. Superficial lesions on the scalp such
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Tuberculosis lymphadenitis and involvement of the reticuloendothelial system in children
Table 35.2 Differential diagnosis of peripheral lymphadenitis Infections
Table 35.3 Clinical characteristics of children diagnosed with tuberculosis lymphadenitis in a TBa endemic area (n = 35) Number (%)
Acute suppurative Bacterial
Gram-positive organisms Staphylococcus aureus, group A streptococci and peptostreptococci Gram-negative organisms
Chronic granulomatous Mycobacteria
Fungi Other Viral
M. tuberculosis, M. bovis, M. bovis BCG, environmental mycobacteria (or non-tuberculous mycobacteria), especially M. avium complex Histoplasmosis, coccidioidomycosis, actinomycosis Brucellosis, tuleraemia, toxoplasmosis, cat scratch disease, sarcoidosis Infectious mononucleosis (EBV), human immunodeficiency virus, mumps, cytomegalovirus
Malignancy Non-Hodgkin’s lymphomata, particularly Burkitt’s lymphoma Kaposi’s sarcoma Hodgkin’s disease Neuroblastoma Rhabdomyosarcoma Histiocytosis X Congenital malformations Branchial, thyroglossal, and/or dermoid cysts Deep cavernous haemangioma Unknown Reactive hyperplasia of undetermined aetiology
as infected tinea capitis may cause persistent cervical adenopathy that disappears only when the local lesions are adequately treated. The most important clinical clues that may assist the diagnosis of TB lymphadenitis are summarized in Table 35.4. A strongly positive tuberculin skin test (TST) and/or radiographic signs suggestive of TB support a diagnosis of TB lymphadenitis.3,18 However, in nonendemic settings, a positive TST is more indicative of environmental mycobacterial disease and provides a fairly accurate diagnosis in the absence of known TB exposure and/or BCG vaccination.6 Radiographic signs of TB are present in less than 50% of children with TB lymphadenitis and few report pulmonary symptoms.3,17 Culture from a discharging sinus may provide bacteriological confirmation. If there is no sinus, fine needle aspiration (FNA) is the diagnostic procedure of choice. FNA provides an excellent bacteriological yield and is a minimally invasive procedure,3,19,20 especially when a fine 22-gauge needle is used. In some cases an excision biopsy may be considered and this is a treatment option as well, particularly in environmental mycobacterial disease where the therapeutic response to chemotherapy is frequently suboptimal.8 Incision biopsy should be discouraged at all times as this may result in sinus formation, a complication not seen with FNA.3,20 Material obtained should be submitted for histology and/or cytology (rapid cytological diagnosis reduces diagnostic delay); performing a mycobacterial culture is also advised as it
35
Lymph node characteristics Persistence (present for > 4 weeks no response to antibiotics) Size < 2 2 cm (2–4) (2–4) cm > 4 4 cm Character Single Multiple Discreet Matted Solid Fluctuant Without secondary bacterial infection With secondary bacterial infection (red and warm)
35 (100)
4 (11) 25 (72) 6 (17) 5 (14) 14 (40) 16 (46) 28 (80) 5 (14) 2 (6)
Associated findings Tuberculin skin test 0 mm 1–9 mm 10 mm 15 mm Mean response 19.1 mm (standard deviation 2.9 mm) Constitutional symptoms Any symptom Fever Cough Night sweats Fatigue Failure to thrive Chest radiograph suggestive of TB Lymph node disease Uncomplicated With airway compression With parenchymal consolidation
2 (6) 0 (0) 33 (94) 32 (91)
21 (60) 7 (20) 9 (26) 8 (23) 19 (54) 10 (29) 13 (37) 8 (23) 1 (3) 4 (11)
Size, transverse diameter of the largest cervical mass. Fatigue, less playful and active since the mass was first noted. Failure to thrive, crossing at least one centile line in the preceding 3 months or having lost more than 10% of bodyweight (minimum 1 kg) over any time interval. a Adapted from Marais et al.3
increases the diagnostic accuracy, and allows identification of mycobacterial species and drug susceptibility testing if required.
HIV INFECTION The impact of HIV infection on TB lymphadenitis in children is not well described. Studies from Zambia have described a marked increase in cases of TB lymphadenitis in adults associated with HIV infection and a change in clinical presentation to more symmetrical, multifocal lymphadenopathy that overlaps with primary HIV lymphadenopathy.21,22 In contrast, a study in Zambian children indicated that TB lymphadenitis may be less common in HIV-
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CLINICAL PRESENTATIONS OF TUBERCLOSIS
Table 35.4 Clues to the diagnosis of TB lymphadenitis 1. History Contact with an adult index case with pulmonary TB 2. Lymph node characteristics Location Cervical, rarely inguinal or axillary (If axillary nodes ipsilateral to site of BCG vaccination, consider BCG adenitis) Size and character Visible, 2 2 cm Non-tender and/or matted Usually solid, but may be fluctuant (may also be secondarily infected) Duration Persistent for > 1 month, despite excluding/treating local causes 3. Reactive tuberculin skin test 10 mm in all children; 5 mm if HIV-infected 4. Chest radiograph suggestive of TB Fine needle aspiration offers a relatively easy and minimally invasive means of establishing a definitive tissue and/or bacteriological diagnosis.
infected (3%) than in HIV-uninfected children (5%),23 although the difference was statistically insignificant. Tuberculosis may be a cause of persistent generalized lymphadenopathy in HIV-infected children with chronic respiratory disease and needs to be differentiated from lymphoid interstitial pneumonitis.24 HIV infection complicates the diagnosis of TB lymphadenitis for a number of reasons. TST is more likely to be negative in HIVinfected children than in HIV-uninfected children.25 In contrast, axillary M. bovis BCG adenitis is more common in HIV-infected children and usually develops within 12 months after BCG immunization, or as a manifestation of IRIS when it presents within 3–6 months of ART initiation.11,12 Persistent generalized lymphadenopathy is common in HIV-infected children and is usually due to primary HIV infection but can also be due to TB lymphadenitis, Kaposi’s sarcoma, and lymphoma. These reasons emphasize the importance of establishing a bacteriological diagnosis.
TREATMENT Randomized controlled trials have demonstrated convincingly that TB lymphadenitis can be treated with short-course chemotherapy. In adults the results of 9 months of treatment with rifampicin (RMP) and isoniazid (INH) accompanied by ethambutol for the initial 2 months did not differ significantly from those receiving prolonged therapy for 18 months.26 Equally good results were achieved by using a regimen of INH and RMP for 6 months supplemented by pyrazinamide (PZA) during the initial 2 months.27 Short-course chemotherapy with intermittent drug administration during the consolidation phase gave satisfactory results in 110 children with TB lymphadenitis in Papua New Guinea.28 These children received 2 months of daily INH, RMP, PZA, and streptomycin followed by 4 months of twice-weekly INH and RMP. There is no convincing reason to add streptomycin during the intensive phase. Good results have been reported in smaller groups of children receiving the same standard TB treatment regimen as used in children with uncomplicated intrathoracic disease.3,29,30 In fact, the organism load in children with isolated peripheral TB lymphadenitis is low and even shorter courses of chemotherapy may suffice in uncomplicated cases, but no randomized studies have been performed
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to support this. Despite successful treatment, nodal enlargement during or following treatment may occur in a minority of patients, which probably represents an immune reaction as cultures from such lesions are usually negative. Surgery is advised only for exceptionally tense fluctuant nodes or in the presence of severe discomfort. Full excision is advised and incision and drainage should not be performed. The treatment of M. bovis and M. bovis BCG adenitis is more problematic. Isolated axillary adenitis ipsilateral to the side of BCG vaccination points to M. bovis BCG disease. The management of disease caused by M. bovis BCG is discussed in Chapter 74. In HIV-infected children there is a risk of developing disseminated BCG disease,11 and local excision is often impossible due to poor anatomical localization and infiltration of the tissues surrounding the lymph node. M. bovis is inherently resistant to PZA;31 thus treatment with ordinary anti-TB therapy seems inadequate. Treatment should include INH in a dose of at least 10– 15 mg/kg together with a third and probably even fourth drug to replace PZA, but no guidelines on the treatment of M. bovis lymphadenitis exist currently. Lymphadenitis caused by environmental mycobacteria is more resistant to chemotherapy. Rifampicin, ethambutol, and the newer macrolides have shown some efficacy but surgical excision is frequently required.8,32 The results of a recent randomized, controlled trial demonstrated that surgical excision offers the most effective treatment for children with cervicofacial lymphadenitis caused by environmental mycobacteria.33
TUBERCULOSIS OF THE RETICULOENDOTHELIAL SYSTEM IN CHILDREN EPIDEMIOLOGY TB of the reticuloendothelial system (RES) in children is rarely reported. It is uncommon as a separate manifestation of extrapulmonary TB but rather TB in children more commonly causes pathology in the bone marrow, liver, or spleen as part of disseminated (miliary) TB.
PATHOGENESIS It is common to find histological evidence of TB or tubercles in the liver or spleen with organ enlargement during primary infection without radiological evidence of miliary lesions in the lungs. Liver biopsy was performed in 241 Indian children with TB.34 Histological evidence of TB was found in 112, of whom only 13 had miliary mottling in the lungs. The same group reported 80 children with TB lesions in the liver – most were young (91% < 6 years) and TST positive (80%) and all had liver enlargement.35 With disseminated (miliary) TB, tubercles may be found in the liver, spleen, and bone marrow, and bone marrow biopsy and culture has been used as a method of diagnosis. Rarely, granulomatous lesions develop extensive caseation and present with large focal or multifocal cold abscesses in the liver or spleen that may later calcify. Jaundice is very uncommon in children with TB but is described as a presentation of an acute tuberculous hepatitis or due to obstruction of the biliary system.36
CLINICAL FINDINGS AND DIAGNOSIS Enlargement of the liver and spleen occurs in children with TB. Ramachandran and Purnayyan34 found that hepatomegaly and
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Tuberculosis lymphadenitis and involvement of the reticuloendothelial system in children
splenomegaly occurred in 7% and 3% of 3,000 children with TB and 1% had both.34 In TB-endemic regions, other causes of hepatomegaly and splenomegaly are common in children without TB due to other endemic diseases such as malaria or typhoid fever and so liver and spleen enlargement are not useful indicators of TB.33 In contrast, Hussey et al.37 found that hepatomegaly and splenomegaly (82% and 54%, respectively) were common in children with miliary TB. The high yield of positive histopathological findings from liver biopsy in Indian children with TB prompted the authors to examine the diagnostic value of the procedure.34,35 They concluded that there was no correlation between the child’s clinical condition and the histological findings from liver biopsy. Other limitations were that the biopsy needle might not always isolate a tuberculous lesion even when present, the histological pattern can be caused by other granulomatous conditions, and the procedure requires hospitalization with an element of risk. Tuberculosis is a rare cause of solitary or multiple abscesses in the liver and/or spleen.38 Diagnosis is often delayed because of the non-specific presentation of fever, chills, and hepatomegaly or as pyrexia of unknown origin without an obvious focus of infection. Tuberculosis liver abscess will need to be differentiated from many other possible infectious causes of liver abscess in children. Needle aspiration and liver biopsy for smear and culture and for characteristic histological features are useful diagnostic procedures for larger granuloma or abscesses and are usually reserved for that purpose. Diagnosis and management can be facilitated by imaging such as ultrasound.36 The commonest ultrasound abnormality found with hepatic TB is a bright liver but hypoechoic or hyperechoic lesions may be seen. Computed tomographic scan findings of intrahepatic lesions show lowdensity lesions with peripheral contrast uptake.38 They may be associated with abdominal lymphadenopathy. Tuberculosis is a recognized cause of anaemia in children but, as for the presentation of hepatosplenomegaly, this relationship is difficult to define when other causes of anaemia such as parasitic disease, micronutrient deficiency, or HIV are also often highly prevalent. Haematological abnormalities did not significantly differ between a group of South African children with TB including 168 with confirmed TB and a control group without TB.39 The study was performed in an urban setting not endemic for malaria or schistosomiasis at a time when HIV prevalence was still low. Although haemoglobin was slightly and significantly lower in those with TB than in controls (10.2 versus 10.8 g/dL, respectively) it was concluded that a full blood count has no diagnostic predictive value when investigating a child for possible TB.
REFERENCES 1. Reddy MP, Moorchung N, Chaudrey A. Clinicopathological profile of paediatric lymphadenopathy. Indian J Pediatr 2002;69:1047–1051. 2. Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of disease in children treated for tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006;10:732–738. 3. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area. Pediatr Infect Dis J 2006;25:142–146. 4. Krishnaswami H, Koshi G, Kulkarni KG, et al. Tuberculous lymphadenitis in South India - a histopathological and bacteriological study. Tubercle 1972;53:215–220. 5. Grzybowski S, Allen EA. History and importance of scrofula. Lancet 1995;346:1472–1474.
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In contrast, disseminated TB causes disease in the bone marrow and may cause a range of haematological abnormalities. TST is usually negative in this context. There are few data from studies in children. A recent study of Indian adults examined abnormalities in 32 patients with disseminated TB and 23 with pulmonary TB.40 Normochromic normocytic anaemia was the commonest abnormality (84% and 86%, respectively) while leucopenia, neutropenia, and pancytopenia were only reported in patients with disseminated TB. Thrombocytopenia was significantly more common in those with disseminated TB while thrombocytosis was more common in those with pulmonary TB. There are isolated case reports of leukaemoid reaction occurring with disseminated TB but pancytopenia is rare.41,42 Autoimmune haemolytic anaemia and thrombocytopenic purpura have been described as rare manifestations of childhood TB. Tuberculosis is also recognized as one of multiple infectious triggers of haemophagocytic syndrome in children.43 Haemophagocytic syndrome is characterized by fever, lymphadenopathy, hepatosplenomegaly, and pancytopaenia (see previous chapter). Disseminated BCG disease has been described as a cause of massive hepatosplenomegaly, fever, and pancytopenia in a 3-monthold infant who died despite TB treatment, and autopsy revealed diffuse histiocytic infiltration of the liver, spleen, and lymph nodes which were loaded with acid-fast bacilli.44
TREATMENT Treatment is as for extrapulmonary TB or miliary TB in children. Surgical intervention may be required to drain or remove abscesses of the liver or spleen if there is a poor response to anti-TB treatment. The anaemia associated with TB improves with TB treatment and a recent study showed that the addition of haematinics such as iron supplementation provided additional benefit in the early stages of treatment.45 This benefit is likely to be most apparent among iron-deficient populations. Concern regarding the use of iron supplementation in patients with TB has been raised, as evidence from mouse studies indicate that an excess of iron may enhance the growth of mycobacteria and impair treatment response.46,47 However, a study performed in India among adults with TB did not report any adverse effects when iron supplementation, together with standard anti-TB therapy, was provided.47 There is no evidence that the addition of corticosteroids accelerates bone marrow recovery and therefore its use is not recommended.
6. Lindeboom JA, Kuijper EJ, Prins JM, et al. Tuberculin skin testing is useful in the screening for nontuberculous mycobacterial cervicofacial lymphadenitis in children. Clin Infect Dis 2006; 43:1547–1551. 7. Primm TP, Lucero CA, Falkinham JO. Health impacts of environmental mycobacteria. Clin Microbiol Rev 2004;17:98–106. 8. Romanus V. Tuberculosis in BCG immunized and unimmunized children in Sweden: A ten-year evaluation following the cessation of BCG immunization of the newborn in 1975. Pediatr Infect Dis J 1987;6:272–280. 9. Kleeberg HH. Epidemiology of mycobacteria other than tubercle bacilli in South Africa. Rev Infect Dis 1981;3:1008–1012. 10. Jeena PM, Chagan MK, Topley J, et al. Safety of intra-dermal Copenhagen 1331 BCG vaccine in neonates in Durban, South Africa. Bull World Health Organ 2001;79:337–343.
11. Hesseling AC, Rabie H, Marais BJ, et al. Bacillus Calmette-Guerin vaccine-induced disease in HIVinfected and HIV-uninfected children. Clin Infect Dis 2006;42:548–558. 12. Puthanakit T, Oberdorfer PM, Akaratum N, et al. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis J 2006; 25:53–58. 13. Miller FJW, Cashman JM. Origin of peripheral tuberculous lymphadenitis in childhood. Lancet 1958;1:286–289. 14. Miller FJW, Cashman JM. The natural history of peripheral tuberculous lymphadenitis associated with a visible primary focus. Lancet 1955;1:1286–1289. 15. Harris LC. Generalized tuberculous adenitis in Bantu children in South Africa. Pediatrics 1959; 23:935–944. 16. Narang P, Narang R, Narang R, et al. Prevalence of tuberculosis lymphadenitis in children in Wardha
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18.
19.
20.
21.
22.
23.
24.
25.
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district, Maharasha state, India. Int J Tuberc Lung Dis 2005;9:188–194. McMaster P, Ezeilo N, Freisen H, et al. Ten-year experience with paediatric lymph node tuberculosis in Port Moresby. J Trop Pediatr 2001;47:160–164. Seth V, Kabra SK, Semwal OP, et al. Tubercular lymphadenitis: Clinical manifestations. Indian J Pediatr 1995;62:565–570. Handa U, Palta A, Mohan H, et al. Fine needle aspiration diagnosis of tuberculous lymphadenitis. Trop Doct 2002;32:147–149. Thomas J, Adeyi AO, Olu-eddo AO, et al. Fine needle aspiration cytology in the management of childhood palpable masses: Ibadan experience. J Trop Pediatr 1999;45:378. Bem C, Patil PS, Luo N. The increased burden of tuberculous lymphadenitis in central Africa: lymph node biopsies in Lusaka, Zambia, 1981 and 1990. Trop Doct 1996;26:58–61. Bem C. Human immunodeficiency virus-positive tuberculous lymphadenitis in Central Africa: a clinical presentation of 157 cases. Int J Tuberc Lung Dis 1997;1:215–219. Chintu C, Bhat G, Luo C, et al. Seroprevalence of human immunodeficiency virus type 1 infection in Zambian children with tuberculosis. Pediatr Infect Dis J 1993;12:499–504. Jeena PM, Coovadia HM, Hadley LG, et al. Lymph node biopsies in HIV-infected and non-infected children with persistent lung disease. Int J Tuberc Lung Dis 2000;4:139–146. Madhi S, Gray G, Huebner RE, et al. Correlation between CD4+ lymphocyte counts, concurrent antigen skin test and tuberculin skin test reactivity in human immunodeficiency virus type 1-infected and uninfected children with tuberculosis. Pediatr Infect Dis J 1999;18:800–805.
FURTHER READING Miller FJW. Tuberculosis in Children. Edinburgh: Churchill Livingstone, 1982.
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26. Campbell IA. The treatment of superficial tuberculous lymphadenitis. Tubercle 1990;71:1–3. 27. Campbell IA, Ormerod LP, Friend JAR, et al. Sixmonths versus nine-months chemotherapy for tuberculosis of lymph nodes: preliminary results. Resp Med 1992;86:15–19. 28. Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990; 9:794–801. 29. Kumar L, Dhand R, Singhi PD, et al. A randomised trial of fully intermittent vs. daily followed by intermittent short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9:802–806. 30. Jawahar MS, Sivasubramanian S, Viajayan VK, et al. Short course chemotherapy for tuberculous lymphadenitis in children. Br Med J 1990;301: 359–361. 31. Hesseling AC, Schaaf HS, Victor T, et al. Resistant M. bovis disease; implications for management of BCG-disease in HIV-infected children. Pediatr Infect Dis J 2004;23:476–479. 32. Hazra R, Robson CD, Perez-Atayde AR, et al. Lymphadenitis due to nontuberculous mycobacteria in children: presentation and response to therapy. Clin Infect Dis 1999;28:123–129. 33. Lindeboom JA, Kuijper EJ, Bruijnesteijn van Coppenraet ES, et al. Surgical excision versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a multicenter, randomized, controlled study. Clin Infect Dis J 2007; 44:1057–1064. 34. Ramachandran RS, Purnayyan S. Tuberculosis in children. Indian Pediatr 1966;3:218–223. 35. Ramachandran RS, Shetty BMV, Kamala KG. Hepatic lesions in childhood tuberculosis. A histopathological study of eighty cases. Indian Pediatr 1966;3:212–217.
36. Schaaf HS, Nel ED. Tuberculosis presenting as cholestatic jaundice in early infancy. J Pediatr Gastrenterol Nutr 1992;15:437–439. 37. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991;10:832–836. 38. Vikas K, Kumar L, Kataria S. Multiple hepatosplenic tuberculous abscesses in an eight-year-old boy. Pediatr Infect Dis J 1996;15:178–179. 39. Singh KJ, Ahluwalia G, Sharma SK, et al. Significance of haematological manifestations in patients with tuberculosis. J Assoc Physicians India 2001;49:790–794. 40. Wessels G, Schaaf HS, Beyers N, et al. Haematological abnormalities in children with tuberculosis. J Trop Paediatr 1999;45:307–310. 41. Vijayan VK. Disseminated tuberculosis. J Indian Med Assoc 2000;98:107–109. 42. Keeton GR, Naidoo G, Jacobs P. Leukaemoid reaction and disseminated tuberculosis. A case report. S Afr Med J 1975;49:1930–1932. 43. Brastianos PK, Swanson JW, Torbenson M, et al. Tuberculosis-associated hemophagocytic syndrome in children. Lancet Infect Dis 2006;6:447–454. 44. Kumar PV, Monabati A, Kadivar R, et al. Peripheral blood and marrow findings in disseminated bacille Calmette-Guerin infection. J Pediatr Hematol Oncol 2005;27:97–99. 45. Lounis N, Truffot-Pernot C, Grosset J, et al. Iron and Mycobacterium tuberculosis infection. J Clin Virol 2001;20:123–126. 46. Lounis N, Maslo C, Truffot-Pernot C, et al. Impact of iron loading on the activity of isoniazid or ethambutol in the treatment of murine tuberculosis. Int J Tuberc Lung Dis 2003;7:575–579. 47. Das BS, Devi U, Mohan Rao C, et al. Effect of iron supplementation on mild to moderate anaemia in pulmonary tuberculosis. Br J Nutr 2003;90:541–550.
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Tuberculosis of lymph nodes and the reticuloendothelial system in adults Helmuth Reuter and Robin Wood
INTRODUCTION Tuberculous lymphadenitis is the most common manifestation of extrapulmonary TB, which is defined as disease involving structures other than lung parenchyma, and is less common than pulmonary TB. It is the result of infection with the same organisms that cause pulmonary TB, namely Mycobacterium tuberculosis, Mycobacterium bovis or Mycobacterium africanum. In areas where TB is endemic and bovine TB is well controlled M. tuberculosis is the most common cause,1,2 whereas infection with M. bovis may be a frequent cause in areas where the control of bovine TB is poor and milk is not routinely pasteurized.3 In developed countries with low rates of TB transmission, environmental mycobacteria, also referred to as non-tuberculous mycobacteria (NTM), are mainly responsible for peripheral lymphadenitis, particularly Mycobacterium avium complex (MAC).4
PERIPHERAL LYMPH NODE TUBERCULOSIS Lymphadenitis is the most frequently occurring form of extrapulmonary TB with cervical nodes being most commonly involved in adults (Figs 36.1 and 36.2), although inguinal, mesenteric and mediastinal nodes may also be involved.5,6 NTM lymphadenitis is rare in adults, but relatively common in children and it may affect human immunodeficiency virus (HIV)-infected adults.7,8 The disease generally remains localized to the cervical region and is usually not accompanied by constitutional symptoms.6,9 It can be adequately managed with local excision, but, if left untreated, the nodes often progress to softening, rupture, sinus formation, healing with fibrosis and calcification.6–9 In contrast to children, M. tuberculosis is the major cause of mycobacterial lymphadenitis in adults and is usually a local manifestation of systemic disease. It seems to affect predominantly young women, although it can affect any age or race and those living in developing countries or immigrants from areas of high tuberculosis prevalence.10–14 Tuberculous lymphadenitis is characteristically indolent and usually presents as a unilateral painless mass sited along the upper border of the sternocleidomastoid muscle, although more than one site may be involved in up to 35% of cases.12 Constitutional symptoms are usually mild or absent9–11,13 and tuberculin skin tests (TSTs) are positive in 75–100% of HIV-uninfected individuals with lymph node TB.5,6,11–14 Fine needle aspiration (FNA) is the diagnostic procedure of choice with a reported diagnostic yield varying from 42% to 83%.4–6,14,15 In children the procedure is most effective when a 22-G needle (fine needle) is used,2 whereas in adults better yields were obtained
with larger needle sizes (18 or 19 G) and the procedure has been termed wide needle aspiration.15 In some cases an excision biopsy is required, and this may result in higher yields, especially if both histology and mycobacterial culture are obtained.6,14 Excision may also be a treatment option, particularly in NTM disease where the therapeutic response to chemotherapy is frequently suboptimal.4 Incisional biopsy should be avoided because it tends to result in sinus formation, a complication not seen with FNA.2 The prevalence of associated chest radiographic abnormalities varies considerably between reported series, probably reflecting differing age distributions, and has been as high as 38% in a predominantly middle-aged adult European cohort.14 HIV infection predisposes to M. tuberculosis dissemination with multifocal involvement, anergic responses to purified protein derivatives (PPDs), an increased presence of constitutional symptoms and higher mortality.9,11,16 HIV infection is associated with modified histological features including less mature tuberculous granulomata with numerous acid-fast bacilli and abundant caseation.17 The prevalence of HIV coinfection among individuals with TB lymphadenitis is considerably higher than that of the general population. In Rwanda, Tanzania and Zambia, HIV infection was confirmed in 80–92% of M. tuberculosis lymphadenitis cases,17–19 and in Sydney, Australia, 18.9% of cases were coinfected.20 HIV infection is a cause of generalized lymphadenopathy, and TB lymphadenitis may thus be an unexpected finding. It was identified in 52% of 727 lymph node biopsies performed in Lusaka, Zambia,19 and in 24% of individuals thought to have HIV-related lymphadenopathy in Rwanda,17 demonstrating the need for a high index of suspicion for TB lymphadenitis in regions with a high prevalence of HIV/TB dual infection.18,19 Needle biopsy has a higher positive acid-fast and mycobacterial culture yield in HIV-infected individuals than in HIV-seronegative individuals, probably reflecting the higher burden of organisms in this group, while cytological and histological findings may be less specific in HIV-infected individuals.21 However, macroscopic caseation, visible on naked-eye examination alone of wide needle aspiration (19 G), may be a useful diagnostic modality in low-resourced areas as it has been observed in up to 41% of 120 consecutive lymph node aspirates conducted in Zambia.15
MEDIASTINAL TUBERCULOUS LYMPHADENOPATHY Mediastinal lymphadenopathy is a feature of primary TB and is a common finding on chest radiographs of children with TB disease.22,23 In contrast, postprimary TB of HIV-seronegative adults
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associated with focally enlarged mediastinal lymph nodes is also a rare cause of fibrosing mediastinitis, which may cause dyspnoea due to compression of intrathoracic vascular structures including the pulmonary veins or arteries and less commonly the superior vena cava.31
MESENTERIC TUBERCULOUS LYMPHADENOPATHY
Fig. 36.1 A 19-year-old woman presented with weight loss and non-tender cervical lymphadenopathy involving anterior and posterior triangle of the neck (white arrows).
Fig. 36.2 Ziehl–Neelsen staining and microscopy yielded numerous acid-fast bacilli.
is characterized by cavitation and poorly defined consolidation of the apical and posterior segments of the upper lobe and/or superior segment of the lower lobe,22 and isolated intrathoracic tuberculous lymphadenopathy is a rare presentation, which must be differentiated from other more common infective and neoplastic causes.24 However, a primary pattern of TB is frequently observed in HIVinfected individuals coinfected with TB,25 and mediastinal lymphadenopathy has been reported in up to 80% of those with AIDS and pulmonary TB in Kigali, Rwanda.26 M. tuberculosis infection was also found to be a major cause of isolated mediastinal adenopathy in HIV-infected patients presenting to a New York City adult HIV outpatient clinic, where it was found in 63%, of whom 37% were coinfected with MAC. The computed tomography (CT) characterization of tuberculous mediastinal adenopathy includes extensive, frequently massive, heterogeneous soft-tissue lesions which appear as matted nodes of low density with peripheral enhancement.28 Magnetic resonance imaging (MRI) of mediastinal tuberculous lymphadenopathy with caseous necrosis shows inhomogeneous nodes with marked hyperintensity on T2-weighted images and peripheral enhancement after injection of contrast.29 Tuberculous mediastinal lymph nodes may rarely erode into neighbouring structures, leading to fistula formation.30 Tuberculosis
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In HIV-seronegative individuals isolated tuberculous mesenteric lymphadenopathy in the absence of peritoneal or bowel involvement is rare. In a series of 49 cases of abdominal TB undergoing CT scans in Kuwait, lymphadenopathy was demonstrated in 47% of cases, of whom most had concomitant evidence of peritonitis, bowel wall thickening or solid organ involvement.32 In almost half of the cases lymph node involvement was diffuse and the remaining individuals had localized disease involving mesenteric, peripancreatic or portal, and para-aortic nodes. A similar distribution of lymph node involvement has been demonstrated in a series of abdominal TB investigated with ultrasound and MRI.33,34 Enlarged peripancreatic/portal nodes may be a rare cause of obstruction of nearby structures and consequently result in pyloric stenosis, portal hypertension and jaundice.35,36 Mesenteric adenopathy is common in HIV-infected individuals as a result of both MAC and M. tuberculosis infections. In industrialized countries MAC appears to be the more frequent cause of mesenteric lymphadenopathy,37,38 while mesenteric adenitis due to M. tuberculosis is the predominant cause in developing world settings.39 Whereas the distribution of intra-abdominal lymph node involvement in HIV-seronegative individuals may reflect the local lymphatic drainage of ingested organisms from the small bowel, in advanced HIV infection there is a wider dissemination of organisms, characterized by frequent involvement of other intraabdominal organs such as the pancreas and kidneys together with abscesses of the spleen, liver and retroperitoneal space.40 Increasing mesenteric lymphadenopathy is also one of the most frequent manifestations of immune restoration disease (IRD) in HIV/TB coinfected individuals starting antiretroviral therapy (ART).40
TREATMENT OF TUBERCULOUS LYMPHADENITIS There have been fewer treatment studies evaluating duration and response to treatment of lymph node TB than that of pulmonary TB. However, tuberculous infection of lymph nodes generally appears to respond to standard 6- to 9-month regimens including isoniazid (INH) and rifampicin, in a fashion similar to that of pulmonary tuberculous lesions and a 2-month regimen of INH, rifampicin, pyrazinamide and ethambutol followed by 4–7 months of INH and rifampicin.5,6,14,41,42 Paradoxical expansion of lymphadenopathy may be seen during the first 2 months of treatment in up to 20% of cases, but the occurrence thereof does not indicate failure of chemotherapy.12 The ideal duration of therapy for lymph node TB caused by drug-resistant organisms is not known. In HIV/TB coinfected patients paradoxical worsening of lymphadenopathy may be associated with initiation of antituberculous chemotherapy,12 but is more commonly seen as a manifestation of antiretroviral-mediated immune reconstitution syndrome, which frequently affects abdominal, axillary and mediastinal lymph nodes.43,44 IRD in the HIV-infected is an adverse consequence of
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Tuberculosis of lymph nodes and the reticuloendothelial system in adults
the restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral therapy (HAART). Conditions previously subclinical may be ‘unmasked’ or previously recognized conditions may worsen as a result of increased immunopathological inflammatory responses. IRD is most frequently associated with mycobacterial infections and was first reported in 1998 soon after the advent of HAART.45–47
TUBERCULOSIS OF THE RETICULOENDOTHELIAL SYSTEM Tuberculosis of the reticuloendothelial system (RES) is usually a manifestation of extrapulmonary TB involving the bone marrow, liver or spleen and being demonstrable as tubercles on liver or bone marrow biopsy. The clinical presentation may include hepatosplenomegaly, hypersplenism, solitary splenic lesions or splenic abscesses.48–50 Diagnosis of tuberculous involvement of the RES is often delayed due to its non-specific presentation as fever, rigors, hepato-
REFERENCES 1. Krishnaswami H, Koshi G, Kulkarni KG, et al. Tuberculous lymphadenitis in South India—a histopathological and bacteriological study. Tubercle 1972; 53:215–220. 2. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area. Pediatr Infect Dis J 2006;25:142–146. 3. Grzybowski S, Allen EA. History and importance of scrofula. Lancet 1995;346:1472–1474. 4. Lindeboom JA, Kuijper EJ, Prins JM, et al. Tuberculin skin testing is useful in the screening for nontuberculous mycobacterial cervicofacial lymphadenitis in children. Clin Infect Dis 2006; 43:1547–1551. 5. Dandapat MC, Mishra BM, Dash SP, et al. Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 1990;77:911–912. 6. Memish ZA, Mah MW, Mahmood SA, et al. Clinico-diagnostic experience with tuberculous lymphadenitis in Saudi Arabia. Clin Microbiol Infect 2000;6:137–141. 7. Stanley BR, Fernandez AJ, Peppard BS. Cervicofacial mycobacterial infections presenting as major salivary gland disease. Laryngoscope 1983;93:1271–1275. 8. Pang SC. Mycobacterial lymphadenitis in Western Australia. Tuber Lung Dis 1992;73:362–367. 9. White MP, Bangash H, Goel KM, et al. Non-tuberculous mycobacterial lymphadenitis. Arch Dis Child 1986;61:368–371. 10. Chen YM, Lee PY, Su WJ, et al. Lymph node tuberculosis: 7-year experience in Veterans General Hospital, Taipei, Taiwan. Tuber Lung Dis 1992; 73:368–371. 11. Artenstein AW, Kim JH, Williams WJ, et al. Isolated peripheral tuberculous lymphadenitis in adults: current clinical and diagnostic issues. Clin Infect Dis 1995;20:876–882. 12. Geldmacher H, Taube C, Kroeger C, et al. Assessment of lymph node tuberculosis in Northern Germany: A clinical review. Chest 2002;121:1177–1182. 13. Ebdrup L, Storgaard M, Jensen-Fangel S, et al. Ten years of extrapulmonary tuberculosis in a Danish university hospital. Scand J Infect Dis 2003;35:244–246. 14. Polesky A, Grove W, Bhatia G. Peripheral tuberculous lymphadenitis: epidemiology, diagnosis, treatment and outcome. Medicine (Baltimore) 2005;84:350–362.
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splenomegaly or pyrexia of unknown origin. Needle aspiration and liver biopsy for smear and culture and for characteristic histological features are useful diagnostic procedures for larger granuloma or abscesses and are usually reserved for that purpose. Diagnosis and management can be facilitated by imaging such as ultrasound or CT imaging of the abdomen, demonstrating the granulomatous lesions often associated with abdominal lymphadenopathy. Tuberculous involvement of the bone marrow may result in a range of haematological abnormalities, including normochromic normocytic anaemia, leucopenia, neutropenia, thrombocytopenia and rarely pancytopenia or leucaemoid reaction occurring with disseminated TB.51,52 The treatment of TB of the RES is as for extrapulmonary TB in adults, but, in addition, surgical intervention may be required to drain or remove abscesses of the liver or spleen if there is a poor response to anti-TB chemotherapy. In HIV/TB coinfected patients paradoxical worsening of hepatic and splenic involvement may be associated with the initiation of ART due to IRD, resulting in rapidly worsening hepatosplenomegaly, splenic abscesses or splenic rupture.45
15. Bem C, Patil PS, Elliot AM, et al. The value of wideneedle aspiration in the diagnosis of tuberculous lymphadenitis in Africa. AIDS 1993;7:1221–1225. 16. Bem C. Human immunodeficiency virus-positive tuberculous lymphadenitis in Central Africa: a clinical presentation of 157 cases. Int J Tuberc Lung Dis 1997;1:215–219. 17. Ngilimana PJ, Metz T, Munyantore S, et al. Lymph node tuberculosis in HIV seropositive patients in Central Africa. A characteristic histopathologic picture. Ann Pathol 1995;15:38–44. 18. Parenboom RM, Richter, Swai AB, et al. Diagnosis of tuberculous lymphadenitis in an area of HIV infection and limited diagnostic facilities. Trop Georg Med 1994;46:228–232. 19. Bem C, Patil PS, Bharucha H, et al. Importance of human immunodeficiency virus-associated lymphadenopathy and tuberculous lymphadenitis in patients undergoing lymph node biopsy in Zambia. Br J Surg 1996;83:75–78. 20. Wark P, Gildberg H, Ferson M, et al. Mycobacterial lymphadenitis in eastern Sydney. Aust N Z J Med 1998;28:453–458. 21. Shriner KA, Mathisen GE, Goetz MB. Comparisons of mycobacterial lymphadenitis among persons infected with human immunodeficiency virus and seronegative controls. Clin Infect Dis 1992; 15:601–605. 22. Kim WS, Choi JI, Cheon JE, et al. Pulmonary tuberculosis in infants: radiographic and CT findings. AJR Am J Roentgenol 2006;187:1024–1033. 23. Mabiala Babela JR, Makosso E, Senga P. Radiological specificities of pulmonary tuberculosis in Congolese children: effect of HIV infection. Med Trop (Mars) 2006;66:255–259. 24. Van den Brande P, Vijgen J, Demedts M. Isolated intrathoracic tuberculous lymphadenopathy. Eur Respir J 1991;4:758–760. 25. Long R, Maycher B, Scalcini M, et al. The chest roentgenogram in pulmonary tuberculosis patients seropositive for human immunodeficiency virus type 1. Chest 1991;99:123–127. 26. Batungwanayo J, Taelman H, Dhote R, et al. Pulmonary tuberculosis in Kigali, Rwanda. Impact of human immunodeficiency virus infection on clinical and radiographic presentation. Am Rev Respir Dis 1992;146:53–56. 27. Haramati LB, Choi Y, Widrow CA, et al. Isolated lymphadenopathy on chest radiographs of HIVinfected patients. Clin Radiol 1996;51:345–349. 28. Pastores SM, Naidich DP, Aranda CP, et al. Intrathoracic adenopathy associated with pulmonary tuberculosis in patients with human
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immunodeficiency virus infection. Chest 1993;103:1433–1437. Moon WK, Im JG, Yu IK, et al. Mediastinal tuberculous lymphadenitis: MR imaging appearance with clinicopathologic correlation. AJR Am J Roentgenol 1996;166:21–25. Fatima SH, Javed MA, Ahmad U, et al. Tuberculous hilar lymph nodes leading to tracheopulmonary artery fistula and pseudoaneurysm of pulmonary artery. Ann Thorac Surg 2006;82:e35–36. Atasoy C, Fitoz S, Erguvan B, et al. Tuberculous fibrosing mediastinitis: CT and MRI findings. J Thorac Imaging 2001;16:191–193. Sinan T, Sheik M, Ramadan S, et al. CT features in abdominal tuberculosis: 20 years experience. BMC Med Imaging 2002;12:3–7. Kim SY, Kim MJ, Chung JJ, et al. Abdominal tuberculous lymphadenopathy: MR imaging findings. Abdom Imaging 2000;25:627–632. Malik A, Saxena NC. Ultrasound in abdominal tuberculosis. Abdom Imaging 2003;28:574–579. Fernandez OU, Canizares LL. Tuberculous mesenteric lymphadenitis presenting as pyloric stenosis. Dig Dis Sci 1995;40:1909–1912. Caroli-Bosc FX, Conio M, Maes B, et al. Abdominal tuberculosis involving hepatic hilar lymph nodes. A cause of portal vein thrombosis and portal hypertension. J Clin Gastroenterol 1997;25:541–543. Koh DM, Burn PR, Mathews G, et al. Abdominal computer tomographic findings of Mycobacterium tuberculosis and Mycobacterium avium intracellulare infection in HIV seropositive patients. Can Assoc Radiol J 2003;54:45–50. Radin DR. Intraabdominal Mycobacterium tuberculosis vs Mycobacterium avium intracellulare infections in patients with AIDS: distinction based on CT findings. AJR Am J Roentgenol 1991;156:487–491. O’Keefe EA, Wood R, Van Zyl A, et al. HIV-related abdominal pain in South Africa: Etiology, diagnosis and survival. Scand J Gastroenterol 1998;33:212–217. Monill-Serra JM, Martinez-Noguera A, Montserrat E, et al. Abdominal ultrasound findings of disseminated tuberculosis in AIDS. J Clin Ultrasound 1997; 25:1–6. Campbell IA, Ormerod LP, Friend PA, et al. Six months versus nine months chemotherapy for tuberculosis of lymph nodes: final results. Respir Med 1993;87:621–623. Yuen APW, Wong SHW, Tam CM, et al. Prospective randomized study of the thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy. Otolaryngol Head Neck Surg 1997;116:189–192.
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43. Rajeswaran G, Becker JL, Michailidis C, et al. The radiology of IRIS (immune reconstitution inflammatory syndrome) in patients with mycobacterial tuberculosis and HIV co-infection: appearances in 11 patients. Clin Radiol 2006;61: 833–843. 44. Lawn SD, Myer L, Bekker L-G, et al. Tuberculosis associated immune reconstitution disease: risk factors and impact in an antiretroviral treatment programme in sub-Saharan Africa. AIDS 2007;21:335–341. 45. Lawn SD, Bekker L-G, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–373.
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46. Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157–161. 47. Crump JA, Tyrer MJ, Lloyd-Owen SJ, et al. Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis 1998;26:1008–1009. 48. Sheen-Chen SM, Chou FF, Wan YL, et al. Tuberculosis presenting as a solitary splenic tumour. Tuber Lung Dis 1995;76:80–83.
49. Soriano V, Tor J, Gabarre E, et al. Multifocal splenic abscesses caused by Mycobacterium tuberculosis in HIV-infected drug users. AIDS 1991;5:901–902. 50. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316–353. 51. Keeton GR, Naidoo G, Jacobs P. Leukaemoid reaction and disseminated tuberculosis. A case report. S Afr Med J 1975;49:1930–1932. 52. Singh KJ, Ahluwalia G, Sharma SK, et al. Significance of haematological manifestations in patients with tuberculosis. J Assoc Physicians India 2001;49:790–794.
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Tuberculosis of the central nervous system in adults Guy E Thwaites
INTRODUCTION Central nervous system TB occurs in approximately 1% of all patients with active TB and can involve both the brain and the spinal cord. The disease can be diffuse – tuberculous meningitis (TBM) – or localized to space-occupying lesions called tuberculomas. TBM is the commonest and most serious manifestation and will be the major focus of this chapter.
EPIDEMIOLOGY Prior to the arrival of human immunodeficiency virus (HIV) the most important determinant for the development of central nervous system TB was age. In populations with high TB prevalence the peak age of incidence is from 0 to 4 years, but in populations with lower TB prevalence most cases are in adults. A recent series suggests that an increasing proportion of these adults are immigrants from areas of high prevalence for TB.1 Risk factors identified for the development of TBM in adults are alcoholism, diabetes mellitus, malignancy, and recent corticosteroid use. However, coinfection with HIV now dwarfs these risk factors. HIV increases the lifetime risk of developing clinical TB post-infection from 1 in 10 to 1 in 3,2 and, in particular, predisposes to the development of extrapulmonary TB with central nervous system involvement.3 The risk of disseminated TB increases as the CD4 count declines and the disease constitutes either reactivation of latent infection or new infection.
HOST GENETIC SUSCEPTIBILITY Immunological and genetic studies support the notion that innate immunity may be important in the control of Mycobacterium tuberculosis, and an inadequate early innate immune response represents one hypothesis to explain the haematogenous dispersal of M. tuberculosis from the lung to other organs such as the brain. Genetic polymorphisms in a macrophage receptor P2X7, which reduce the capacity of macrophages to kill M. tuberculosis, are associated with the development of extrapulmonary TB.4 A recent study from Vietnam reported an association between the development of TBM in adults and a single nucleotide polymorphism in the Toll–interleukin 1 receptor domain containing adaptor protein (TIRAP).5 TIRAP mediates signals from Toll-like receptors which recognize a wide variety of microbial ligands and initiate the innate immune response.
BACTERIAL GENETIC VARIATION AND DISEASE PHENOTYPE There is gathering evidence from animal models of TB that bacterial genotype influences the host immune response. However, whether genotype influences clinical disease phenotype and the development of cerebral TB remains unclear. It is hypothesized that different clinical strains elicit different innate immune responses which influence the ability of the strain to cause disseminated disease. Beijing strains are associated with a reduced level of proinflammatory signalling, resulting in more progressive disease and a more rapidly lethal phenotype following infection in experimental animal models.6 In a rabbit model of TBM a Beijing strain of M. tuberculosis resulted in higher bacillary loads in the cerebrospinal fluid (CSF) and brain, increased dissemination of bacilli to other organs, and more severe clinical disease than infection with other strains.7 In the clinic, Beijing strains of M. tuberculosis have been associated with drug-resistant TBM in adults.8 These findings may be explained by the ability of Beijing strains to produce a phenolic glycolipid (PGL), which appears responsible for an anti-inflammatory cytokine response.6 Based on these studies, it can be proposed that strain-dependent differences in inflammatory stimulus contribute to the extrapulmonary dissemination of M. tuberculosis and may influence the development of central nervous system disease.
SYMPTOMS AND SIGNS TUBERCULOUS MENINGITIS Physicians find the diagnosis of TBM difficult because the clinical features are variable and non-specific. These features have been extensively described in a multitude of case reports and clinical series.9 The patient’s description of the onset and variety of symptoms is often unhelpful. One series reported that on admission to hospital only 28% complained of headache, 25% were vomiting, 13% reported fever, and 2% described the classical meningitic symptoms of photophobia and neck stiffness.10 As a consequence, TBM was considered a diagnosis in 36% of cases and only 6% received immediate treatment. A history of recent contact with TB may be more helpful in children than adults. The neurological complications of TBM are legion and their nature and diversity can be predicted from the site of disease and the pathogenesis.9 Cranial nerve palsies are found in 30% at presentation, particularly of the IIIrd, VIth, and VIIth nerves. Mono- or
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hemiparesis occurs in 20%; paraparesis complicates 1–5% of cases. CSF obstruction leads to raised intracranial pressure, hydrocephalus, and reduced conscious level. Seizures are unusual in adults, but may be caused by hydrocephalus, tuberculoma, and hyponatraemia. Hyponatraemia affects more than 50% of patients with TBM and causes confusion and coma. A ‘cerebral salt wasting syndrome’ associated with TBM and attributed to a renal tubular defect was described more than 50 years ago. The syndrome of inappropriate anti-diuretic hormone (SIADH) may cause some cases of TBM-associated hyponatraemia,11 but reduced plasma volumes and persistent natriuresis despite normal concentrations of anti-diuretic hormone (ADH) have been reported that suggest other mechanisms.12 TBM occurs with spinal involvement in 10% of cases and should always be considered in those presenting with root pain, with both spastic or flaccid paralysis, and loss of sphincter control.9 Vertebral TB (Pott’s disease) accounts for 25% of cases and may be associated with a gibbus (Fig. 37.1A). Extradural cord tuberculomas cause more than 60% of cases of non-osseous paraplegia, although tuberculomas can occur in any part of the cord (Fig. 37.1B). Tuberculous radiculomyelitis is a rare but well-reported accompaniment to TBM and is characterized by a subacute paraparesis, radicular pain, and bladder dysfunction. MRI reveals loculation and obliteration of the spinal subarachnoid space with nodular intradural enhancement. The usual CSF findings are of between 100 and 1000 white cells/ mm3.13 Most of the cells are lymphocytes, although neutrophils may predominate early in the disease. Those with depressed cellmediated immunity may have atypical findings and acellular CSF is reported in elderly and HIV-infected patients.14,15 An elevated CSF total protein of between 150 and 500 mg/dL occurs in the majority; very high CSF protein concentrations (> 2000 mg/dL) suggest spinal block. The ratio of CSF to blood glucose is less than 0.5 in 95% and is a useful way of distinguishing TBM from viral meningitis (when CSF–blood glucose is usually > 0.5).
CEREBRAL TUBERCULOMAS The clinical features of cerebral tuberculomas without meningitis are dependent on their anatomical location. In adults, most are supratentorial and present with seizures. They can develop whilst on therapy for TB at a different site.16 Constitutional symptoms vary but most patients complain of headache, fever, and weight loss.17 Focal weakness and papilloedema are the most frequently reported clinical signs. Unusual manifestations include pituitary apoplexy, chorea, and rare brainstem syndromes.16 Examination of the CSF reveals an elevated total protein in most patients and a pleocytosis of 10–100 cells/mm3 in 50%. The major differential diagnosis in the developed world is neoplasia. In other settings cysticercosis can produce similar clinical and radiological findings, as can toxoplasmosis in immunocompromised individuals.
CENTRAL NERVOUS SYSTEM TUBERCULOSIS AND HIV COINFECTION Over the past 15 years there have been a number of studies documenting the relationship between HIV and central nervous system TB in adults. These reports suggest HIV-infected patients are at increased risk of all forms of the disease, but the clinical features are similar to those of HIV-uninfected individuals. A study performed on 53 Indian adults (22 HIV-infected, 31 HIV-uninfected) reported HIV infection did not alter the presenting clinical features of TBM, although cognitive dysfunction was more severe in the HIV-infected group at diagnosis.18 The investigators also found that basal meningeal enhancement and hydrocephalus on cerebral computed tomography (CT) were less common in HIV-infected adults, and postmortem histopathology reported less basal exudates and larger numbers of acid-fast bacilli in the cerebral parenchyma and meninges of the HIV-infected patients. A study from two tertiary referral hospitals in Ho Chi Minh City, Vietnam, compared the presenting clinical features and response to treatment in 528 adults
Fig. 37.1 (A) Radiograph of thoracic spine showing vertebral destruction (Pott’s disease). (B) MRI of the spinal cord showing a tuberculoma in the lumbar cord of an adult coinfected with HIV. Thwaites GE, Hien TT. Tuberculous meningitis: many questions, too few answers. Reprinted from The Lancet Neurology 4(2):11. # 2005 with permission from Elsevier.
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treated consecutively for TBM (96 with HIV infection, 432 without).19 The median concentrations of CD4 lymphocytes in those infected with HIV was 67106/mL (range 7–694) and anti-retroviral drugs were not available during the study. At presentation, adults with HIV-associated TBM were significantly ( p < 0.05) more likely to be younger, lighter, and male; to have extrapulmonary/meningeal TB and lower Glasgow coma scores; and to have a lower haematocrit, peripheral blood leucocyte counts (with fewer neutrophils), and plasma sodium. Concentrations of aspartate transaminase and alanine aminotransferase were significantly higher in the HIV-infected patients, and a greater proportion had hepatitis B surface antigenaemia. Male sex (odds ratio 24.4, 95% confidence interval (CI) 7.7–76.9), younger age (odds ratio 0.90, 95% CI 0.86–0.93), extrapulmonary/ meningeal TB (odds ratio 3.20, 95% CI 1.25–8.22), and lower haematocrit (odds ratio 0.83, 95% CI 0.77–0.90) were independently associated with HIV-associated TBM at presentation. These findings relate partly to the epidemiology of HIV infection within the study population (young, male, intravenous drug users with a high prevalence of viral hepatitis) and partly to the effects of systemic immunosuppression (low weight, low haematocrit, and a high prevalence of extrapulmonary/meningeal TB). As reported by other studies, the neurological manifestations of TBM were not altered by HIV infection. Initial reports suggested the outcome of HIV-associated TBM was similar to that of uninfected individuals, but follow-up in these studies was restricted to hospital stay. The Vietnam study followed patients for 9 months and showed a dramatically reduced chance of survival in the HIV-infected patients: 62/96 (64.9%) HIV-infected adults died by 9 months compared with 122/432 (28.2%) of the HIV-uninfected (relative risk of death 2.91, 95% CI 2.14–3.96).19 The high mortality may be explained by other undiagnosed fatal opportunistic infections. Whether highly active retroviral treatment improves outcome is uncertain and is under active investigation.
Clinical diagnostic methods Few studies have attempted to define exactly which clinical features are predictive of the diagnosis of TBM. A study in Vietnamese adults developed simple diagnostic aids for distinguishing TBM from bacterial meningitis based on presenting clinical features and response to 48 hours of treatment with ceftriaxone.13 Data were compared between 251 adults with TBM and 108 adults with bacterial meningitis. Multivariate logistic regression was used to model variables associated with TBM and classification tree methods were used to develop diagnostic algorithms. Only eight patients were known to be infected with HIV. Five features were independently associated with TBM at presentation: young age, longer length of history, lower peripheral blood leucocyte count, lower total CSF leucocyte count, and lower CSF neutrophil proportion. A diagnostic rule was constructed from this analysis with weighted scores for each variable and the total score indicating a diagnosis of TBM or bacterial meningitis (Table 37.1). Two classification trees were Table 37.1 Admission diagnostic rule for discriminating 13 TBM from pyogenic bacterial meningitis (BM) Variable
Score
Age (years) 36 < 36 Blood WCC (103/mL) 15,000 < 15,000 History of illness (days) 6 <6 CSF total WCC (103/mL) 900 < 900 CSF % neutrophils 75 < 75
INVESTIGATIONS AND DIAGNOSIS TUBERCULOUS MENINGITIS
CSF WCC <760 • 103/mL
Yes
Yes
Blood WCC <10,200 • 103/mL
A
Yes
No
TBM
BM
þ4 0
TBM
No Rise in CSF/ blood glucose <100%
Yes
No
Yes BM
þ3 0
Blood neutrophils < 80%
CSF neutrophils < 81%
Age <42 years
TBM
5 0
History of illness < 8 days
History of illness < 7 days
No
þ4 0
Yes
No
History of illness <6 days
þ2 0
CSF, cerebrospinal fluid; WCC, white cell count. Diagnostic rule: total score þ4 ¼ TBM; total score > þ4 ¼ BM. Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Reprinted from The Lancet 360(9342):1287–92. # 2002 with permission from Elsevier.
The diagnosis of TBM is difficult regardless of the resources available to the physician. A diagnostic test must be sensitive and rapid, as missed or delayed treatment is strongly associated with death. At present, no test satisfies these requirements and the methods available are limited, despite the wealth of possibilities suggested in the literature.
Yes
37
Yes
No BM
B
TBM
No
Yes
No
No BM
BM
TBM
BM
Fig. 37.2 (A) Diagnostic classification tree to discriminate TBM from pyogenic bacterial meningitis (BM) at presentation. (B) Diagnostic classification tree to discriminate TBM from BM after 48 hours of ceftriaxone in those not treated immediately with anti-TB drugs. CSF, cerebrospinal fluid; WCC, white cell count. Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Reprinted from The Lancet 360 (9342):1287–92. # 2002 with permission from Elsevier.
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generated: one for use at presentation (Fig. 37.2A) and the other after 48 hours of parenteral ceftriaxone in those not treated immediately for TBM (Fig. 37.2B). The diagnostic aids were then tested prospectively using data from a further 75 adults admitted to the same hospital with meningitis (44 with TBM, 31 with bacterial meningitis). The admission diagnostic tree (Fig. 37.2A) was 88% sensitive and 70% specific; the admission diagnostic rule (Table 37.1) was 86% sensitive and 79% specific; and the second diagnostic tree (Fig. 37.2B) was 57% sensitive and 76% specific, although there were few data to test this tree. This study suggests that simple clinical and laboratory data can be used to help diagnose TBM in adults, although there are some important limitations. First, the prevalence of TB will affect the performance of the diagnostic aids. Second, the aids should not be used in those infected with HIV without validation of their performance in this group. However, these simple diagnostic aids may be of particular benefit to clinicians working with limited microbiological diagnostic facilities, when the majority of adult meningitides are diagnosed and treated on clinical grounds alone. Alternatively, they can be used to focus the use of specific laboratory diagnostic tests on patients most likely to have TBM.
Direct CSF examination and culture for acid–alcoholfast bacilli The search for acid-fast bacilli in clinical specimens has remained the cornerstone of diagnosis ever since Robert Koch first saw the bacillus in 1882. In 1953 Stewart20 described the method by which her laboratory demonstrated acid-fast bacilli in 91 of 100 consecutive cases of TBM, all of which were subsequently confirmed by culture.20 Similar results were reported by Kennedy and Fallon21 in 1979, who found that with repeated examination bacilli were present in the CSF of 45/52 (87%) patients with a clinical diagnosis of TBM. However, many laboratories find these results difficult to reproduce. A recent study prospectively assessed the clinical and laboratory factors responsible for the variation in performance of conventional bacteriology.22 A diagnosis of TBM was microbiologically confirmed in 107/132 (81%) adults. The presenting clinical features were recorded together with the volume of CSF taken and the time taken to confirm or reject the presence of acid-fast bacilli in the CSF by microscopy. The median time to see bacilli in the CSF was 10 minutes (range 1–50 minutes), and 75% of bacteria were seen within 20 minutes. The authors suggested bacteria were found quickly by first examining the highly cellular areas of the slide. The sensitivity of culture rose with volume of CSF taken, but appeared to increase little if > 6 mL were examined. Multivariate analysis showed the bacteriological confirmation of TBM was independently associated with larger volumes of CSF, a longer duration of illness, higher proportions of neutrophils in the CSF, lower concentrations of CSF glucose, and higher concentrations of CSF lactate. Interestingly, M. tuberculosis was isolated from smaller CSF volumes from HIV-infected than that from HIV-uninfected individuals (medians 1.5 vs 4.0 mL, p = 0.001), which suggests these adults have greater bacterial loads in the CSF and careful bacteriology may be especially helpful in this group. CSF adenosine deaminase activity The activity of adenosine deaminase (ADA), an enzyme produced by CD4+ lymphocytes and monocytes, is raised in the CSF of patients with TBM. A number of studies have evaluated ADA activity as a diagnostic assay, but assessment from these studies of its usefulness is difficult. Different assays have been used to measure enzyme activity and the cut-off values used to distinguish TBM from other diagnoses varied from 4 to 10 IU/mL. Diagnostic sensitivity ranged between 44% and 100%, and specificity between 71% and 99%. The lack of
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specificity is the major problem with the assay. High concentrations of CSF ADA activity have been reported from patients with lymphomas, malaria, brucellosis, and pyogenic meningitides. Also, a recent study in HIV-infected adults with a range of neurological diagnoses suggested a limited diagnostic role for ADA in this group.23 TBM diagnostic sensitivity was 57% and false-positive tests were observed with cerebral cytomegalovirus infection, cryptococcal meningitis, and cerebral lymphomas. Currently, there is little to support the widespread use of ADA activity as a diagnostic test for TBM.
The detection of M. tuberculosis nucleic acid in the CSF The amplification and detection of M. tuberculosis nucleic acid from CSF is an attractive diagnostic prospect and the method would appear to be particularly suitable for the diagnosis of TBM when there are few tubercle bacilli in the CSF and a low chance of contamination with other bacteria. However, despite the development of commercially available assays, the promise of nucleic acid amplification (NAA) is not yet matched by consistent diagnostic performance. A systematic review and meta-analysis calculated that commercial nucleic acid amplification assays for the diagnosis of TBM was 56% sensitive (95% CI 46–66%) and 98% specific (95% CI 97–99%).24 The variety of nucleic acid targets and ‘gold standard’ diagnostic criteria was a major impediment to comparing studies. Few studies have carefully compared the sensitivity of NAA, smear, and culture using large volumes of CSF. Those that have suggest the sensitivity of CSF smear is similar to that of NAA,25 and repeated testing using large volumes of CSF gives the highest diagnostic yield. However, once treatment has begun NAA may be more helpful as the sensitivity of smear and culture fall rapidly whereas mycobacterial DNA may remain detectable within the CSF for up to 1 month after the start of treatment.25 Advances in NAA technology may improve the sensitivity of these methods. A recent study explored the utility of a quantitative real-time polymerase chain reaction (PCR) assay and demonstrated high diagnostic sensitivity and specificity in a small group of adults with suspected TBM.26 Real-time PCR provides measurement of the mycobacterial DNA copy number from which an assessment of bacterial load in the CSF can be made. These quantitative data may have several uses, including predicting outcome and assessing response to treatment. The chest radiograph and brain imaging About one-half of patients with TBM have chest radiographs suggesting active or previous pulmonary TB.9 In areas of high TB prevalence radiological evidence of previous pulmonary infection is common and the finding must be interpreted with caution. Around 10% of patients with TBM have a miliary chest radiograph appearance which is a helpful finding as it strongly suggests extrapulmonary disease. Hydrocephalus and contrast-enhancing exudates in the basal cisterns are the most common findings on cerebral CT.27 Some have suggested that a normal scan in a drowsy patient excludes the diagnosis of TBM,28 but Ozates et al.27 reported a normal scan in 10/ 203 (5%) of patients with TBM and reduced consciousness. The common findings in this large series (289 adults and children) were hydrocephalus (80% of children, 43% of adults), parenchymal enhancement (26% of children, 8% of adults), contrast enhancement of basal cisterns (15% of children, 23% of adults), cerebral infarct and focal or diffuse brain oedema (14% of children, 13% of adults), and tuberculoma (4% of children, 7% of adults).27 Cranial magnetic resonance imaging (MRI) may provide more diagnostic information than CT when assessing space-occupying lesions, infarcts, and the extent of the inflammatory exudates
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Fig. 37.3 Contrast-enhanced axial T1-weighted MRI reveals thick leptomeningeal enhancement in the suprasellar cistern extending into the Sylvian fissures and the ambient cisterns. The temporal horns are also dilated.
(Fig. 37.3).29 Indeed, the ability of MRI to detect small lesions has revealed that meningeal tuberculomas develop during treatment in 80% of adults with TBM and are usually asymptomatic.30 Data regarding the diagnostic sensitivity and specificity of MRI for TBM are limited – those studies that do exist are small and only include a highly selected patient population. Cryptococcal meningitis, cytomegalovirus encephalitis, toxoplasmosis, sarcoidosis, meningeal metastases, and lymphoma may all produce similar clinical and radiographic findings. The major role of neuroradiology has been in the management and follow-up of the complications of TBM or requiring neurosurgery.
Alternative diagnostic approaches The challenge facing new diagnostic strategies in TBM is that they must improve on the sensitivity of conventional bacteriology, but maintain the specificity. In the developed world cost is less critical, but in the developing world cost considerations mandate tests that are cheap, use standard reagents with long shelf lives, and are simple to perform. Frequency-pulsed electron-capture gas–liquid chromatography has been used to detect femtomole quantities of tuberculosteric acid in CSF, a structural component of the mycobacterial cell wall, and reported a diagnostic sensitivity of 91% and specificity 95%.31 However, the cost of the equipment and the complexity of the technique mean it is unlikely to be adopted as standard diagnostic procedure. Serological techniques that detect the intrathecal synthesis of anti-mycobacterial antibodies have been studied over many years. Many have shown promise, but none have demonstrated consistent performance in a routine diagnostic laboratory. Enzyme-linked immunosorbent assays (ELISA) using crude antigens such as PPD have resulted in low sensitivity and specificity.32 A large study using a solid-phase antibody competition assay with mouse monoclonal antibodies to the 38-kDa antigen (also known as antigen 5, or antigen 78) reported a diagnostic sensitivity of 73% and specificity of
37
98% for extrapulmonary TB, regardless of organ site.33 More recently, the presence of immunoglobulin (Ig)G against six protein antigens (ESAT-6, 14 kDa, 19 kDa, MPT63, MPT64, 38 kDa) were assessed by ELISA in the CSF of 442 patients with TBM and 102 controls.34 Antigen-specific IgG was undetectable in all of the controls, but IgG to at least one antigen was detectable in 228/ 264 (87%) of HIV-uninfected patients with clinical TBM, 50/69 (72%) with culture-proven TBM, and 47/72 (65%) with autopsyproven TBM. There was evidence of preferential antigen recognition according to clinical grouping: the culture-confirmed cases reacted most strongly against the 14 kDa, and antibodies against MPT64 were lowest in the CSF from autopsy-proven cases. Different stages of TBM may correlate with preferential recognition of different antigens, and disease progression may alter the antibody profiles. Future assays may have to assess reactivity to a range of antigens and overcome the problems of differentiating acute infection from previous exposure. The detection of peripheral blood lymphocytes that produce interferon-g in response to ex vivo stimulation with specific M. tuberculosis antigens (e.g. ESAT and CFP-10) – the enzymelinked immunospot (Elispot) assay – has been a major advance in the diagnosis of latent TB.35 Whether these assays can be adapted to detect M. tuberculosis-specific cells in other body fluids to diagnose active TB is uncertain. The assay has been used recently to detect interferon-g-producing T cells in bronchoalveolar lavage fluid of patients with smear-negative pulmonary TB and performed with high sensitivity and specificity.36 A study from China investigated the use of an Elispot assay to detect anti-Mycobacterium bovis Bacillus Calmette–Gue´rin (BCG) antibody-secreting cells in CSF to diagnose TBM,37 and found Elispot was more sensitive than PCR or culture. Others have found this approach less helpful: investigators from Vietnam studying adults with TBM found that ex vivo stimulation of CSF lymphocytes with M. tuberculosisspecific antigens by Elispot failed because the cells underwent rapid activation-induced cell death.38 A further study of adults with TBM by the same investigators found that 50% of patients with culture-confirmed TBM had a negative peripheral blood Elispot for M. tuberculosis at presentation.39 These findings suggest that, like the skin tests, these assays may lack sensitivity in those with severe disseminated TB. Further investigation is required before they can be recommended for routine use in the diagnosis of TBM.
CEREBRAL TUBERCULOMAS Distinguishing tuberculomas from other infectious and noninfectious causes is difficult. Biopsy of the lesion is the diagnostic gold standard and stereotactic techniques have greatly improved the safety of this procedure. In one series, stereotactic biopsy was diagnostic in 75/80 (94%) patients and only one patient suffered complications from the procedure.40 The tissue obtained should be examined for the presence of classical caseating granulomas and the presence of acid-fast bacilli. NAA techniques may be more helpful than bacteriology in confirming a diagnosis of tuberculoma, although they have not been subject to systematic comparison. Immunohistochemical detection of M. tuberculosis antigens in tissue has been reported to be more sensitive than bacteriology or PCR by researchers in India.41 Non-invasive diagnostic techniques have been widely investigated but, to date, lack the required diagnostic sensitivity and specificity. Recent advances in magnetic resonance spectroscopy (MRS) have shown most promise: tuberculomas typically show a
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Fig. 37.4 Contrast-enhanced coronal T1-weighted MRI. Multiple enhancing nodules: principally parenchymal, but also ependymal and leptomeningeal.
large lipid CH2 peak, which can be used to differentiate them from other causes.42 Other investigators have suggested MRS can distinguish tuberculomas from neurocysticercosis – a common diagnostic dilemma in the developing world – on the basis of a choline/creatine ratio > 1 in cases of tuberculoma.43 Conventional MRI is less helpful: non-caseating cerebral tuberculomas appear hyperintense on T2-weighted imaging with nodular post-contrast enhancement (Fig. 37.4), but these findings are not sufficiently specific to define treatment. Likewise, the CT scan appearances of tuberculomas lack specificity, although various criteria have been proposed in India to differentiate tuberculoma from neurocysticercosis by CT alone.44 Examination of the CSF for M. tuberculosis by bacteriology or by PCR is unhelpful in most cases unless the patient also has meningitis. The diagnostic use of empiric anti-TB treatment with assessment of the therapeutic response is fraught with difficulty and cannot be recommended if other diagnostic options are available. Tuberculomas can take many months to resolve – in one series over half were still visible on imaging after 2 years of treatment45 – and corticosteroids cause non-specific symptomatic improvement in many other causes of cerebral masses.
PATHOLOGY AND PATHOGENESIS Central nervous system TB results from the haematogenous dissemination of M. tuberculosis to the brain with the formation of small subpial or subependymal foci. These are called Rich foci, after the author of the original pathological studies describing the sequence of events that lead to TBM.46 The development of TBM requires rupture of a Rich focus with release of M. tuberculosis into the subarachnoid space. This heralds the onset of meningitis, which, if left untreated, will result in death in most cases. Three processes produce the subsequent neurological pathology: granulomatous meningeal inflammation with exudate and adhesion formation, an obliterative vasculitis, and an encephalitis or
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myelitis.47 Granulomas can coalesce to form tuberculomas, predominantly meningeal in origin, which can cause diverse clinical consequences dependent upon their anatomical location (Fig. 37.5A). Adhesions result from a dense basal meningeal exudate that contains lymphocytes, plasma cells, and macrophages, with increasing quantities of fibrin. Adhesions can block the basal subarachnoid cisterns, obstruct the flow of CSF, and cause hydrocephalus (Fig. 37.5B); they can also compromise cranial nerves, particularly II, III, IV, VI, and VII. An obliterative vasculitis of both large and small vessels can cause infarctions, which commonly occur in the territories of the proximal middle cerebral artery and the perforating vessels to the basal ganglia (Fig. 37.5C).30 The intensity of the basal inflammatory process extends into the parenchyma, resulting in encephalitis. Oedema, occurring as a consequence, can be marked throughout both hemispheres and contributes to rising intracranial pressure and the global clinical neurological deficit. The pathogenesis of symptomatic, expanding, intracranial tuberculomas (that occur without meningitis) is more speculative. An ill-defined ‘immunological’ hypothesis that suggests localized upregulation of the cellular immune response to M. tuberculosis antigens within Rich foci has been proposed. Evidence for this suggestion is scant, although the ability of corticosteroids to reduce the size of lesions, and the association between tuberculoma development in HIV-infected individuals and immune reconstitution with highly active retroviral therapy, is persuasive. The cellular and molecular pathogenesis of all forms of central nervous system TB is poorly understood. A rabbit model of TBM showed CSF concentrations of tumour necrosis factor (TNF)-a were correlated with clinical progression, and intervention with antibiotics and thalidomide, an anti-TNF-a agent, resulted in improved survival and neurological outcome.48 However, CSF concentrations of TNF-a from human subjects with TBM are lower than that in the rabbit TBM model and have not been correlated with disease severity or outcome.39 A protective response to M. tuberculosis is dependent on cellmediated immunity, but few studies have attempted to phenotype the cells beyond the basic divisions of neutrophil and lymphocyte. Older studies suggested that CD4+ T-helper cells were the dominant lymphocyte subset in the CSF,49 and this has been confirmed by recent investigations using flow cytometry.38 These cells co-expressed CD45RA+ and CD45RO+, a phenotype identical to alveolar CD4+ lymphocytes recovered from the lungs of pulmonary TB patients.50 They probably represent activated effector T cells that have emigrated to the central nervous system. Neutrophils make up 10–50% of the cells in the CSF of patients with TBM, but their role in pathogenesis has been largely neglected. Intriguing data from adults with TBM have shown that higher proportions of neutrophils in the CSF are associated with a greater chance of isolating M. tuberculosis from the CSF,22 the development of cerebral tuberculomas,30 and improved survival.51 The matrix metalloproteinases may also be involved in the pathogenesis of TBM. These molecules, secreted by monocytes and macrophages, are zinc-containing proteases that degrade extracellular matrix. They may cause cerebral injury by disrupting the blood–brain barrier, facilitating leucocyte migration, and cleaving myelin proteins. Elevated CSF matrix metalloproteinase-9 concentrations have been associated with focal neurological deficit and fatal outcome in Vietnamese adults with TBM.52
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Fig. 37.5 (A) Enhanced axial T1-weighted MRI. There is a large nodular focus of enhancement within the left Sylvian fissure extending into the left temporal lobe associated with marked low signal change. (B) Axial T1-weighted MRI reveals hydrocephalus with dilated lateral and third ventricles. (C) Gadolinium-enhanced T1 coronal MRI demonstrating extensive basal meningeal enhancement and established left capsulostriate lacunar infarct.
MANAGEMENT ANTITUBERCULOSIS CHEMOTHERAPY The anti-TB chemotherapy of TBM and cerebral tuberculoma are the same and follow the model of short course chemotherapy for pulmonary TB – an intensive phase of treatment, followed by a continuation phase. But, unlike pulmonary TB, the optimal drug regimen and duration of each phase are uncertain. Streptomycin was first used to treat TB in 1944, and in 1946 the British Medical Research Council began studies using streptomycin for TBM. In
1948 they published data that demonstrated a marked improvement in outcome for those with TBM treated with streptomycin.53 Mortality fell from nearly 100% without treatment to 46% in those presenting with stage 1 (conscious, no neurological deficit), 66% in stage 2 (disturbed consciousness, with or without focal neurology), and 86% in stage 3 (comatose, with or without focal signs). The introduction of isoniazid and para-aminosalicylic acid (PAS) led to further improvements in prognosis. A report documenting the changes in available chemotherapy between 1947 and 1958 showed mortality fell from 64% using streptomycin alone to 27% with streptomycin and PAS, then to 17% with the addition of
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isoniazid.54 The addition of rifampicin to the treatment of TBM was immediately accepted although the prognostic benefits of rifampicin have been questioned, and uncertainty surrounds its penetration into the CSF. Rifampicin is 80% protein bound in plasma, enabling a maximum of 20% to penetrate the CSF in those with an intact blood–brain barrier. Studies have shown slow penetration of rifampicin into the CSF of patients with TBM, with levels just above the minimum inhibitory concentrations (MICs) for M. tuberculosis.55 Meningeal inflammation enhances CSF penetration of antiTB drugs, although there is limited evidence to suggest rifampicin penetration occurs independently of inflammation. There is no conclusive evidence to demonstrate improvement in outcome with the use of pyrazinamide. It is well absorbed orally, and achieves high concentrations in the CSF. These factors, and the sterilizing effect on tubercle bacilli, have resulted in pyrazinamide being considered mandatory at the beginning of TBM treatment.56 It has been suggested that, given the uncertain benefit and penetration of rifampicin, pyrazinamide should be given for the duration of the treatment. The British Thoracic Society (BTS), the Infectious Diseases Society of America, and the American Thoracic Society (ATS) recommend that all patients start on isoniazid, rifampicin, and pyrazinamide.57,58 Isoniazid is believed to be critical because it penetrates the CSF freely and has potent early bactericidal activity. Choosing the fourth drug of the intensive phase is more difficult. Most authorities recommend either streptomycin or ethambutol, although neither penetrates the CSF well in the absence of inflammation, and both can produce significant adverse reactions. Streptomycin should not be given to those who are pregnant or have renal impairment. Intrathecal streptomycin is no longer used, although this route of administration is being revisited for the treatment of multidrug-resistant cases.59 Some centres, notably in South Africa, advocate ethionamide, which penetrates healthy and inflamed meninges. However, despite theoretical attractions, there are no data demonstrating any clear advantage of one drug over another. The prevalence and patterns of drug resistance may influence the choice of drug. For example, streptomycin resistance is becoming increasingly prevalent worldwide and ethambutol may be favoured as a consequence. Isoniazid and rifampicin should be given throughout the continuation phase of treatment. Some authorities suggest pyrazinamide should accompany these drugs given the high CSF concentrations achieved throughout the course of the disease,56 but there are no data from controlled trials to support this recommendation. The British and American thoracic societies’ recommendations for the dosages of the standard anti-TB drugs are shown in Table 37.2. Some authors have suggested using doses of isoniazid greater than 5 mg/kg for the treatment of TBM in adults,56 and higher doses (10 mg/kg) are widely used in children. The potent early bactericidal effect of isoniazid, and the uncertain CSF penetration of other drugs in the standard regimen, makes this an attractive proposition. However, at standard doses isoniazid achieves CSF levels 10–15 times the minimum inhibitory concentration of M. tuberculosis,60 and there are no data to suggest higher doses improve outcome or shorten treatment in adults with TBM. Indeed, the increased risk of adverse events with higher doses of drugs needs careful consideration for, unlike the treatment of pulmonary TB, interruptions in anti-TB chemotherapy are an independent risk factor for death from TBM.61 TBM should be treated for at least 6 months. It is unclear whether more prolonged treatment is required. The BTS recommends 12 months in uncomplicated cases, extending to 18 months should pyrazinamide be omitted.57 Treatment for 12 months is probably an overestimate of the time required for bacterial cure, and there is
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Table 37.2 Recommended daily dosages of standard antituberculosis drugs for the treatment of adults with 57,58 central nervous system tuberculosis Drug
Daily dose
Route
Duration
British Thoracic Society guidelines, 2006 Isoniazid Rifampicin Pyrazinamide Ethambutol OR Streptomycin
300 mg 450 mg (< 50 kg) 600 mg (> 50 kg) 1.5 g (< 50 kg) 2.0 g (> 50 kg) 15 mg/kg 15 mg/kg (maximum 1 g)
Oral Oral
12 months 12 months
Oral
2 months
Oral Intramuscular
2 months 2 months
Guidelines of the Joint Committee of the American Thoracic Society, the Infectious Diseases Society of America, and the Centers for Disease Control, 2003 Isoniazid Rifampicin Pyrazinamide
Ethambutol
5 mg/kg (300 mg) 10 mg/kg (600 mg) 40–55 kg: 1000 mg 56–75 kg: 1500 mg 76–90 kg: 2000 mg 40–55 kg: 800 mg 56–75 kg: 1200 mg 76–90 kg: 1600 mg
Oral Oral Oral
9–12 months 9–12 months 2 months
Oral
2 months
National Collaborating Centre for Chronic Conditions. Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. Royal College of Physicians, UK; 2006. And Treatment of tuberculosis. MMWR Recomm Rep. 2003 Jun 20;52(RR-11):1–77.
evidence to suggest shorter courses are effective. A recent systematic review concluded that 6 months of anti-TB drugs for TBM is probably sufficient, provided the likelihood of drug resistance is low.62 Disease severity, drug toxicity, and patient compliance should all be considered when deciding the duration of treatment.
CENTRAL NERVOUS SYSTEM TUBERCULOSIS CAUSED BY DRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS There have been few studies examining the relationship between different patterns of drug resistance and their effect on treatment response and outcome from TBM and tuberculomas. The potent early bactericidal effect of isoniazid, together with excellent CSF penetration, suggests disease caused by organisms resistant to this drug may be harder to treat. Isoniazid resistance has been associated with significantly longer times to CSF sterility in patients with TBM,25 implying an attenuated bactericidal response in these individuals that might influence outcome. However, the limited existing clinical data have failed to demonstrate a clear impact of isoniazid resistance (either alone or in combination with streptomycin) on outcome from TBM.63 At present, TBM caused by bacteria with these susceptibility profiles should be treated with the standard four-drug regimens (including isoniazid). There are convincing data that demonstrate cases of TBM caused by M. tuberculosis resistant to at least isoniazid and rifampicin (multidrug resistance (MDR)) require alternative therapy. A retrospective
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review of 30 South African patients with MDR TBM reported an in-hospital case fatality of 17/30 (57%) with significant functional impairment in most of the survivors.64 Another report described how seven out of eight cases of HIV-associated MDR TBM died within 16 weeks of treatment in the United States (the eighth was lost to follow-up).65 A study from Vietnam observed MDR TBM was strongly predictive of death (relative risk of death 11.63; 95% CI 5.21–26.32) and independently associated with HIV coinfection.63 All the patients with MDR TBM died within 60 days of diagnosis and before the results of conventional susceptibility testing were available or any second-line drugs were given. These findings highlight the need for new tests that rapidly detect resistance. Molecular assays, such as the amplification and detection of mutations in the M. tuberculosis rpoB gene that predict phenotypic rifampicin resistance, may be helpful but have yet to be evaluated for the diagnosis of MDR TBM and are unlikely to be universally available. More encouraging is the microscopic observation drug susceptibility (MODS) assay developed in Peru and shown to be as accurate as the gold standard conventional assays, but far quicker.66 This method is currently being studied in Vietnam for the rapid diagnosis of drugresistant TBM. Regardless of the diagnostic difficulties, the treatment of MDR TBM represents a formidable therapeutic challenge. For suspected or proven MDR pulmonary TB the World Health Organization recommends an injectable agent (aminoglycoside, e.g. amikacin, or capreomycin), ethionamide, pyrazinamide, and a fluoroquinolone (e.g. moxifloxacin) for the initial phase of treatment.67 There are no equivalent recommendations for MDR TBM, and few data are available on the CSF penetration and effectiveness of possible agents. Ethionamide, prothionamide, and cycloserine have been reported to penetrate the blood–brain barrier and may be effective. The combination of intrathecal amikacin and levofloxacin has also been suggested.68 Until more data become available, the treatment of patients with MDR TBM should be guided by individual resistance profiles and the predicted CSF penetration of candidate drugs.
ADJUNCTIVE CORTICOSTEROIDS Tuberculous meningitis Adjunctive corticosteroid treatment of TBM has been recommended for more than 50 years, although evidence that it improves outcome has been difficult to obtain. Early studies suggested corticosteroids reduced CSF inflammation and time to recovery, but were too small to confirm an effect upon survival. A meta-analysis of all randomized, controlled trials published before 2000 suggested corticosteroids were effective in reducing death in children (relative risk 0.77; 95% CI 0.62–0.96), but not in adults (relative risk 0.96; 95% CI 0.50–1.84), although only six trials involving 595 patients (158 adults) met the analysis inclusion criteria and there were no data from HIV-infected individuals.69 A randomized, controlled trial of dexamethasone in 545 Vietnamese adults (defined as > 14 years old) published in 2004 provided substantial evidence for a beneficial effect of adjunctive corticosteroids in adults and included data on HIV-infected patients.61 Dexamethasone treatment was associated with a reduced risk of death (relative risk 0.69; 95% CI 0.52–0.92; p = 0.011), but was not associated with a reduction in the proportion of severely disabled survivors (dexamethasone, 34/274 (12.4%); placebo, 22/271 (8.1%); p=0.120) or the proportion either dead or severely disabled (odds ratio 0.81; 95% CI 0.58–1.13; p = 0.216). The effect
37
of dexamethasone on survival was consistent across all grades of disease severity, contradicting a previously held belief that corticosteroids only benefited those with more severe disease. Ninety-eight HIV-infected adults were recruited to the Vietnam trial; most were severely immunocompromised (median CD4 lymphocyte count 66 106/mL) and none were treated with antiretroviral drugs. Dexamethasone was associated with a non-significant reduction in death and death or severe disability in those infected with HIV (stratified relative risk, 0.78; 95% CI 0.59–1.04; p ¼ 0.082). The survival curves show that, unlike the HIVuninfected, HIV-infected adults continued to die throughout the 9-month study period. Cause of death was not determined but other undiagnosed opportunistic infections may account for this observation. These data indicate dexamethasone is safe and may be of benefit, although the numbers of HIV-infected patients in the study were too small to confirm a treatment effect. There has been long-standing concern that corticosteroids might reduce mortality but increase the number of disabled survivors. The data from Vietnam do little to allay these fears. Meta-analysis of previous data suggested corticosteroids reduced disability, but was compromised by variable methods of outcome assessment, loss to follow-up, and small numbers of survivors.69 The Vietnam study assessed disability by two scores – the ‘simple questions’ and modified Rankin scores – which depend upon survivors answering a short series of questions concerning the help they required with daily living activities. These scores have been well validated for the assessment of disability following stroke in the developed world, but may not perform so well in assessing long-term neurological sequelae following TBM in the developing world. True effects of dexamethasone on morbidity may have been missed by these scores, although dexamethasone did not alter the incidence or resolution of hemiparesis, paraparesis, or quadriparesis, the commonest sequelae to cause severe disability. The impact of dexamethasone on survival, but not long-term disability, raises important questions concerning how dexamethasone influences outcome. There are no satisfactory answers. Earlier studies suggested corticosteroids reduced CSF inflammation and time to recovery, but this has not been demonstrated consistently by recent investigators. The controlled trial of prednisolone in South African children failed to show that adjunctive prednisolone altered CSF inflammatory paremeters, intracerebral pressure, or the cerebral CT scan appearances during treatment.70 A subgroup of adults recruited to the trial in Vietnam were subject to a detailed study of the kinetics of the CSF and peripheral blood immune response.38 Other than reduced total CSF protein in the dexamethasone arm, there were no significant observable differences between the treatment groups. Patients within the same study were also subject to serial MRI scans to determine the impact of dexamethasone on hydrocephalus, infarction, and tuberculoma formation.30 Intriguingly, dexamethasone was associated with a marked (but non-significant) reduction in the proportion with hydrocephalus and infarcts at the end of corticosteroid therapy. Other mechanisms for improving outcome may be at play; dexamethasone was strongly associated with a reduction in the frequency of adverse events, in particular severe drug-related hepatitis, in the Vietnam study.61 This study and others have shown adverse events that necessitate a change in anti-TB dose or regimens are an independent risk factor for death. Dexamethasone may improve outcome from TBM by simply allowing uninterrupted treatment. Importantly, none of the controlled trials investigating the use of corticosteroids for TBM have observed an increase in
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corticosteroid-related adverse events, in particular gastrointestinal bleeding. Other authors have been concerned that corticosteroids may reduce the penetration of anti-TB drugs into the CSF by reducing inflammation, but there is little evidence for this occurring.60 There are no data from controlled trials comparing different corticosteroid regimens in adults; therefore choice of regimen should be based on those used in the published controlled trials. The following regimen was shown to improve outcome in Vietnam:61 those with a Glasgow coma score < 15 or focal neurological deficit at the start of treatment received intravenous drug for 4 weeks (0.4 mg/kg/24 hours in week 1, 0.3 mg/kg/24 hours in week 2, 0.2 mg/kg/24 hours in week 3, 0.1 mg/kg/24 hours in week 4) followed by 4 mg/24 hrs total of oral drug, reducing each week by 1 mg/24 hrs until zero. Those without coma or neurological signs received intravenous drug for 2 weeks (0.2 mg/kg/24 hours in week 1, 0.1 mg/kg/hours in week 2), followed by the same oral reducing course described above.
Tuberculoma It is uncertain whether adults who present with symptoms from intracranial tuberculomas without meningitis benefit from adjunctive corticosteroids, although they are widely advocated. No controlled trials have been performed examining this issue. Anecdotally, adjunctive corticosteroid treatment improves symptoms and seizure control and reduces tuberculoma size and perilesional oedema radiographicaly. Duration of therapy varies depending on response; enlargement of tuberculomas with symptom return as the corticosteroid dose is reduced is common. There are case reports describing successful treatment of cerebral tuberculomas with thalidomide in such cases;71 although unproven this approach may be helpful in patients with lesions not responding to anti-TB drugs and corticosteroids. NEUROSURGERY Neurosurgical intervention may be indicated for the complications of TBM – especially hydrocephalus – and tuberculomas that have coalesced to form a tuberculous cerebral abscess. There are no published randomized trials of surgery for any of these complications. Hydrocephalus is the commonest reason for neurosurgical referral in patients with TBM, but how and when to intervene is unclear. Most published data are from children and have documented poor outcomes following ventriculoperitoneal shunting, although there were no control groups.72 Response to external ventricular drainage has been assessed to determine who might benefit from shunting, but failed to predict benefit. Others have suggested early ventriculoperitoneal shunting should be considered in all patients with hydrocephalus, especially if the hydrocephalus is noncommunicating.73 Until better data become available, neurosurgical intervention must depend upon local resources and surgical experience and acknowledge the significant complications of shunt surgery and the lack of trials demonstrating any benefit.
suggests the diagnosis is wrong. The CSF mirrors the slow clinical response – cell counts are raised for 1–2 months, glucose remains low for a similar duration, and total CSF protein can rise before falling slowly over many months. Transient episodes of high fever, worsening headache, and increased neck rigidity can occur during the first 2 months of treatment, particularly in those with more severe disease. Distinguishing self-limiting events from the onset of more serious complications is difficult. Brain imaging should be arranged urgently if new clinical signs develop during treatment. Hydrocephalus, cerebral infarction, and the expansion of intracranial tuberculoma are the foremost reasons for severe acute deterioration.9 Severe hyponatraemia is often overlooked as a cause of deepening coma, although the best way of correcting the plasma sodium remains uncertain. Sodium and fluid replacement is probably indicated in hypovolaemic hyponatraemia, whereas fluid restriction may be more appropriate in those who are euvolaemic. There is anecdotal evidence to suggest fludrocortisone replacement therapy and demeclocycline may be useful. The expansion of intracranial tuberculoma after the start of anti-TB chemotherapy is a widely reported complication of TBM and can occur at any time during treatment.75 As discussed, most authorities suggest treatment with prolonged high-dose corticosteroids. Adverse reactions to anti-TB drugs are a common problem, and can have a devastating effect on the outcome. Hepatic toxicity is the commonest and many authorities recommend stopping isoniazid, rifampicin, and pyrazinamide immediately if the serum transaminases rise to five times normal, or the bilirubin concentration rises.57,58 In most forms of TB a short period without treatment does not affect outcome, but this is not true of TBM. Streptomycin and ethambutol should be prescribed if isoniazid, rifampicin, and pyrazinamide are stopped, and the addition of a fluoroquinolone (e.g. moxifloxacin) is considered. Isoniazid and rifampicin should be restarted as soon as possible and treatment extended if the patient cannot adhere to the conventional 9month regimen. Some of the drugs cause adverse reactions with neurological manifestations that may be confused with the complications of TBM and the most important of these are presented in Table 37.3.
Table 37.3 Adverse reactions of antituberculosis drugs with neurological manifestations Drug
Neurological adverse event
Isoniazid
Peripheral neuropathy, convulsions, optic neuritis, mania/psychosis, dysarthria/dysphoria Headaches, confusion, drowsiness Retrobulbar neuritis, peripheral neuropathy, confusion Neuromuscular block, ototoxicity, circumoral paraesthesia immediately post injection Anxiety/depression, psychosis, optic neuritis, peripheral neuritis Dizziness, tremor, insomnia, confusion Headache/restlessness, psychosis, seizures, exacerbation of mental illness, peripheral neuritis
Rifampicin Ethambutol Streptomycin
RESPONSE TO TREATMENT AND COMPLICATIONS Ninety per cent of deaths from TBM occur in the first month of treatment.74 The response to treatment is usually slow and may fluctuate. Indeed, a rapid and sustained response over a few days
410
Ethionamide Fluoroquinolones Cycloserine
CHAPTER
Tuberculosis of the central nervous system in adults
PREVENTION OF CENTRAL NERVOUS SYSTEM TUBERCULOSIS It is generally accepted that BCG vaccination protects against haematogenous dissemination of M. tuberculosis in childhood, in particular against miliary and cerebral TB, and is a highly cost-
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children with tuberculous meningitis. Pediatrics 1997;99(2):226–231. Roberts MT, Mendelson M, Meyer P, et al. The use of thalidomide in the treatment of intracranial tuberculomas in adults: two case reports. J Infect 2003;47(3):251–255. Lamprecht D, Schoeman J, Donald P, et al. Ventriculoperitoneal shunting in childhood tuberculous meningitis. Br J Neurosurg 2001; 15(2):119–125. Mathew JM, Rajshekhar V, Chandy MJ. Shunt surgery in poor grade patients with tuberculous meningitis and hydrocephalus: effects of response to external ventricular drainage and other variables on long term outcome. J Neurol Neurosurg Psychiatry 1998;65(1):115–118. Girgis NI, Sultan Y, Farid Z, et al. Tuberculosis meningitis, Abbassia Fever Hospital-Naval Medical Research Unit No. 3-Cairo, Egypt, from 1976 to 1996. Am J Trop Med Hyg 1998;58(1):28–34. Afghani B, Leiberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 1994;19:1092–1099. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367(9517):1173–1180.
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Central nervous system tuberculosis in children Peter R Donald and Johan F Schoeman
INTRODUCTION Epidemiological studies from the early twentieth century identified tuberculous meningitis (TBM) as the commonest cause of childhood bacterial meningitis. Tuberculosis statistics from many developed countries are, however, now marked by a complete absence of TBM or incidence rates close to 1 per 100,000 population or less.1 In developing countries accurate data as to the incidence of TBM are seldom available, but when they are available they paint a very different picture. Thus in the Western Cape Province of South Africa TBM is the commonest cause of bacterial meningitis in children,2 and for the period 1985–1987 an incidence of TBM of 24 per 100,000 population was reported for children aged 0–4 years of age.3 Disseminated forms of TB and TBM are particularly likely to follow a primary infection in early childhood, and the careful studies of Arvid Wallgren showed that a majority of cases of TBM develop within 3–6 months of primary infection.4 In high-incidence communities TBM will have its highest incidence between the ages of 1 and 3 years. Nonetheless, because of the time needed for the infectious process to run its course and establish a focus within the central nervous system, TBM is very unusual before 3 months of age.5 Recently, in areas of high TB and HIV prevalence, cases of TBM presenting before 3 months of age appear to be becoming more common and this can be ascribed to an increasing incidence of TB in pregnant women in these communities. Also as a result of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), dissemination of bacilli may occur long after primary infection, leading to the more frequent development of TBM, even in individuals who have successfully survived primary infection.
THE PATHOGENESIS OF TUBERCULOUS MENINGITIS Shortly after primary infection lymphohaematogenous dissemination seeds bacilli in areas of high oxygen tension such as bone-ends, kidneys, meninges and lung apices. Usually disease development at these sites is prevented by an appropriate immune response; should this fail disease may follow. In the case of the meninges and underlying cerebral tissue the development of meningitis is delayed while a granulomatous focus (the Rich focus) matures, before starting to discharge its contents into the subarachnoid space.5 Depending upon the amount of material discharged and the degree of host hypersensitivity an inflammatory response develops and with
it the first prodromal symptoms. Often this will be an insidious process accompanied by subtle symptoms. Should a large amount of granulomatous material be suddenly discharged into the cerebrospinal fluid (CSF), a more acute response ensues and, confusingly, a CSF cell count of > 500 106/L with a predominance of polymorphonuclear leucocytes may be found (whereas the expected TBM CSF cell count would be lymphocytic predominance of < 500 106/L). As the disease progresses, the child becomes increasingly irritable and, with the formation of characteristically florid gelatinous exudates that surround the base of the brain, focal signs appear. This exudate envelop the structures across the base of the brain, obstructs the free flow of CSF and contributes to a peri-arteritis of the cerebral arteries and their main perforating branches. At this point rising intracranial pressure may cause headache or cranial nerve palsies and lead to convulsions and loss of consciousness, while the vasculitis may cause infarctions and various neurological deficits, but most often hemiplegia. It is unfortunate that the majority of patients are diagnosed only at this point; irreversible damage has already occurred and overt clinical signs leave little doubt as to the diagnosis. Obstructive hydrocephalus and the associated raised intracranial pressure (ICP) are important features of TBM. The exudate that fills the basal cisterns causes a bottleneck obstruction of the CSF pathways at the level of the tentorium, causing a communicating hydrocephalus, which is by far the most common cause of raised ICP in TBM. In the absence of a spinal block, the lumbar and ventricular CSF pressures in this type of meningitis will be equal.6 In a minority of patients CSF obstruction occurs when the basal exudate obstructs the outflow foramina of the fourth ventricle, leading to a non-communicating hydrocephalus. Other rare causes of non-communicating hydrocephalus are obstruction of the foramina of Munro or the aqueduct by strategically located tuberculomas. Other causes for raised ICP include vasogenic brain oedema secondary to infarction and cytotoxic brain swelling associated with infection (tuberculomas or border zone encephalopathy) which may contribute in some cases.7,8 Giant intracranial tuberculomas and tuberculous brain abscesses may cause life-threatening intracranial pressure by mass effect and often associated CSF obstruction.9
THE DIAGNOSIS OF TUBERCULOUS MENINGITIS CLINICAL FEATURES Tandon10 calls TBM the ‘great imposter’ of childhood neurology because it may mimic any neurological disease. It may ‘be acute, subacute or chronic in course, febrile or afebrile in onset, with or
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without evidence of raised intracranial pressure and associated with sudden or progressive neurological deficit.’ TBM may cause any known neurological symptom and sign. The diagnosis of TBM is in the first instance clinical; without suspicion of TB as the cause of the presenting condition no special investigations will be of any avail. The symptoms and signs of early (stage 1) TBM are non-specific and relate more readily to the primary lung infection than to the central nervous system. A subtle change in behaviour, listlessness, apathy and anorexia may be the first signs of approaching disaster; children older than 3 years may complain of headache. Other prominent symptoms at this stage include fever, vomiting, cough and constipation. Overt malnutrition or more subtle failure to gain adequate or static weight, although common in developing communities, should strengthen suspicion of TB. A ‘Road to Health’ card may be very helpful in this respect. A history of close contact with an adult with sputum microscopy smear-positive pulmonary TB provides valuable supporting evidence and approximately 60% of children with TBM will have such a history. As the disease progresses and enters stages 2 and 3, localizing neurological signs and symptoms and signs closely related to underlying brain pathology and degree of parenchymal involvement develop. As a rule the clinical features can be explained by the combined effects of raised ICP and vasculitis with infarction. However, in a minority of patients, cranial computed tomography (CT) demonstrates either hydrocephalus or infarction as the main cause of the clinical features. Neurological symptoms and signs now dominate the clinical picture and include the following.
Meningeal irritation This is often the first neurological sign in TBM and is often associated with irritability and drowsiness. Since most of the patients are too young to complain verbally of headache, the latter will usually present as excessive crying or irritability. Depressed level of consciousness Coma occurs when either the midbrain or the cerebral hemispheres (or both these structures) are dysfunctional.11 Possible pathological correlates of coma in TBM include brain parenchymal infarction secondary to periarteritis (hemispheres and/or brainstem), border zone encephalopathy (brainstem), raised ICP (cerebral hemispheres and brainstem when herniation occurs) and strategically situated tuberculoma (brainstem). Udani et al.12 reported children with TBM who at autopsy showed white matter oedema and perivenous demyelination. This condition was named tuberculous encephalopathy but has never been demonstrated by cranial CT. The degree and course of depressed level of consciousness are best expressed objectively by one of the existing coma scales such as the Glasgow Coma Scale. However, subtle changes in behaviour (drowsiness and irritability) and unresponsiveness or lethargy (decreased visual fixation and following) are early signs of depressed level of consciousness in a young infant which may be easily missed by the more formal assessment tools. The long-standing staging of TBM, used by the British Medical Research Council during the first trials of streptomycin in 1948,13 remains a valuable simple guide to the likely prognosis of TBM (Table 38.1). Raised intracranial pressure The clinical signs of raised ICP in childhood TBM are not unique and have been shown to correlate poorly with monitored ICP and the degree of hydrocephalus as demonstrated by neuroimaging.14
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Table 38.1 Clinical stages of progression of tuberculous meningitis in children Stage of disease
Clinical features
1
Glasgow coma score (GCS) of 15/15 with no focal neurological signs Either GCS of 11–14 or GCS of 15 with focal neurological signs GCS 10
2 3
Adapted from Medical Research Council (1948).13
This can be explained by the fact that parenchymal brainstem damage in TBM may mimic the signs of raised ICP and progression of hydrocephalus usually results in lowering of ICP. An animal model of hydrocephalus demonstrated that acute CSF obstruction usually presents with markedly raised ICP, while chronic hydrocephalus often presents as ‘normal pressure hydrocephalus’. In our experience continuous lumbar ICP monitoring is the most accurate way of measuring ICP in a child with TBM.14 In cases with communicating hydrocephalus, repeated lumbar CSF pressure monitoring is a useful method of assessing the patient’s response to treatment.15 However, although the equipment to undertake continuous pressure monitoring is relatively simple, it is not readily available in regions where TBM is most prevalent. ICP monitoring is best undertaken in association with preceding CT scanning. In practice, the diagnosis of raised ICP in TBM is dependent on the demonstration of hydrocephalus by means of CT or magnetic resonance (MR) imaging, which is usually done as part of the diagnostic work-up on admission. Once the disease has progressed to the second stage (meningism and depressed level of consciousness) the yield of hydrocephalus on neuroimaging is about 70%.16 The degree of hydrocephalus has been shown to be more severe in stage 3 TBM. In addition to the presence and degree of hydrocephalus, neuroimaging will also demonstrate periventricular oedema, a sign of acute, obstructive hydrocephalus and those cases of hydrocephalus caused by a tuberculoma or tuberculous abscess.9 The symptoms and signs of raised ICP in childhood TBM will be determined by the patient’s age and type of onset (acute or chronic). Acutely raised ICP in a young infant with tuberculous hydrocephalus will present with a bulging fontanelle, while sudden onset strabismus (due to nervus abducens paresis) is common in all age groups. Chronically raised ICP in a young infant with TBM often presents with too rapid head growth and widened skull sutures while papilloedema may be present in older patients.17 Cerebrospinal fluid pressure monitoring is useful in determining whether signs of brainstem dysfunction in TBM (e.g. deep coma, decerebration, neurogenic hyperventilation, pupillary abnormalities and absent oculocephalic reflex) are related to raised ICP or other brainstem pathology (microinfarcts and border zone encephalopathy).14
Motor paralyses Motor involvement in advanced TBM is usually the result of ischaemic changes in the basal ganglia and internal capsule on one (hemiparesis) or both (quadriparesis) sides due to occlusion of
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one or more of the perforating branches of the middle cerebral artery.12 Less frequently hemiparesis is the result of a large infarct because of occlusion of the middle cerebral artery itself.16 Other non-ischaemic causes of acute hemiparesis in TBM include Todd’s paresis as a result of a hemi-seizure, a strategically situated tuberculoma and tuberculoma en plaque involving the motor cortex. The last condition is a thick tuberculous exudate covering the cortex and is a form of border zone encephalopathy. However, cranial MR imaging has shown that, because the middle cerebral artery is almost invariably encased by the exudate, the cause of motor dysfunction in tuberculoma en plaque is mostly the result of a combination of infective and ischaemic changes in brain parenchyma. Motor paralysis is very common in advanced (stages 2 and 3) TBM on presentation. Udani et al.12 found hemiparesis in 98 (19.6%) and bilateral hemiplegia (quadriplegia) in 96 (19.2%) out of 500 children with TBM. Dastur and Lalitha7 found hemiparesis in 36 out of 100 children with acute TBM. However, hemiparesis can also develop during the first month of treatment due to the development of new cerebral infarcts.16 The cause of these new infarcts is probably multifactorial and includes progressive periarteritis that occurs in some patients on anti-TB therapy, dehydration due to poor fluid intake or fluid restriction, and a hypercoaguable state (prothrombotic and antifibrinolytic) that has been described in acute TBM.18 Hemiparesis may rarely present late during the course of treatment or even after completion of anti-TB therapy. Possible causes are the development of a tuberculoma, dilatation of one lateral ventricle due to obstruction at the foramen of Munro or vascular constriction and infarction due to organization of the basal exudates.12,18 Mycobacterial drug resistance or bacteriological relapse should always be excluded in these late-onset cases.
Movement disorders Infarction of the basal ganglia is common in TBM. This may result in extrapyramidal movement disorders such as a coarse tremor, chorea and dystonia. Involvement of the subthalamic nuclei causes hemi-ballismus, often opposite to the side of the hemiplegia. DELAYED CLINICAL DIAGNOSIS OF TUBERCULOUS MENINGITIS It has been repeatedly demonstrated that the prognosis of TBM is closely associated with the stage of the disease at the time of diagnosis and treatment commencement. It is thus instructive to review factors associated with delayed diagnosis. A study of TBM in childhood from the Western Cape Province of South Africa described its presentation in 207 children.19 The commonest presenting complaints were fever (62%), vomiting (57%), anorexia (46%) and cough (34%). A mean of 12 days passed between the first complaint and the diagnosis of TBM; in this period 136 children (66%) were seen one or more times at a health facility where gastrointestinal or upper respiratory tract infection was frequently diagnosed. Many children made repeated visits to a health facility before the diagnosis was made. In another similar study it was distressing that in 25% of children with TBM a mean of 5 days passed following admission to a peripheral hospital before the condition was diagnosed.20 Alternative diagnoses included viral meningitis, other forms of bacterial meningitis, encephalitis, tetanus and brain abscess. The need for urgency in the diagnosis of the condition is emphasized by the finding of Lincoln21 that, before the availability of any anti-TB chemotherapy,
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a mean of 20 days elapsed between the onset of symptoms and death.
SPECIAL INVESTIGATIONS A Mantoux test may help confirm TB infection, but may be nonsignificant in 7–70% of cases. A chest radiograph may reveal changes compatible with primary infection in 50–80% of children. In the presence of any degree of meningeal irritability a lumbar puncture should be undertaken and may confirm the presence of meningitis. Should any localizing signs be present it is wiser to start treatment for the most likely causes and to undertake cranial CT imaging before proceeding to a lumbar puncture. Following this, further investigations may support a diagnosis of TBM. Based on considerable experience, Merrit and Fremont-Smith22 described the characteristic changes of CSF in cases of TBM. ‘In most instances’ the fluid was clear, but nearly always faint yellow. On standing, a fine fibrin clot was noted in 43% of specimens; the mean cell count was 265 106/L (range 5–2021) and was > 500 106/L in only 9% of cases, and in only a minority of cases was a polymorphonuclear predominance noted. The mean protein concentration was 2 g/ L (range < 0.45 to > 5 g/L), but with values between 0.45 and 1 g/L in 27% of cases; the glucose concentration was < 2.2 mmol/L in 77% of cases. Many subsequent descriptions have done little to alter this picture. Thus, although there is a set of typical CSF findings in TBM, findings compatible with every other form of meningitis may be found in a significant minority of patients. In particular, in cases with a more acute onset, a higher cell count and a predominance of polymorphonuclear leucocytes may cause considerable confusion and diagnostic doubt. The persistence of CSF changes after the start of treatment for TBM may be of considerable diagnostic help as it is unusual for changes associated with other forms of bacterial meningitis to persist for more that 7–10 days in the face of appropriate treatment, while it would be equally very unusual for the CSF changes of TBM to normalize within 2 weeks. Both the protein concentration and cell count may fluctuate significantly during the first 4 weeks of treatment and in a minority of patients may rise higher than at diagnosis.23 Such changes may be a normal phenomenon and do not necessarily indicate an incorrect diagnosis. By the end of 4 months of treatment between 40% and 50% of children will have normal CSF protein concentrations and more than 90% normal glucose concentrations and cell counts.24 The finding of acid-fast bacilli (AFB) on microscopy of the CSF or the culture of Mycobacterium tuberculosis from the CSF places the diagnosis of TBM beyond doubt, but the frequency with which this is achieved varies considerably. With careful attention to detail and procedure and 10–20 mL of CSF it was possible to find AFB in 91 out of 100 consecutive cases of TBM in children and to culture M. tuberculosis in all 100 cases.25 The success of this investigation in children in many published studies is, however, notoriously low, probably due to the relatively small volume of CSF supplied to the laboratory. During a recent adult study confirmation of the diagnosis was possible in 107 of 132 adults (81%) by either microscopy or culture of the CSF. The authors emphasized the importance of the volume of CSF submitted for examination and the diligence with which microscopy is undertaken.26 A positive Gram’s stain assists in confirming another form of bacterial meningitis, but it should be remembered that, in exceptional cases, M. tuberculosis may appear as Gram-positive.
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NUCLEIC ACID AMPLIFICATION TECHNIQUES Nucleic acid amplification (NAA) techniques have been available for more than a decade. Despite indications that they should be exquisitely sensitive for the detection of small numbers of mycobacteria, this promise remains to be fulfilled. In the case of TBM the sensitivity of a number of ‘in house’ and commercially available tests has varied from 38% to > 90%.27–29 By contrast specificity has nearly always been high. In vitro evaluations have indicated that negative results tended to occur in the face of very low numbers of bacilli in the CSF.30 The advantages of NAA techniques include a very rapid result and the ability to provide a diagnosis up to a month after the start of treatment.28,29 For those countries where TB is a common problem the costs of NAA are not inconsiderable and it is doubtful whether present NAA techniques should take precedence over the diligent application of existing microscopy and culture techniques. A number of other specific and non-specific tests for aiding the differentiation of TBM from other forms of meningitis have been described. These include cerebrospinal fluid adenosine deaminase activity, the detection of various antigens and antibodies or tuberculostearic acid in the CSF and the bromide partition test.30–35 All of these will assist in differentiating TBM from other forms of meningitis, but, unfortunately, in precisely those difficult early cases of meningitis, when the conventional CSF investigations fail, so do many of these investigations. Serum hyponatraemia is found in a significant number of children with TBM. Evidence that this may be a form of the syndrome of inappropriate secretion of anti-diuretic hormone secretion has been provided.36 Care should, however, be exercised before instituting vigorous fluid restriction in these cases as cerebral salt wasting has also been demonstrated in children with TBM and has responded to fludrocortisone.37 In most cases hyponatraemia responds within several days to anti-TB treatment without active intervention. As in other forms of bacterial meningitis a conservative approach, providing normal fluid requirements, is justified in most cases.38
NEUROIMAGING Contrasted cranial CT is invaluable as a diagnostic and prognostic aid in childhood TBM. The main radiological features are hydrocephalus, basal meningovascular enhancement, basal ganglia infarction and tuberculomas. All these features are more common in TBM than in bacterial meningitis, and basal enhancement and tuberculoma are both 89% sensitive and 100% specific for the diagnosis of TBM.39 Recently pre-contrast hyperdensity in the basal cisterns has been suggested as the most specific radiological sign of TBM in children.40 Unfortunately most of the radiological features of TBM, with the exception of tuberculomas, are absent or poorly developed in early-onset disease where the clinical diagnosis is most difficult. Bilateral infarction of the central grey matter carries a poor prognosis.16 Magnetic resonance imaging of the brain is superior to CT in demonstrating pathology of the brainstem and cerebellum in TBM. The extent of ischaemic change, meningovascular enhancement and tuberculomas is also shown better by MR than CT.41
the clinical presentation and CSF findings did not differ between those who were HIV-infected and those who were uninfected, in common with other forms of TB, those who were HIV-infected had a higher mortality and were more likely to have an abnormal chest radiograph than those who were uninfected. The classic signs of obstructive hydrocephalus and basal enhancement were also less common in those who were HIV-infected.
DIFFERENTIAL DIAGNOSIS Because of the difficulty of confirming the diagnosis of TBM the clinician is exposed to two dangers. Firstly the treatment of TBM may be unduly delayed because of uncertainty; secondly, having started anti-TB treatment, the possibility of other diagnoses may be neglected. It should be clear from the description given above that, although there are cases in which the clinician can make the diagnosis of TBM with confidence, supported by history, clinical findings, tuberculin skin testing, chest radiography, CSF findings, CT or MR scanning and other ancillary investigations, there will always be a minority of cases, particularly early cases, in which there will be diagnostic doubt. For the practitioner without immediate access to investigations other than lumbar puncture and chest radiography it is better in cases of doubt to start treatment for the most likely causes of meningitis in the particular patient and then, if stable, to refer the patient to the nearest facility where appropriate investigations can be undertaken. In most cases this will mean starting treatment for both TBM and other forms of bacterial meningitis. Table 38.2 provides a list of alternative diagnoses. The commonest problem is to differentiate viral meningitis and early or partially treated bacterial meningitis. Many of the others might be considered unusual, but may, nonetheless, cause problems in individual patients.
THE MANAGEMENT OF TUBERCULOUS MENINGITIS The management of TBM encompasses three main aspects: the treatment of the tuberculous infection, the control of raised ICP and immunomodulation.
Table 38.2 The differential diagnosis of tuberculous meningitis in children
TUBERCULOUS MENINGITIS AND HUMAN IMMUNODEFICIENCY VIRUS Several groups have now reported their observations related to the occurrence of TBM amongst children with HIV infection.42,43 While
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Other forms of bacterial meningitis: early bacterial meningitis, partially treated bacterial meningitis. Viral meningitis, in particular mumps meningoencephalitis. Spirochaetes: Leptospira, Treponema pallidum, Lyme disease. Rickettsia: tick-bite fever, Rocky Mountain spotted fever, typhus. Protozoa: malaria, Toxoplasma, trypanosomiasis, amoebiasis, acanthamoeba. Fungi: Cryptococcus neoformans, histoplasmosis, Coccidioides imitis. Para-meningeal infections causing a ‘neighbourhood’ syndrome. Helminth infestations: cysticercosis, echinococcosis, Trichinella spiralis. Possible infectious conditions: mucocutaneous lymph node syndrome, sarcoidosis. Non-infectious conditions: malignancies, both those primarily involving the central nervous system and metastases, leukaemia, lymphomata. Autoimmune diseases, especially lupus erythematosis. Heavy metal poisoning and intrathecal injections.
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THE TREATMENT OF TUBERCULOSIS INFECTION The anti-TB treatment of TBM rests on the same principles as the treatment of pulmonary TB, although there are several caveats. It is likely that the population of bacilli in the lesions of TBM is relatively small and under the influence of hypoxia and acidity and thus only intermittently active or dormant. Under these conditions the acknowledged sterilizing agents rifampicin (RMP) and pyrazinamide (PZA) are probably of relatively greater importance. The drugs must also cross the blood–brain barrier in sufficient concentrations to achieve optimal activity. In the case of isoniazid (INH), PZA and ethionamide (ETH) the concentrations reached in the CSF are very close to those in serum.44–47 Rifampicin, by contrast, is highly protein bound and CSF concentrations are approximately 20% of serum concentrations.47 Given that RMP in pulmonary TB is considered to be operating at the lower limit of its efficacy this is cause for concern. Neither ethambutol (EMB) nor streptomycin (SM) and other aminoglycosides have good entry into the CSF and their CSF concentrations are approximately 20% of those in the serum.47 As the healing process proceeds, the blood–brain barrier will also be reconstituted and this will further limit the penetration of agents such as SM, EMB and RMP. In contrast to pulmonary TB there are few randomized controlled clinical trials of the treatment of TBM, although some impression of the efficacy of the various drugs can be gained from the consequences of their introduction into treatment regimens. Before the availability of anti-TB agents TBM was almost universally fatal. With SM alone Lorber48 recorded an overall mortality of 64%, which fell to 27% when para-aminosalicylic acid (PAS) was added, and 17% when INH was introduced. Despite these improvements the prognosis remained dismal for younger children and those unconscious at diagnosis. Of those who were unconscious 74% died, as did 50% of those < 3 years of age compared with 33% of those > 3 years. With the introduction of RMP reports appeared of its use, documenting an improved outcome when it was included in regimens and compared with historical controls. In the relatively few controlled clinical trials undertaken, however, no significant advantage could be shown for the inclusion of RMP, and relapses were reported, even with RMPcontaining regimens.49 Current World Health Organization recommendations for the treatment of TBM are for the standard 2-month INH, RMP and PZA intensive phase accompanied by EMB or SM and a 4-month continuation phase of INH and RMP.50 It is acknowledged in the recommendations that some practitioners may wish to extend the continuation phase to 7 months. Several groups describe using a 6-month standard regimen of 2HRZE or SM/4RH,51–54 while others use a 6-month regimen of HRZETH for the full 6 months or 3HRZE or SM and a continuation phase of 6HRZ.49,55 Perhaps as important as the precise constitution of a regimen for the treatment of TBM is the early commencement of treatment. In all studies prognosis is linked to the stage of the disease at the start of treatment; there is no place for a ‘wait-and-see’ approach in the management of TBM. In case of doubt rather start treatment and reconsider the evidence once the patient has recovered.
38
with TB infection such as cerebral infarction or border zone encephalopathy when the effect of surgery on outcome is assessed.57 We believe that knowledge of the type of hydrocephalus is the key to the rational management of tuberculous hydrocephalus (Figs 38.1 and 38.2). By injecting 5–10 mL of air into the lumbar subarachnoid at the time of lumbar puncture (limited air encephalography) the position of air on a subsequent lateral radiograph of the skull will accurately indicate the level of CSF block. Air demonstrated in the ventricular system is indicative of communicating hydrocephalus (80% of cases) while air which is present only in the basal cisterns (mainly pre-pontine cistern) indicate noncommunicating hydrocephalus (20% of cases).58 Conventional imaging (CT and MR) of the brain will not differentiate between these two types of hydrocephalus since pan-ventricular dilatation is present in both.59 Advanced MR techniques can detect CSF flow from the fourth ventricle but this technology is not freely available where TBM occurs most frequently. The lateral skull radiograph in Fig. 38.1 demonstrates air both at the basal cisterns and in the lateral ventricles (arrows) after limited air encephalography. This finding indicates that the hydrocephalus is communicating due to a basal cistern obstruction to the flow of
Fig. 38.1 Communicating hydrocephalus.
THE MANAGEMENT OF RAISED INTRACRANIAL PRESSURE AND TUBERCULOUS HYDROCEPHALUS The literature regarding the management of tuberculous hydrocephalus is confusing. Although there is general agreement that the hydrocephalus should be treated, modes of therapy (medical or surgical) and the timing of surgery are unclear.56 Most studies do not determine the type of hydrocephalus before shunt surgery is done and do not consider the role of other mechanisms associated
Fig. 38.2 Non-communicating hydrocephalus.
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CSF. In this condition lumbar cerebrospinal pressure equals intraventricular pressure and repeated lumbar punctures and/or diuretics are beneficial in relieving ICP with no danger of cerebral herniation. Medical treatment with furosemide and acetazolamide normalizes ICP in 70% of these cases within the first month of treatment. The lateral skull radiograph in Fig. 38.2 shows air at the level of the basal cisterns (arrow) but no air in the ventricles after limited air encephalography. Non-communicating hydrocephalus is due to obstruction of the fourth ventricular outlet foramina. This type of CSF obstruction often results in sudden onset of coma and brainstem signs due to impending cerebral herniation. Children with this condition need an urgent ventriculoperitoneal shunt or a third ventriculostomy. Cases with communicating hydrocephalus should first be given the option of medical treatment (acetazolamide 50 mg/kg/day and furosemide 1 mg/kg/day in three divided daily doses) for a month. This drug combination reduces CSF production by blocking carbonic anhydrase activity and reduces ICP by decreasing the rate of CSF production. A follow-up CT scan of the brain after 1 month of medical therapy will show that the hydrocephalus has become compensated (reduced ventricular size and resolution of periventricular oedema) in about 70% of cases.15 Excellent correlation has been found between normalization of ICP and resolution of hydrocephalus in this condition (Fig. 38.3).59 Hydrocephalus that does not respond to diuretic therapy within a month should be referred for ventriculoperitoneal shunting (Fig. 38.4). Non-communicating tuberculous hydrocephalus often presents clinically with a rapidly deteriorating level of consciousness or other signs of impending cerebral herniation. These cases need urgent ventriculoperitoneal shunting or endoscopic third ventriculostomy to prevent cerebral herniation and death. Reducing the number of unnecessary shunting procedures in TBM has definite advantages. The complication risk of ventriculoperitoneal shunting in TBM is about 30% and the morbidity of shunt dysfunction due to secondary infection is high.57,58 In addition, patients may become shunt dependent for life with obvious risks for death when shunt dysfunction occurs, especially in a third world environment. The question whether patients with irreversible brain damage due to TBM (e.g. extensive bilateral infarction of the basal ganglia) should be shunted poses an ethical dilemma. Patients with this degree of brain damage may survive after ICP had been normalized by a shunt but will be severely mentally and physically handicapped and often vegetative. Clinical response to temporary external ventricular drainage can give an indication whether these patients will benefit from a permanent shunt.57 Whenever the effect of normalization of ICP (either medically or surgically) on tuberculous hydrocephalus is assessed, the stage of TBM should be taken into account because it is an indication of the degree of underlying parenchymal brain damage and is the best predictor of outcome. Table 38.3 gives the outcome in a large series of TBM patients whose hydrocephalus was normalized by medical treatment (communicating hydrocephalus) or ventriculoperitoneal shunting (non-communicating hydrocephalus) at our institution.16 All the children had stage 2 or 3 TBM. The following conclusions can be reached from this study:
Successful normalization of tuberculous hydrocephalus decreases mortality but the number of handicapped survivors is still significant. This poor outcome in the survivors probably relates to the infection-related brain damage. No significant difference was found in outcome between medically and surgically treated patients.
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Table 38.4 shows outcome according to stage in a series of TBM patients who received ventriculoperitoneal shunts at our institution.
IMMUNE MODULATION Since the introduction of chemotherapy in 1948 corticosteroids have been used as adjunctive therapy in TBM. Despite this long history there is as yet no consensus as to the precise role of corticosteroids in the management of TBM in children. A recent Cochrane review identified six controlled clinical trials describing the use of corticosteroids in TBM.60 After reviewing these trials they stated that ‘Steroids were associated with fewer deaths (relative risk [RR] 0.79; 95% confidence interval [CI] 0.65–0.97)’. The authors were, however, critical of the lack of blinding in these studies and considered that publication bias might have prevented the publication of studies with negative findings. A recent controlled trial enrolled 545 Vietnamese adults with TBM and showed that intention to treat with dexamethasone was strongly associated with a reduced risk of death, but did not prevent severe disability in those who survived.61 Our own experience in a controlled trial has encouraged us to use steroids in the form of prednisone in a dose of 2 mg/kg body weight (maximum dose 60 mg/day) for the first month of treatment of our patients.62 Children receiving steroids had a significantly improved survival and intellectual outcome and improved resolution of basal exudates and tuberculomas was evident on serial CT scanning. The development of new tuberculomas was also significantly less in those children receiving steroid therapy. Steroid therapy, however, had no effect on increased intracranial pressure nor was the incidence of basal ganglia infarction reduced. Thalidomide, which inhibits monocyte production of tumour necrosis factor-alpha (TNF-a), reduced the cytokine concentrations in CSF and meningeal inflammation in experimental TBM.63 However, as an adjunctive in a controlled trial of childhood TBM, thalidomide did not decrease TNF-a levels. Because of serious side-effects, the study was prematurely discontinued and no definite conclusions regarding the role of thalidomide on clinical outcome in TBM could be reached.64 Resolution of tuberculomas seemed to be enhanced by the patients who received thalidomide during this study. We have since reported on four consecutive cases of intractable intracranial tuberculoma, mostly with abscess formation, in whom adjunctive thalidomide possibly enhanced resolution.9
PROGNOSIS IN TUBERCULOUS MENINGITIS A number of studies have found that young age and stage of TBM on admission are poor prognostic indicators. A more recent study found that tonic posturing, focal neurological deficit and papilloedema were additional independent parameters that affect prognosis adversely in childhood TBM.65 Other associated factors that worsen the outcome in childhood TBM are disseminated disease, coinfection with HIV and being infected with a multidrug-resistant organism.43,66,67 We conducted a long-term follow-up study of survivors of TBM treated at our institution.68 The mean age of the 76 children who were followed up was 9 years. Main areas of functional deficit were cognitive impairment (80%), poor scholastic progress (43%) and emotional disturbance (40%). All children were mobile although 25% had evidence of motor impairment. One child was blind but no child had residual sensorineural deafness. This is in stark contrast to previous
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Central nervous system tuberculosis in children
38
80 70
50 40 30
ICP mm Hg
60
20 5 min
A
10 0
Fig. 38.3 Successful medical treatment of hydrocephalus. (A) Continuous lumbar CSF pressure recordings in a child before and after 1 month of medical treatment of hydrocephalus with acetazolamide and furosemide. The initial recording (top) shows a markedly raised baseline CSF pressure as well as a plateau wave and repeated high-amplitude B waves. These findings are indicative of acutely raised ICP. The follow-up recording (bottom) shows normal baseline CSF pressure (< 15 mmHg) and only a few high-pressure B waves at the start of the recording. (B) Cranial computed tomography of the above child prior to treatment. Note the degree of dilatation of the lateral ventricles and periventricular lucency indicative of acute hydrocephalus. (C) Cranial computed tomography 1 month after successful medical treatment. Note the decrease in the size of the lateral ventricles and the absence of periventricular oedema in comparison with the pre-treatment tomogram (B). The subarachnoid space absent on the previous CT scan is now visible. All these findings indicate that the hydrocephalus has become compensated and that medical treatment was successful.
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80 70
50 40 30
ICP mm Hg
60
20 5 min
A
10 0
Fig. 38.4 Unsuccessful medical treatment of hydrocephalus. (A) Continuous lumbar CSF pressure recordings before and after 1 month of medical treatment (furosemide and acetazolamide) of tuberculous hydrocephalus. The initial recording (top) shows a markedly raised baseline CSF pressure and two pressure waves (plateau waves). The mean baseline pressure after 1 month (bottom) is significantly lower than before treatment. However, the baseline pressure > 15 mmHg and the presence of many high-amplitude B waves are both indicative that the hydrocephalus has not become compensated. (B) Cranial computed tomography before medical treatment. (C) Cranial computed tomography after 1 month of treatment with diuretics (acetazolamide and furosemide) shows that the hydrocephalus has deteriorated (ventricles larger and periventricular lucency has increased).
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Table 38.3 Tuberculous hydrocephalus: clinical outcome in 143 children
Medical Surgical Total 143
Normal
Mildly disabled
Severely disabled
Death
17 (15%) 8 (26%) 25 (17%)
50 (45%) 11 (35%) 61 (43%)
32 (28%) 9 (29%) 41 (27%)
13 (12%) 3 (10%) 16 (11%)
Adapted from Schoeman et al. (1995).16
Table 38.4 TBM outcome according to stage of disease Outcome
Stage 2
Stage 3
Total
Good Moderate disability Severe disability Death Total
7 (24%) 17 (57%) 3 (10%) 2 (7%) 29 (45%)
3 (8.3%) 9 (25%) 18 (50%) 6 (16%) 36 (55%)
10 (15%) 26 (40%) 21 (32%) 8 (12%) 65
Adapted from Lamprecht et al. (2001).58
studies which used streptomycin as part of the treatment regimen and found moderate-to-severe hearing loss in up to 21% of survivors.69
TUBERCULOMA
38
Both TB and neurocysticercosis can result in a small single granuloma. This is such a common CT finding in children who present with a first (usually focal) seizure that the term SECCTL (single enhancing cranial CT lesion) has been coined to describe this entity. In the absence of other clinical or laboratory evidence of either TB or cysticercosis, it is often impossible to discern between these aetiologies without histology. One study of histologically proven single granulomas found that tuberculomas tend to be larger (> 20 mm) and have a more irregular outline on CT of the brain than cysticercus granulomas.74 Since most of these solitary granulomas have been shown to resolve spontaneously over a period of time, patients are generally managed conservatively with anti-convulsants (usually carbamazepine) and then re-scanned after a period of 3 months.75 The lesions that disappear during this time interval are usually regarded as granulomas due to cysticercosis while those that do not resolve or enlarge are most likely tuberculomas. The tuberculous origin of multiple or huge intracranial tuberculomas on CT is usually evident when other radiological evidence of TB (pulmonary TB or TBM) is present. However, in many cases of intracranial tuberculoma in whom no other evidence of TB can be found, neuroimaging plays an important role in diagnosis. The characteristic CT appearance of a solid caseous tuberculoma is that of a brain isodense or mildly hyperdense lesion with marked surrounding low density which present vasogenic oedema.76 A hypodense centre is indicative of liquefaction and abscess formation. Marked rim enhancement is always present after contrast administration (Fig. 38.5). The added benefit of MR is
Apart from TBM, TB of the central nervous system can also present as a localized tuberculous lesion or tuberculoma. Intracranial tuberculomas are space-occupying masses of granulomatous tissue that result from haematogenous spread from a distant focus of tuberculous infection, usually the lung. Histologically tuberculomas consist of a necrotic caseous centre surrounded by a capsule that contains fibroblasts, epithelioid cells, Langhans giant cells and lymphocytes.70 Liquefaction of the caseous centre may result in a tuberculous abscess.
CLINICAL PRESENTATION Intracranial tuberculomas may be silent and unsuspected, especially if no clinical evidence of TB is present. Asymptomatic tuberculomas are often an incidental CT finding in children with TBM.71 The first clinical evidence of a previously undiagnosed intracranial tuberculoma is often a seizure in a child who is otherwise completely well. Strategically situated tuberculomas may cause signs of acutely raised ICP due to obstructive hydrocephalus or focal neurological signs.72 Large tuberculomas can mimic a brain tumour with signs of chronically raised ICP and focal neurological signs.
DIAGNOSTIC WORK-UP The symptomatology of intracranial tuberculomas, whether a first focal seizure, focal neurological signs or signs of raised ICP, will usually result in a brain scan (CT or MR) being done. The scan will invariably demonstrate the lesion responsible for the patient’s symptoms, but often also reveals other unsuspected tuberculomas. Childhood tuberculomas may be located in the brain (parenchymal) but often clearly have their origin from the meninges or even ependyma (meningeal).71 Tuberculomas are often adjacent to the dense basal meningovascular enhancement. Childhood intracranial tuberculomas have been shown to develop or increase in size despite anti-TB therapy.73
Fig. 38.5 Cranial computed tomography demonstrating a large tuberculoma in the left cerebral hemisphere. The lesion is isodense and shows irregular rim enhancement with marked surrounding oedema and mass effect.
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mainly the characteristic T2-hypointense appearance (‘T2 black’) of solid, caseous tuberculomas which differentiates them from other solid rim-enhancing lesions such as brain tumours.77
TREATMENT AND PROGNOSIS The mainstay of the treatment of intracranial tuberculomas is anti-TB therapy and corticosteroids. Although no controlled studies have been done to assess the effect of corticosteroids on the resolution of tuberculomas, steroids are generally believed to be beneficial.
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Most tuberculomas will become smaller or even resolve within 3 months of medical treatment although large tuberculomas may take years to heal.78 Acute obstructive hydrocephalus should be treated surgically (usually by ventriculoperitoneal shunting or endoscopic third ventriculostomy) and debulking of huge lesions (by excision or drainage) may be clinically indicated. Tuberculous abscesses are notoriously resistant to medical treatment and should preferably be excised and not only drained. Adjunctive thalidomide may assist the resolution of tuberculous abscesses which are surgically inaccessible.9
20. Donald PR, Schoeman JF, Coton MF, et al. Missed opportunities for the prevention and early diagnosis of tuberculous meningitis in children. S Afr J Epidemiol Infect 1990;5:76–78. 21. Lincoln EM. Tuberculous meningitis in children. With special reference to serous meningitis. Part I. Tuberculous meningitis. Am Rev Tuberc 1947; 56:75–94. 22. Merrit HH, Fremont-Smith F. Cerebrospinal fluid in tuberculous meningitis. Arch Neurol 1935; 33:516–536. 23. Donald PR, Schoeman JF, Cotton MF, et al. Cerebrospinal fluid investigations in tuberculous meningitis. Ann Trop Paediatr 1991;11:241–246. 24. Sumaya CV, Simek M, Smith MHD, et al. Tuberculous meningitis in children during the isoniazid era. J Pediatr 1975;87:43–49. 25. Stewart SM. The bacteriological diagnosis of tuberculous meningitis. J Clin Pathol 1953;6:241–242. 26. Thwaites GE, Cahu TTH, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. Int J Tuberc Lung Dis 2004;42:378–379. 27. Shankar P, Manjunath N, Mohan KK, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991;337:5–7. 28. Donald PR, Victor TC, Jordaan AM, et al. Polymerase chain reaction in the diagnosis of tuberculous meningitis. Scand J Infect Dis 1993;25:613–617. 29. Thwaites GE, Caws M, Chau TTH, et al. Comparison of conventional bacteriology with nucleic acid amplification (Amplified Mycobacterium Direct Test) for diagnosis of tuberculous meningitis before and after inception of antituberculosis chemotherapy. J Clin Microbiol 2004;42:996–1002. 30. Pfyffer GE, Kisling P, Jahn EM, et al. Diagnostic performance of amplified Mycobacterium tuberculosis direct test with cerebrospinal fluid, other nonrespiratory and respiratory specimens. J Clin Microbiol 1996;34:834–841. 31. Corral I, Querada C, Navas E, et al. Adenosine deaminase activity in cerebrospinal fluid of HIVinfected patients: limited value for diagnosis of tuberculous meningitis. Eur J Microbiol Infect Dis 2004;23:471–476. 32. Sada E, Ruiz-Palacios GM. Lopez-Vidal Y, et al. Detection of mycobacterial antigens in cerebrospinal fluid of patients with tuberculous meningitis by enzyme linked immunosorbent assay. Lancet 1983;2:651–652. 33. Krambovitis E, McIllmurray MB, Lock PE, et al. Rapid diagnosis of tuberculous meningitis by latex particle agglutination. Lancet 1984;2: 1229–1231. 34. Chandramuki A, Lyaschenko K, Bahubali H, et al. Detection of antibody to Mycobacterium tuberculosis protein antigen in the cerebrospinal fluid of patients with tuberculous meningitis. J Infect Dis 2002;186: 678–683. 35. Coovadia YM, Dawood A, Ellis ME, et al. Evaluation of adenosine deaminase activity and antibody to Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid and the radioactive bromide partition test for the early diagnosis of tuberculous meningitis. Arch Dis Child 1986;61:428–435. 36. Cotton MF, Donald PR, Schoeman JF, et al. Plasma arginine vasopressin and the syndrome of inappropriate antidiuretic hormone secretion in
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tuberculous meningitis. Pediatr Infect Dis J 1991;10:837–842. Celik US, Alabaz D, Yildizdas D, et al. Cerebral SALT wasting in tuberculous meningitis. Ann Trop Paediatr 2005;25:297–302. Sunit C, Singhi MD, Pratibha D, et al. Fluid restriction does not improve the outcome of acute meningitis. Pediatr Infect Dis J 1995;14:495–503. Kumar R, Kohli N, Thavnani H, et al. Value of CT scan in the diagnosis of meningitis. Indian Pediatr 1996;33:465–468. Andronikou S, Smith B, Hatherhill M, et al. Definitive neuroradiological diagnostic features of tuberculous meningitis in children. Pediatr Radiol 2004;34:876–885. Offenbacher H, Fazekas F, Schmidt R, et al. MRI in tuberculous meningoencephalitis: Report of four cases and review of the neuroimaging literature. J Neurol 1991;238:340–344. Topley JM, Bamber S, Coovadia HM, et al. Tuberculous meningitis and co-infection with HIV. Ann Trop Paediatr 1998;18:261–266. Van der Weert EM, Hartgers NM, Schaaf HS, et al. Comparison of diagnostic criteria of tuberculous meningitis in human immunodeficiency virusinfected and uninfected children. Pediatr Infect Dis J 2006;25:65–69. Donald PR, Gent WL, Seifart HI, et al. Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status. Pediatrics 1992;89:247–250. Donald PR, Seifart HI. Cerebrospinal fluid concentrations of pyrazinamide in children with tuberculous meningitis. Pediatr Infect Dis J 1988;7: 469–471. Donald PR, Seifart HI. Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis. J Pediatr 1989;115:483–486. Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis 1993; 148:650–655. Lorber J. Treatment of tuberculous meningitis. BMJ 1960;1:582–596. Donald PR, Schoeman JF, Van Zyl LE, et al. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998;2:704–711. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. WHO/CDS/TB/ 2003.313. Geneva: World Health Organization, 2003. Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9:794–801. Alarco´n F, Escalante L, Pe´rez Y, et al. Tuberculous meningitis. Short course of chemotherapy. Arch Neurol 1990;47:1313–1317. Erratum: Arch Neurol 1991;48:920. Chotmongkol V. Treatment of tuberculous meningitis with 6-month course of chemotherapy. Southeast Asian J Trop Med Public Health 1991; 22:372–374. Jacobs RF, Sunakorn P, Chotpityasunonah T, et al. Intensive short course chemotherapy for tuberculous meningitis. Pediatr Infect Dis J 1992;11:194–198. Thwaites GE, Chau TTH, Caws M, et al. Isoniazid resistance, mycobacterial genotype and outcome in Vietnamese adults with tuberculous meningitis. Int J Tuberc Lung Dis 2002;6:865–871.
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Central nervous system tuberculosis in children 56. Kumar R. Comment on: Role of shunt surgery in pediatric tubercular meningitis with hydrocephalus. Indian Pediatr 2005;42:735–736. 57. Agrawal D, Gupta A, Mehta VS. Role of shunt surgery in pediatric tubercular meningitis with hydrocephalus. Indian Pediatr 2005;42:245–250. 58. Lamprecht D, Schoeman JF, Donald P, et al. Ventriculo-peritoneal shunting in tuberculous meningitis. Br J Neurosurg 2001;15:119–125. 59. Schoeman JF, Laubscher JA, Donald PR. Serial lumbar CSF pressure measurements and cranial computed tomographic findings in childhood tuberculous meningitis. Child’s Nerv Syst 2000;16:203–209. 60. Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous meningitis (Cochrane Review). In: The Cochrane Library, Issue 3. Chichester: Wiley, 2004. 61. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741–1751. 62. Schoeman JF, Van Zyl LE, Laubscher JA, et al. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226–231. 63. Tsenova L, Sokol K, Freedman VH, et al. A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death. J Infect Dis 1998;177:1563–1572.
64. Schoeman JF, Springer P, Janse van Rensburg A, et al. Adjunctive thalidomide therapy of childhood tuberculous meningitis; results of a randomized study. J Child Neurol 2004;19:911–913. 65. Mahadevan B, Mahadevan S, Tiroumourougane Serane V. Prognostic factors in childhood tuberculous meningitis. J Trop Pediatr 2002; 48:362–365. 66. Van den Bos F, Terken M, Ypma L, et al. Tuberculous meingitis and miliary tuberculosis in young children. Trop Med Int Health 2004;9:309–313. 67. Padayatchi N, Bamber S, Dawood H, et al. Multidrug-resistant tuberculous meningitis in children in Durban, South Africa. Pediatr Infect Dis J 2006;25:147–150. 68. Schoeman JF, Wait J, Burger M, et al. Long-term follow up of childhood tuberculous meningitis. Dev Med Child Neurol 2002;44:522–526. 69. Wasz-Ho¨ckert O, Donner M. Late prognosis in tuberculous meningitis. Acta Paediatr 1964;51(Suppl 141):5–119. 70. Kim TK, Chang KH, Kim CJ, et al. Intracranial tuberculoma: comparison of MR with pathological findings. J Neuroradiol 1995;16:1903–1908. 71. Ravenscroft A, Schoeman JF, Donald PR. Tuberculous granulomas in childhood tuberculous meningitis: radiological features and course. J Trop Pediatr 2001;47:5–12.
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72. Dastur DK, Lalitha VS, Udani PM, et al. The brain and meningitis-gross pathology in 100 cases and pathogenesis. Neurol India 1970;18:86–100. 73. Afghani B, Lieberman JM. Paradoxical enlargement or development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 1994;19:1092–1099. 74. Rajshekhar V, Haran RP, Prakash GS, et al. Differentiating solitary small cysticercus granulomas and tuberculomas in patients with epilepsy. Clinical and computerized tomographic criteria. J Neurosurg 1993;78;402–407. 75. Thussu A, Arora A, Prabhakar S, et al. Acute symptomatic seizures due to single CT lesions: How long to treat with antiepileptic drugs? Neurol India 2002;50:141–144. 76. de Castro CC, de Barros NG, de Sousa Campos ZM, et al. CT scans of cranial tuberculosis. Radiol Clin North Am 1995;33:753–769. 77. Wasay M, Kheleani BA, Moolani MK, et al. Brain CT and MRI findings in 100 consecutive patients with intracranial tuberculoma. J Neuroimaging 2003;13:240–247. 78. Poonnoose SI, Rajshekhar V. Rate of resolution of histologically verified intracranial tuberculomas. Neurosurgery 2003;53:873–878.
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Abdominal (gastrointestinal tract) tuberculosis in adults Mahesh P Sharma and Vineet Ahuja
INTRODUCTION Extrapulmonary TB accounts for about 10–12% of the total number of cases of TB, and 11–16% of these cases involve the abdomen.1–3 Tuberculosis of the gastrointestinal tract is the sixth most frequent extrapulmonary site, after lymphatic, genitourinary, bone and joint, miliary and meningeal TB.4 Tuberculosis can involve any part of the gastrointestinal tract from the mouth to the anus, the peritoneum and the pancreatobiliary system. It can have a varied presentation, frequently mimicking other common and rare diseases.5 In particular, in developing countries, the clinician must look for TB, and confirm or exclude this treatable malady in any patient who presents with gastrointestinal disease.
EPIDEMIOLOGY Overall resurgence of TB has also accounted for the recent rise in incidence of abdominal TB in developed countries. In 2000 there were an estimated 8.3 million new TB patients globally and it was observed that newly diagnosed cases increased at a rate of 1.8% per year between 1997 and 2000.6,7 This resurgence is, in part, due to the pandemic of human immunodeficiency virus (HIV). A study conducted in Bradford, UK, found that the mean standardized incidence of abdominal TB in the South Asian population during the study period was 9.32 cases/100,000/year, whereas in the local white population it was 0.1/100,000/year (relative risk 93).3 In another study conducted amongst Bangladeshi patients in East London, it was observed that the incidence of inflammatory bowel disease had increased and that of abdominal TB had fallen over the past decade. The standardized incidence of abdominal TB was 2.5/ 100,000/year (95% confidence interval (CI) 0.2–4.8) in 1997– 2001, and 7.4 (95% CI 2.1–12.7) in 1985–1989 ( p < 0.05). The standardized ratio for the incidence of TB in the two periods was 0.22 (95% CI 0.07–0.53).8 Autopsies conducted on patients with pulmonary TB before the era of effective antituberculosis drugs revealed intestinal involvement in 55–90% cases, with the frequency related to the extent of pulmonary involvement. Pimparkar9 found evidence of abdominal TB (bowel, peritoneum and liver) in 3.72% of 11,746 autopsies carried out at the KEM Hospital, Mumbai, between 1964 and 1970. Both the incidence and the severity of abdominal TB are expected to increase with increasing incidence of HIV infection. In a study from Mumbai, India, HIV infection was found in 16.6% in patients with abdominal TB as
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compared with 1.4% in voluntary blood donors.10 Extrapulmonary forms of TB, which account for 10–15% of all cases, may represent up to 50% of patients with acquired immunodeficiency syndrome (AIDS).
PATHOGENESIS The postulated mechanisms by which the tubercle bacilli reach the gastrointestinal tract are: 1. haematogenous spread from the primary lung focus in childhood, with later reactivation; 2. ingestion of bacilli in sputum from active pulmonary focus; 3. direct spread from adjacent organs; and 4. through lymph channels from infected nodes. The most common site of involvement is the ileocaecal region, possibly because of the increased physiological stasis, increased rate of fluid and electrolyte absorption, minimal digestive activity and an abundance of lymphoid tissue at this site. It has been shown that the M cells associated with Peyer’s patches can phagocytose tubercle bacilli.
TYPE AND SITE OF INVOLVEMENT Abdominal TB may present as intestinal, peritoneal or lymph nodal TB, either as independent involvement of these sites or involving two or all three sites. The most common type is intestinal TB, which may account for 50–78% of abdominal TB cases.11,12 In one study, jejunoileal and ileocaecal involvement was present in more than 75% of all gastrointestinal TB.6 The next, most common type of abdominal TB is peritoneal with involvement of around 43% of cases.13 Hoon et al.14 originally classified the gross morphological appearance of the involved bowel into ulcerative, ulcerohyperplastic and hyperplastic varieties. Tandon and Prakash15 described the bowel lesions as ulcerative and ulcerohypertrophic types. The ulcerative form has been found more often in malnourished adults, while the hypertrophic form is classically found in relatively wellnourished adults. The bowel wall is thickened and the serosal surface is studded with nodules of variable size. These ulcerative and stricturous lesions are usually seen in the small intestine. Colonic and ileocaecal lesions are ulcerohypertrophic. The patient often presents with a right iliac fossa lump constituted by the ileocaecal region, mesenteric fat and lymph nodes. The ileocaecal angle is
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Abdominal (gastrointestinal tract) tuberculosis in adults
distorted and often obtuse. In tuberculous peritonitis, the peritoneum is studded with multiple yellow–white tubercles. It is thick and hyperaemic with a loss of its shiny luster. The omentum is also thickened. Peritoneal TB occurs in three forms: 1. wet type with ascites; 2. encysted (loculated) type with a localized abdominal swelling; and 3. fibrotic type with abdominal masses composed of mesenteric and omental thickening, with matted bowel loops felt as lump(s) in the abdomen. A combination of these types is also common. Peritoneal involvement may occur from spread from lymph nodes, intestinal lesions or tuberculous salpingitis in women. Abdominal lymph nodal and peritoneal TB may occur without gastrointestinal involvement in about one-third of the cases. In Bhansali’s series,16 including 196 patients with gastrointestinal TB, ileum was involved in 102 and caecum in 100 patients. Of the 300 patients in a study ileocaecal involvement was present in 162. The frequency of bowel involvement declines as one proceeds both proximally and distally from the ileocaecal region.17
39
ulcerated lesion or gastric outlet obstruction. Rarer presentations include massive gastrointestinal bleed, gastric perforation and linitis plastica.21,22 Gastroduodenal TB may mimic peptic ulcer disease with a shorter duration of history and non-response to antisecretory therapy. Hence, in patients presenting with gastric outlet obstruction the possibility of gastric TB should be kept in mind, especially in areas endemic for TB.23 Duodenal TB is increasingly being recognized and is often isolated with no associated pulmonary lesions in more than 80% of cases.24,25 The largest published series of duodenal TB reported 30 cases from India.26 Most patients (73%) had symptoms of duodenal obstruction. In a majority of these cases obstruction was due to extrinsic compression by tuberculous lymph nodes, rather than by intrinsic duodenal lesion. The remainder (27%) had a history of dyspepsia and were suspected of having duodenal ulcers. Two of these patients presented with haematemesis. Other complications reported by various authors are perforation, fistulae (pyeloduodenal, duodenocutaneous, blind), excavating ulcers extending into the pancreas and obstructive jaundice by compression of the common bile duct.27,28
ILEOCAECAL TUBERCULOSIS
SYMPTOMS AND SIGNS: USUAL/UNUSUAL PRESENTATIONS Abdominal TB is predominantly a disease of young adults. Twothirds of the patients are 21–40 years old and the sex incidence is equal, although some Indian studies have suggested a slight female predominance. The spectrum of disease in children is different from that in adults, in whom adhesive peritoneal and lymph nodal involvement is more common than gastrointestinal disease. The clinical presentation of abdominal TB can be acute, chronic or acute on chronic. Most patients have constitutional symptoms of fever (40–70%), pain (80–95%), diarrhoea (11–20%), constipation, alternating constipation and diarrhoea, weight loss (40–90%), anorexia and malaise. Pain can be either colicky due to luminal compromise or dull and continuous when the mesenteric lymph nodes are involved. Other clinical features depend upon the site, nature and extent of involvement and are detailed below.
TUBERCULOSIS OF THE OESOPHAGUS Oesophageal TB is a rare entity, constituting only 0.2% of cases of abdominal TB. Until 1997 only 58 cases had been reported in the English literature.18 Oesophageal TB can be either primary or secondary, the former being less common than the latter. Oesophageal involvement occurs mainly by extension of disease from adjacent lymph nodes. The patient usually presents with low-grade fever, dysphagia, odynophagia and an ulcer, most commonly midoesophageal. The disease usually mimics oesophageal carcinoma and extraoesophageal focus of TB may not be evident.19 Cases of oesophageal TB mimicking carcinoma of the oesophagus have been reported and create considerable diagnostic difficulty.20
GASTRODUODENAL TUBERCULOSIS Tuberculosis of the stomach is not common. This is attributed to the bactericidal property of gastric acid, and intact gastric mucosa. Stomach and duodenal TB each constitute around 1% of cases of abdominal TB. Gastric TB is rare and usually presents as an
Ileocaecal TB is the commonest presentation of abdominal TB. The ileocaceal region was involved in 86% of patients in a study from Hong Kong,29 and in 40% of cases of abdominal TB in the UK.3 Concomitant active pulmonary TB was present in 18–36% of the cases.3,29 In a large series of 348 cases of intestinal obstruction, Bhansali and Sethna30 found TB to be responsible for 54 (15.5%) cases; 33 cases were of small bowel and 21 were of large bowel obstruction. Tuberculosis accounts for 5–9% of all small intestinal perforations in India, and is the second commonest cause after typhoid fever.31 Patients complain of colicky abdominal pain, borborygmi and vomiting.31,32 Abdominal examination may reveal no abnormality or a doughy feel. A well-defined, firm, usually mobile mass is often palpable in the right lower quadrant of the abdomen. Associated lymphadenitis is responsible for the presence of one or more lumps, which are mobile if mesenteric nodes are involved and fixed if the paraaortic or iliac group of nodes are enlarged. The most common complication of small bowel or ileocaecal TB is obstruction due to narrowing of the lumen by hyperplastic caecal TB, by strictures of the small intestine, which are commonly multiple, or by adhesions. Adjacent lymph nodal involvement can lead to traction, narrowing and fixity of bowel loops. Tuberculous perforations are usually single and proximal to a stricture. Malabsorption is a common complication. In a patient with malabsorption, a history of abdominal pain suggests the diagnosis of TB.33 Pimparkar and Donde34 studied 40 patients with intestinal TB and malabsorption and divided them into those with and those without bowel stricture. They performed glucose and lactose tolerance tests, D-xylose test, faecal fat, and Schilling’s test for vitamin B12 malabsorption and found them to be abnormal in 28%, 22%, 57%, 60%, and 63%, respectively, in patients with stricture compared with 0%, 0%, 8%, 25%, and 30%, respectively, in those without strictures. Tandon et al.35 also reported biochemical evidence of malabsorption in 75% of patients with intestinal obstruction and in 40% of those without it. The cause of malabsorption in intestinal TB is postulated to be bacterial overgrowth in a stagnant loop, bile salt deconjugation, diminished absorptive surface due to ulceration, and involvement of lymphatics and lymph nodes.
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SEGMENTAL COLONIC TUBERCULOSIS Segmental or isolated colonic TB refers to involvement of the colon without the ileocaecal region, and constitutes 9.2% of all cases of abdominal TB. It commonly involves the sigmoid, ascending and transverse colon.36 Multifocal involvement is seen in onethird (28–44%) of patients with colonic TB.37 The median duration of symptoms at presentation is less than 1 year. Pain is the predominant symptom in 78–90% of patients and haematochezia occurs in less than one-third. The bleeding is frequently minor and massive bleeding is less common. Singh et al.38 reported rectal bleeding in 31% of patients with colonic TB, and massive bleeding in 13%. Bhargava et al.39 reported bleeding in 70% of cases. Other manifestations of colonic TB include fever, anorexia, weight loss and change in bowel habits. Cases of colonic TB presenting like chronic ulcerative colitis have also been reported.40,41 In addition, a rare presentation of colonic TB where colonoscopy revealed only aphthous ulceration of the colonic mucosa has been reported.42 Colonic TB may also mimic tumour perforation.43
RECTAL AND ANAL TUBERCULOSIS Clinical presentation of rectal TB is different from more proximal disease. Haematochezia is the most common symptom (88%), followed by constitutional symptoms (75%) and constipation (37%).44 The high frequency of rectal bleeding may be because of mucosal trauma caused by scybalous stool traversing the strictured segment. Digital examination reveals an annular stricture. The stricture is usually tight and of variable length with focal areas of deep ulceration. It is usually within 10 cm of the anal verge. Associated perianal disease is very rare. Excessive fibrosis associated with the rectal inflammation results in an increase in presacral space. Overall rectal TB is rare and may occur in the absence of other lesions in the chest and small and large bowel.45 Rectal TB may also present as a rectal submucosal growth.46 Anal TB is less uncommon and has a distinct clinical presentation. Ano-perianal TB may be associated with abdominal TB either as an extension of the original lesion or due to its spread via the lymphatics. They may present as pilonidal sinus, anal ulceration with inguinal adenopathy, recurrent perianal growth, anal fissure, anal fistulae and anal strictures.47–49 Tuberculous fistulae are usually multiple. Dandapat et al.50 reported that 12 out of 15 multiple fistulae were of tuberculous origin, as compared with only four out of 61 solitary perianal fistulae. Shukla et al.51 reported that, in India, TB accounted for up to 14% of cases of fistula in ano. Anal discharge was present in all cases and perianal swelling in one-third. Constitutional symptoms were not present in any patient. It is important to differentiate Crohn’s disease from perianal TB, and other conditions that should be considered are herpes simplex, syphilis, sarcoidosis, amoebiasis, deep mycosis and lymphogranuloma venereum.
HEPATOBILIARY AND PANCREATIC TUBERCULOSIS The primary site of TB is usually not evident in most cases of hepatobiliary and pancreatic TB. Hepatic TB can occur in miliary, nodular and solitary abscess form.52,53 Series from the Philippines and China showed that patients with hepatic TB presented with fever, abdominal pain and hepatomegaly, and patients in both series had similar complaints.54,55 Gallbladder TB may present with features of cholecystitis, a gallbladder mass or obstructive jaundice due to
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associated enlarged pericholedochal lymph nodes.56 Pancreatic TB can have various clinical presentations such as acute pancreatitis, portal vein thrombosis and obstructive jaundice with pancreatic mass mimicking malignancy.57 The common presenting complaints as seen in a large series of patients are abdominal pain (66%) followed by fever/night sweats (52%), anorexia/weight loss (46%), malaise/ weakness (28%), back pain (20%) and jaundice (15%).58
DIAGNOSIS AND INVESTIGATIONS Paustian4 in 1964 stated that one or more of the following four criteria must be fulfilled to diagnose abdominal TB: 1. histological evidence of tubercles with caseation necrosis; 2. a good typical gross description of operative findings with biopsy of mesenteric nodes showing histological evidence of TB; 3. animal inoculation or culture of suspected tissue resulting in growth of Mycobacterium tuberculosis; and 4. histological demonstration of acid-fast bacilli in a lesion. These criteria must be kept in mind, and the diagnosis substantiated by adequate radiological and histopathological studies. Non-specific findings include raised erythrocyte sedimentation rate, anaemia and hypoalbuminaemia.
RADIOLOGICAL STUDIES Chest radiograph Evidence of TB in a chest radiograph supports the diagnosis but a normal chest radiograph does not rule it out. Kapoor et al.59 studied 70 cases of abdominal TB and found evidence of active or healed lesions on chest radiograph in 32 (46%). Radiographs were more likely to be positive in patients with acute complications (80%). In Prakash’s series60 of 300 patients, none had active pulmonary TB but 39% had evidence of healed TB. Tandon et al.61 found chest radiograph to be positive in only 25% of their patients. Hence, about 75% of cases do not have evidence of concomitant pulmonary disease. Plain radiograph of the abdomen Plain radiograph of the abdomen may show enteroliths, features of obstruction, i.e. dilated bowel loops with multiple air fluid levels, evidence of ascites, perforation or intussusception. In addition, there may be calcified lymph nodes, calcified granulomas and hepatosplenomegaly. Small bowel barium meal The features which may be seen include accelerated intestinal transit; hypersegmentation of the barium column (‘chicken intestine’), precipitation, flocculation and dilution of the barium; stiffened and thickened folds; luminal stenosis with smooth but stiff contours (‘hour glass stenosis’); possibly multiple strictures with segmental dilatation of bowel loops; and fixity and matting of bowel loops. Barium enema The following features may be seen: 1. Early involvement of the ileocaecal region manifesting as spasm and oedema of the ileocaecal valve. Thickening of the lips of the ileocaecal valve and/or wide gaping of the valve with narrowing of the terminal ileum (‘Fleischner’ or ‘inverted umbrella sign’) are characteristic. 2. Fold thickening and contour irregularity of the terminal ileum, better appreciated on double-contrast study.
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3. ‘Conical caecum’, shrunken in size and pulled out of the iliac fossa due to contraction and fibrosis of the mesocolon. The hepatic flexure may also be pulled down. 4. Loss of normal ileocaecal angle and dilated terminal ileum, appearing suspended from a retracted, fibrosed caecum (‘goose neck deformity’). 5. ‘Purse string stenosis’, a localized stenosis opposite the ileocaecal valve with a rounded-off smooth caecum and a dilated terminal ileum. 6. ‘Stierlin’s sign’, a manifestation of acute inflammation superimposed on a chronically involved segment and characterized by lack of barium retention in the inflamed segments of the ileum, caecum and variable lengths of the ascending colon, with a normal configured column of barium on either side. It appears as a narrowing of the terminal ileum with rapid empyting into a shortened, rigid or obliterated caecum. 7. ‘String sign’, a persistent narrow stream of barium indicating stenosis. Both Stierlin and String signs can also be seen in Crohn’s disease and hence are not specific for TB. Before the introduction of newer imaging modalities described later, enteroclysis followed by a barium enema was considered the best protocol for evaluation of intestinal TB.
ULTRASONOGRAPHY Barium studies, though accurate for intrinsic bowel abnormalities, do not detect lesions in the peritoneum. Ultrasound is very useful for imaging peritoneal TB. The following features may be seen, usually in combination.62 1. Intra-abdominal fluid which may be free or loculated, and clear or complex (with debris and septae). Fluid collections in the pelvis may have thick septa and can mimic ovarian cyst. 2. ‘Club sandwich’ or ‘sliced bread’ sign due to localized fluid between radially oriented bowel loops, due to local exudation from the inflamed bowel (interloop ascites). 3. Lymphadenopathy, possibly discrete or conglomerated (matted). The echotexture is mixed heterogeneous, in contrast to the homogeneously hypoechoic nodes of lymphoma. Small discrete anechoic areas representing zones of caseation may be seen within the nodes. With treatment the nodes show a transient increase in size for 3–4 weeks and then gradually reduce in size. Calcification in healing lesions is seen as discrete reflective lines. Both caseation and calcification are highly suggestive of a tuberculous aetiology, neither being common in malignancy-related lymphadenopathy. 4. Bowel wall thickening, best appreciated in the ileocaecal region. The thickening is uniform and concentric as opposed to the eccentric thickening at the mesenteric border found in Crohn’s disease and the variegated appearance of malignancy. 5. Pseudokidney sign, involvement of the ileocaecal region which is pulled up to a subhepatic position.
COMPUTED TOMOGRAPHIC (CT) SCAN Ileocaecal TB is usually hyperplastic and well evaluated on CT scan.63 In early disease there is slight symmetric circumferential thickening of caecum and terminal ileum. Later the ileocaecal valve and adjacent medial wall of the caecum is asymmetrically thickened. In more advanced disease gross wall thickening, adherent
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loops, large regional nodes and mesenteric thickening can together form a soft-tissue mass centred around the ileocaecal junction.63 CT scan can also pick up ulceration or nodularity within the terminal ileum, along with narrowing and proximal dilatation. Other areas of small and large bowel involvement manifest as circumferential wall thickening, narrowing of the lumen and ulceration. In the colon, involvement around the hepatic flexure is common. Complications of perforation, abscess and obstruction are also seen. Tuberculous ascitic fluid is of high attenuation value (25–45 HU) due to its high protein content. Strands, fine septae and debris within the fluid are characteristic, but are better appreciated on ultrasonography. Thickened peritoneum and enhancing peritoneal nodules may be seen. Mesenteric disease on CT scan is seen as a patchy or diffuse increase in density, strands within the mesentery and a stellate appearance. Lymph nodes may be interspersed. Omental thickening is well seen often as an omental cake appearance. A fibrous wall can cover the omentum, developing from long-standing inflammation and is called an omental line. An omental line is less common in malignant infiltration.64 Caseating lymph nodes are seen as having hypodense centres and peripheral rim enhancement. Along with calcification, these findings are highly suggestive of TB. In TB the mesenteric, mesenteric root, coeliac, porta hepatis and peripancreatic nodes are characteristically involved, reflecting the lymphatic drainage of the small bowel. The retroperitoneal nodes (i.e. the periaortic and pericaval) are relatively spared, and are almost never seen in isolation, unlike lymphoma.
COLONOSCOPY Colonoscopy is an excellent tool for diagnosing colonic and terminal ileal involvement. Mucosal nodules of variable sizes (2–6 mm) and ulcers in a discrete segment of colon, 4–8 cm in length, are pathognomonic. The nodules have a pink surface with no friability and are most often found in the caecum especially near the ileocaecal valve. Large (10–20 mm) or small (3–5 mm) ulcers are commonly located between the nodules. The intervening mucosa may be hyperaemic or normal. Areas of strictures with nodular and ulcerated mucosa may be seen. Other findings are pseudopolypoid oedematous folds, and a deformed and oedematous ileocaecal valve. Diffuse involvement of the entire colon is rare (4%), but endoscopically can look very similar to ulcerative colitis. Lesions mimicking carcinoma have also been described.37,38,44,65 The frequency of strictures in 130 patients with colonic TB was studied. Of these 22 (17%) had impassable colonic strictures.66 In another study from India including 53 patients with colonic TB it was seen that the terminal ileum was involved in only 11 patients.67 Eight of these patients had involvement of the caecum in addition. A study from Japan classified mucosal lesions as seen in patients with colonic TB into four types: type 1, circumferential ulceration with nodules; type 2, round or irregularly shaped small ulcers, arranged circumferentially, without nodules; type 3, multiple erosions restricted to the large intestine; and type 4, small ulcers or erosions restricted to the ileum.68 The gross endoscopic appearance of healed lesions included patulous ileocaecal valve, pseudodiverticular deformity and atrophic mucosal areas with aggregated ulcer scars. The frequency of type 1, 2, 3 and 4 endoscopic findings was, respectively, 36%, 36%, 9% and 18%. The frequencies for patulous ileocaecal valve, pseudodiverticular deformity and atrophic mucosal area were, respectively, 45%, 45% and 91%. Most workers take up to 8–10 colonoscopic biopsies for histopathology and culture. Biopsies should be
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taken from the edge of the ulcers. However, there is a low yield on histopathology because of predominant submucosal involvement. Granulomas have been reported in 8–48% of patients and caseation in a third (33–38%) of positive cases. The yield of acid-fast bacilli stains has been variable in studies. Culture positivity is not related to the presence of granulomas. Bhargava et al.37 reported positive cultures in 40% of patients and concluded that routine culture of biopsy tissue increases the diagnostic yield. A combination of histology and culture of the biopsy material can be expected to establish the diagnosis in over 60% of cases.
LAPAROSCOPIC FINDINGS Bhargava et al.76 studied 87 patients with high protein ascites, of whom 38 were diagnosed as having TB. They found visual appearances to be more helpful (95% accurate) than histology, culture or guinea pig innoculation (82%, 3% and 37.5% sensitivity, respectively). Caseating granulomas may be found in 85–90% of the biopsies. The laparoscopic findings in peritoneal TB can be grouped into three categories: 1. Thickened peritoneum with tubercles: multiple, yellowishwhite, uniform-sized (about 4–5 mm) tubercles diffusely distributed on the parietal peritoneum. The peritoneum is thickened, is hyperaemic and lacks its usual shiny lustre. The omentum, liver and spleen can also be studded with tubercles. 2. Thickened peritoneum without tubercles. 3. Fibro-adhesive peritonitis with markedly thickened peritoneum and multiple thick adhesions fixing the viscera.
IMMUNOLOGICAL TESTS Bhargava et al.69 used a competitive enzyme-linked immunosorbent assay (ELISA) with monoclonal antibody against 38-kDa protein and found a sensitivity of 81%, specificity of 88% and diagnostic accuracy of 84%. However, ELISA remains positive even after therapy, the response to mycobacteria is variable and its reproducibility is poor. Hence the value of immunological tests remains undefined in clinical practice.
POLYMERASE CHAIN REACTION (PCR) PCR has been evaluated for the identification of M. tuberculosis in abdominal TB, amplifying a 340-bp nucleotide sequence located within the 38-kDa protein gene of M. tuberculosis.70 The diagnostic accuracy of PCR as a single test remains questionable. The utility of PCR in the diagnosis of intestinal TB for tiny endoscopic biopsy specimens may lie especially in the cases where histopathology is inconclusive.71
ASCITIC FLUID EXAMINATION The ascitic fluid in TB is straw-coloured with protein > 3 g/dL, and total cell count of 150–4000/mL, consisting predominantly of lymphocytes (> 70%). The ascites-to-blood glucose ratio is less than 0.96 and the serum–ascites albumin gradient is less than 1.1 g/dL. The yield of organisms on smear and culture is low. Staining for acid-fast bacilli is positive in less than 3% of cases. A positive culture is obtained in less than 20% of cases, and it takes 6–8 weeks for the mycobacterial colonies to appear. However, Singh et al.72 in an earlier study cultured 1 L of ascitic fluid after centrifugation and obtained 83% culture positivity. Adenosine deaminase (ADA) is an aminohydrolase that converts adenosine to inosine and is thus involved in the catabolism of purine bases. The enzyme activity is more in T-than in B-lymphocytes, and is proportional to the degree of T-cell differentiation. ADA is increased in tuberculous ascitic fluid due to the stimulation of T cells by mycobacterial antigens. ADA levels were determined in the ascitic fluid of 49 patients by Dwivedi et al.73 The levels in tuberculous ascites were significantly higher than those in cirrhotic or malignant ascites. Taking a cut-off level of 33 U/L, the sensitivity, specificity and diagnostic accuracy were 100%, 97% and 98%, respectively.51 In the study by Bhargava et al.,74 a serum ADA level above 54 U/L, ascitic fluid ADA level above 36 U/L and an ascitic fluid-to-serum ADA ratio > 0.985 were found to be suggestive of TB. In coinfection with HIV the ADA values can be normal or low. False high values can occur in malignant ascites. High interferon-g levels in tuberculous ascites have been reported to be useful diagnostically.75 Combining both ADA and interferon estimations may further increase sensitivity and specificity.
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DOUBLE-BALLOON ENTEROSCOPY The two most common causes of ulceroconstrictive diseases of the small intestine are intestinal TB and Crohn’s disease. However, diagnosis is often delayed because of the difficulty in examining the small bowel. Until recently there was no modality available to directly visualize small bowel and take targeted biopsies; hence, diagnosis of small bowel diseases was challenging. Conventional push enteroscopy is a popular method but the entire small bowel is not accessible. The novel video capsule endoscopy system has the potential to view the entire gastrointestinal tract. Capsule endoscopy was reported to be superior to push enteroscopy and small bowel radiograph for the evaluation of small bowel diseases. However, capsule endoscopy is contraindicated when strictures are suspected in the gastrointestinal tract. The new method of enteroscopy, namely double-balloon enteroscopy (DBE), is a useful procedure which enables visualization of the entire small intestine while preventing overstretching of the intestinal tract (Box 39.1).77 This method could be used in an antegrade or retrograde route, and any part of the small intestine can be accessed. Moreover, to-and-fro observation of an affected area with controlled movement of the endoscope with an accessory channel enables interventions such as biopsies and dilatations. Thus, this new method has the potential to contribute to the diagnosis and treatment of the diseases in the small intestine where endoscopic approach has been difficult so far.
MAGNETIC RESONANCE ENTEROCLYSIS Magnetic resonance enteroclysis (MRE) imaging is emerging as a technique of choice for evaluation of the small bowel.78 Administration of 1.5–2 L of isosmotic water solution through a nasojejunal
Box 39.1 Recent advances in the subject
Role of double-balloon enteroscopy in visualizing small intestinal lesions and taking targeted biopsies has improved. Magnetic resonance enteroclysis is emerging as the technique to visualize small bowel. Endoscopic ultrasound-guided fine needle aspiration helps in differentiating inflammatory and malignant lesions of pancreas.
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catheter ensures distension of the bowel and facilitates identification of wall abnormalities. Though superficial abnormalities ideally delineated with conventional enteroclysis are not consistently depicted with MRE, the characteristic transmural abnormalities of Crohn’s disease such as bowel wall thickening, linear ulcers and cobblestoning are better shown with MRE imaging, especially with the true fast imaging with steady-state precession (true-FISP) sequence. MRE is comparable to conventional enteroclysis in the detection of the number and extent of involved small bowel segments and in the disclosure of luminal narrowing or prestenotic intestinal dilatation (Fig. 39.1).
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ENDOSCOPIC ULTRASOUND-GUIDED FINE NEEDLE ASPIRATION (EUS-FNA) EUS has been shown to have a high sensitivity for detecting pancreatic masses. It must be coupled with a guided FNA to distinguish TB from a mitotic lesion. Pancreatic EUS-guided FNA allows for an accurate and safe diagnosis without the risk, cost and time expenditure of an open biopsy or laparotomy (Fig. 39.2). EUS-FNA has a relatively high sensitivity (64–98%), specificity (80–100%) and positive predictive value (98.4–100%) in diagnosing pancreatic TB.79,80 Volmar et al.81 have shown in a logistic regression analysis that, for lesions < 3 cm, the EUS-guided FNA method has a higher diagnostic accuracy than ultrasound- or CT-guided FNA.
DIFFERENTIATING INTESTINAL TUBERCULOSIS FROM CROHN’S DISEASE
Fig. 39.1 Magnetic resonance enteroclysis of small intestine showing strictures in a patient with intestinal TB.
Intestinal TB is often difficult to distinguish from Crohn’s disease particularly in areas where both coexist. This is because both conditions have overlapping clinical, radiological, endoscopic and histological characteristics (Box 39.2).82 Both diseases can involve focal sites from the mouth to the anus. Clinical features such as fever, anorexia, weight loss, diarrhoea, abdominal pain and partial recurrent intestinal obstruction can be seen in intestinal TB as well as in Crohn’s disease. Diagnostic criteria for Crohn’s disease exist but there is no gold standard for diagnosing Crohn’s. Lee et al.83 evaluated colonoscopic features in an attempt to distinguish between both these entities. Presence of anorectal lesions, longitudinal ulcers, aphthous ulcers and cobblestone appearance were more present in Crohn’s disease while transverse ulcers, pseudopolyps, involvement of fewer than four segments and a patulous ileocaecal valve was more prevalent in intestinal TB. A scoring system based on these parameters diagnosed Crohn’s disease with 94.9% positive predictive value and intestinal TB with 88.9% positive predictive value. Studies from Southern India and South Africa have discussed histological differentiating features between both diseases.84,85 Both diseases are characterized by granulomatous inflammatory lesions. Presence of
Fig. 39.2 (A) Endoscopic ultrasound image (EUS) showing pancreatic head mass in a patient with pancreatic TB. (B) EUS-guided fine needle aspiration (FNA) of pancreatic head mass.
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Box 39.2 Unanswered questions
Crohn’s disease and intestinal TB have overlapping clinical, endoscopic and histological features. There is no gold standard diagnostic test to differentiate Crohn’s disease from intestinal TB. Role of polymerase chain reaction as a diagnostic test for Mycobacterium tuberculosis is uncertain.
caseous necrosis and acid-fast bacilli are pathognomonic features of intestinal TB. Other histological features seen more frequently in TB include large, confluent, multiple and submucosal granulomas. Features seen far more frequently in Crohn’s disease include single granulomas as the only foci of granulomatous inflammation and architectural distortion distant from granulomatous inflammation.
MANAGEMENT All patients should receive conventional antituberculosis therapy for at least 6 months, including an initial 2 months of rifampicin, isoniazid, pyrazinamide and ethambutol. A randomized comparison of a 6-month short course of chemotherapy with a 12-month course of ethambutol and isoniazid (supplemented with streptomycin for the initial 2 weeks) was conducted by Balasubramanium et al.86,87 at the Tuberculosis Research Centre, Chennai, in 193 adult patients. The cure rate was 99% and 94% in patients given the short-course and the 12-month regimen respectively. This study highlighted the fact that 6 months of chemotherapy is adequate for treating abdominal TB. The surgical treatment of intestinal TB has gone through three phases. Bypassing the stenosed segment by enteroenterostomy or by ileotransverse colostomy was practised when effective antituberculosis drugs were unavailable, as any resectional surgery was considered hazardous in the
REFERENCES 1. Wang HS, Chen WS, Su WJ, et al. The changing pattern of intestinal tuberculosis: 30 years’ experience. Int J Tuberc Lung Dis 1998;2:569–574. 2. Aston NO. Abdominal tuberculosis. World J Surg 1997;21:492–499. 3. Singhal A, Gulati A, Frizell R, et al. Abdominal tuberculosis in Bradford, UK: 1992–2002. Eur J Gastroenterol Hepatol 2005;17: 967–971. 4. Paustian FF. Tuberculosis of the intestine. In: Bockus HL (ed.). Gastroenterology, vol. 11, 2nd edn. Philadelphia: WB Saunders, 1964: 311. 5. Peda Veerraju E. Abdominal tuberculosis. In: Satya Sri S (ed.). Textbook of Pulmonary and Extrapulmonary Tuberculosis, 3rd edn. New Delhi: Interprint, 1998: 250–252. 6. Horvath KD, Whelan RL. Intestinal tuberculosis: return of an old disease. Am J Gastroenterol 1998;93:692–696. 7. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163: 1009–1021. 8. Tsironi E, Feakins RM, Probert CS, et al. Incidence of inflammatory bowel disease is rising and abdominal tuberculosis is falling in Bangladeshis in East London, United Kingdom. Am J Gastroenterol 2004;99(9): 1749–1755.
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presence of active disease. This practice, however, produced blind loop syndrome, and fistulae and recurrent obstruction often occurred in the remaining segments. With the advent of antituberculous drugs, more radical procedures became popular in an attempt to eradicate the disease locally. These included right hemicolectomy with or without extensive removal of the draining lymph nodes and wide bowel resections. These procedures were often not tolerated well by the malnourished patient. Moreover the lesions are often widely spaced and not suitable for resection. Laparotomy should be performed only when complications develop or diagnosis remains unclear despite these diagnostic modalities. The recommended surgical procedures today are conservative.88,89 A period of preoperative drug therapy is controversial. Strictures which reduce the lumen by half or more and which cause proximal hypertrophy or dilation are treated by strictureplasty.90 This involves a 5- to 6-cm-long incision along the antimesenteric side, which is closed transversely in two layers. A segment of bowel bearing multiple strictures or a single long tubular stricture may merit resection. Resection is segmental with a 5-cm margin. Tuberculous perforations are usually ileal and are associated with distal strictures. Resection and anastomosis is preferred as simple closure of the lesions is associated with a high incidence of leak and fistula formation. Two reports suggest that obstructing intestinal lesions may be relieved with antituberculosis drugs alone without surgery. Anand et al.91 reported clinical and radiological resolution of tuberculous strictures with drug therapy even in patients with subacute intestinal obstruction. They treated 39 patients with obstructive symptoms using medical therapy. At the end of 1 year 91% showed clinical improvement, 70% had complete radiological resolution and surgery was needed in only three cases (8%). Predictors of the need for surgery were long strictures (> 12 cm) and multiple areas of involvement.57 Similar observations were made by Balasubramaniam et al.87 The mean time required for the relief of obstructive symptoms was 6 months. Emergency surgery was associated with high mortality.92
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18. DiFebo G, Calabrese C, Areni A, et al. Oesophageal tuberculosis mimicking secondary oesophageal involvement by mediastinal neoplasm. Ital J Gastroenterol Hepatol 1997;29:564–568. 19. Tassios P, Ladas S, Giannopoulos G, et al. Tuberculous esophagitis. Report of a case and review of modern approaches to diagnosis and treatment. Hepatogastroenterology 1995;42:185–188. 20. Cheung HY, Siu WT, Yau KK, et al. Abdominal tuberculosis mimicking metastasis in a patient with carcinoma of the oesophagus. Hong Kong Med J 2006;12(6):473–476. 21. Geo SK, Harikumar R, Varghese T, et al. Isolated tuberculosis of gastric cardia presenting as perforation peritonitis. Indian J Gastroenterol 2005;24(5):227–228. 22. Talukdar R, Khanna S, Saikia N, et al. Gastric tuberculosis presenting as linitis plastica: a case report and review of the literature. Eur J Gastroenterol Hepatol 2006;18(3):299–303. 23. Amarapurkar DN, Patel ND, Amarapurkar AD. Primary gastric tuberculosis–report of 5 cases. BMC Gastroenterol 2003;3:6. 24. Pratap A, Cerda SR, Varghese JC, et al. Duodenal tuberculosis. Gastrointest Endosc 2006;64(4):648–649. 25. Nair KV, Pai CG, Rajagopal KP, et al. Unusual presentations of duodenal tuberculosis. Am J Gastroenterol 1991;86:756–760. 26. Gupta SK, Jain AK, Gupta JP, et al. Duodenal tuberculosis. Clin Radiol 1988;39:159–161. 27. Berney T, Badaoui E, Totsch M, et al. Duodenal tuberculosis presenting as acute ulcer perforation. Am J Gastroenterol 1998;93:1989–1991.
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Abdominal (gastrointestinal tract) tuberculosis in adults 28. Shah P, Ramakantan R, Deshmukh H. Obstructive jaundice—an unusual complication of duodenal tuberculosis: treatment with transhepatic balloon dilatation. Indian J Gastroenterol 1991;10:62–63. 29. Leung VK, Law ST, Lam CW, et al. Intestinal tuberculosis in a regional hospital in Hong Kong: a 10-year experience. Hong Kong Med J 2006;12(4): 264–271. 30. Bhansali SK, Sethna JR. Intestinal obstruction: a clinical analysis of 348 cases. Indian J Surg 1970;32: 57–70. 31. Alvares JF, Devarbhavi H, Makhija P, et al. Clinical, colonoscopic, and histological profile of colonic tuberculosis in a tertiary hospital. Endoscopy 2005; 37(4):351–356. 32. Kapoor VK. Abdominal tuberculosis: the Indian contribution. Indian J Gastroenterol 1998;17:141–147. 33. Ranjan P, Ghoshal UC, Aggarwal R, et al. Etiological spectrum sporadic malabsorption syndrome in Northern Indian adults at a tertiary hospital. Indian J Gastroenterol 2004;23:94–98. 34. Pimparkar BD, Donde UM. Intestinal tuberculosis. II. Gastrointestinal absorption studies. J Assoc Physicians India 1974;22:219–228. 35. Tandon RK, Bansal R, Kapur BML, et al. A study of malabsorption in intestinal tuberculosis: stagnant loop syndrome. Am J Clin Nutr 1980;33:244–250. 36. Chawla S, Mukerjee P, Bery K. Segmental tuberculosis of the colon: a report of ten cases. Clin Radiol 1971;22:104–109. 37. Bhargava DK, Tandon HD, Chawla TC, et al. Diagnosis of ileocecal and colonic tuberculosis by colonoscopy. Gastrointest Endosc 1985;31:68–70. 38. Singh V, Kumar P, Kamal J, et al. Clinicocolonoscopic profile of colonic tuberculosis. Am J Gastroenterol 1996;91:565–568. 39. Bhargava DK, Kushwaha AKS, Dasarathy S, et al. Endoscopic diagnosis of segmental colonic tuberculosis. Gastrointest Endosc 1992;38:571–574. 40. Misra SP, Misra V, Dwivedi M, et al. Colonic tuberculosis mimicking ulcerative colitis. J Assoc Physicians India 1998;46:309–310. 41. Misra A, Khanduri A, Jain M, et al. Colonic tuberculosis presenting as diffuse pancolitis. Indian J Gastroenterol 1996;15:105. 42. Tarumi K, Koga H, Iida M, et al. Colonic aphthoid erosions as the only manifestation of tuberculosis: case report. Gastrointest Endosc 2002;55:743–745. 43. Comert FB, Comert M, Kulah C, et al. Colonic tuberculosis mimicking tumor perforation: a case report and review of the literature. Dig Dis Sci 2006;51(6):1039–1042. 44. Puri AS, Vij JC, Chaudhary A, et al. Diagnosis and outcome of isolated rectal tuberculosis. Dis Colon Rectum 1996;39:1126–1169. 45. Chaudhary A, Gupta NM. Colorectal tuberculosis. Dis Colon Rectum 1986;29:738–741. 46. Sahoo D, Mahapatra MK, Salim S. Rectal tuberculosis: a rare case. Trop Gastroenterol 2004; 25(2):84–85. 47. Akgun E, Tekin F, Ersin S, et al. Isolated perianal tuberculosis. Neth J Med 2005;63(3):115–117. 48. Gupta PJ. Ano-perianal tuberculosis—solving a clinical dilemma. Afr Health Sci 2005;5(4):345–347. 49. Romelaer C, Abramowitz L. [Anal abscess with a tuberculous origin: report of two cases and review of the literature.] Gastroenterol Clin Biol 2007;31(1): 94–96. 50. Dandapat MC, Mukherjee LM, Behra AN. Fistula in ano. Indian J Surg 1990;52:265–268. 51. Shukla HS, Gupta SC, Singh C, et al. Tubercular fistula in ano. Br J Surg 1988;75:38–39.
52. Chien RN, Lin PY, Liaw YF. Hepatic tuberculosis comparison of miliary and local forms. Infection 1995;23:5–8. 53. Achem SR, Kolts BE, Grisnik J, et al. Pseudotumoral hepatic tuberculosis: atypical presentation and comprehensive review of literature. J Clin Gastroenterol 1992;14:72–77. 54. Alvarez SZ. Hepatobiliary tuberculosis. J Gastroenterol Hepatol 1998;13(8):833–839. 55. Fang X, Li J, Fan S. Clinical characteristics of hepatic tuberculosis. Zhonghua Nei Ke Ka Zhi 1995;34:34–37. 56. Saluja SS, Ray S, Pal S, et al. Hepatobiliary and pancreatic tuberculosis: A two decade experience. BMC Surg 2007;7(1):10. 57. Foo FJ, Verbeke CS, Guthrie JA, et al. Pancreatic and peripancreatic tuberculosis mimicking malignancy. JOP 2007;8(2):201–205. 58. Xia F, Poon RT, Wang SG, et al. Tuberculosis of pancreas and peripancreatic lymph nodes in immunocompetent patients: experience from China. World J Gastroenterol 2003;9:1361–1364. 59. Kapoor VK, Chattopadhyay TK, Sharma LK. Radiology of abdominal tuberculosis. Australas Radiol 1988;32:365–367. 60. Prakash A. Ulcero-constrictive tuberculosis of the bowel. Int Surg 1978;63:23–29. 61. Tandon RK, Sarin SK, Bose SL, et al. A clinicoradiological reappraisal of intestinal tuberculosischanging profile? Gastroenterol Jpn 1986;21:17–22. 62. Kedar RP, Shah PP, Shivde RS, et al. Sonographic findings in gastrointestinal and peritoneal tuberculosis. Clin Radiol 1994;49:24–29. 63. Gulati MS, Sarma D, Paul SB. CT appearances in abdominal tuberculosis. A pictorial assay. Clin Imaging 1999;23:51–59. 64. Ha HK, Jung JI, Lee MS, et al. CT differentiation of tuberculosis peritonitis and peritoneal carcinomatosis. Am J Roentgenol 1996;167:743–748. 65. Misra SP, Misra V, Dwivedi M, et al. Colonic tuberculosis:clinical features, endoscopic appearance and management. J Gastroenterol Hepatol 1999;14: 723–729. 66. Misra SP, Misra V, Dwivedi M, et al. Tuberculous colonic strictures: impact of dilation on diagnosis. Endoscopy 2004;36(12):1099–1103. 67. Misra SP, Misra V, Dwivedi M. Ileoscopy in patients with ileocolonic tuberculosis. World J Gastroenterol 2007;13(11):1723–1727. 68. Sato S, Yao K, Yao T, et al. Colonoscopy in the diagnosis of intestinal tuberculosis in asymptomatic patients. Gastrointest Endosc 2004;59(3):362–368. 69. Bhargava DK, Dasarathy S, Shriniwas MD, et al. Evaluation of enzyme linked immunosorbent assay using mycobacterial saline extracted antigen for the serodiagnosis of abdominal tuberculosis. Am J Gastroenterol 1992;87:105–108. 70. Kulkarni S, Vyas S, Supe A, et al. Use of polymerase chain reaction in the diagnosis of abdominal tuberculosis. J Gastroenterol Hepatol 2006;21(5): 819–823. 71. Anand BS, Schneider FE, El-Zaatari FAK, et al. Diagnosis of intestinal tuberculosis by polymerase chain reaction on endoscopic biopsy specimens. Am J Gastroenterol 1994;89:2248–2249. 72. Singh MM, Bhargava AN, Jain KP. Tuberculous peritonitis. An evaluation of pathogenetic mechanisms, diagnostic procedures and therapeutic measures. N Engl J Med 1969;281(20):1091–1094. 73. Dwivedi M, Misra SP, Misra V, et al. Value of adenosine deaminase estimation in the diagnosis of tuberculous ascites. Am J Gastroenterol 1990;85: 1123–1125.
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74. Bhargava DK, Gupta M, Nijhawan S, et al. Adenosine deaminase (ADA) in peritoneal tuberculosis: diagnostic value in ascites fluid and serum. Tubercle 1990;71:121–126. 75. Sathar MA, Simjer AE, Coovadia YM, et al. Ascitic fluid gamma interferon concentrations and adenosine deaminase activity in tuberculous peritonitis. Gut 1995;36:419–421. 76. Bhargava DK, Shriniwas, Chopra P, et al. Peritoneal tuberculosis: laparoscopic patterns and its diagnostic accuracy. Am J Gastroenterol 1992;87:109–112. 77. Monkemuller K, Weigt J, Treiber G, et al. Diagnostic and therapeutic impact of double-balloon enteroscopy. Endoscopy 2006;38(1):67–72. 78. Gourtsoyiannis NC, Papanikolaou N. Magnetic resonance enteroclysis. Semin Ultrasound CT MR 2005;26(4):237–246. 79. Boujaoude JD, Honein K, Yaghi C, et al. Diagnosis by endoscopic ultrasound guided fine needle aspiration of tuberculous lymphadenitis involving the peripancreatic lymph nodes: a case report. World J Gastroenterol 2007;13(3):474–477. 80. Antillon MR, Chang KJ. Endoscopic and endosonography guided fine-needle aspiration. Gastrointest Endosc Clin N Am 2000;10:619–636. 81. Volmar KE, Vollmer RT, Jowell PS, et al. Pancreatic FNA in 1000 cases: a comparison of imaging modalities. Gastrointest Endosc 2005;61:854–861. 82. Epstein D, Watermeyer G, Kirsch R. Review article: the diagnosis and management of Crohn’s disease in populations with high-risk rates for tuberculosis. Aliment Pharmacol Ther 2007;25(12):1373–1388. 83. Lee YJ, Yang SK, Byeon JS, et al. Analysis of colonoscopic findings in the differential diagnosis between intestinal tuberculosis and Crohn’s disease. Endoscopy 2006;38:592–597. 84. Kirsch R, Pentecost M, Hall Pde M, et al. Role of colonoscopic biopsy in distinguishing between Crohn’s disease and intestinal tuberculosis. J Clin Pathol 2006;59:840–844. 85. Pulimood AB, Peter S, Ramakrishna B, et al. Segmental colonoscopic biopsies in the differentiation of ileocolic tuberculosis from Crohn’s disease. J Gastroenterol Hepatol 2005;20:688–696. 86. Balasubramanian R, Nagarajan M, Balambal R, et al. Randomised controlled clinical trial of short course chemotherapy in abdominal tuberculosis: a five-year report. Int J Tuberc Lung Dis 1997;1:44–51. 87. Balasubramanian R, Ramachandran R, Joseph PE, et al. Interim results of a clinical study of abdominal tuberculosis. Indian J Tuberc 1989;36:117–121. 88. Leone V, Misuri D, Fazio C, et al. [Abdominal tuberculosis: clinical features, diagnosis and role of surgery]. Minerva Chir 2007;62(1):25–31. [In Italian] 89. Akgun Y. Intestinal and peritoneal tuberculosis: changing trends over 10 years and a review of 80 patients. Can J Surg 2005;48(2):131–136. 90. Pujari BD. Modified surgical procedures in intestinal tuberculosis. Br J Surg 1979;66:180–181. 91. Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antituberculous treatment. Gut 1988;29:62–69. 92. Clarke DL, Thomson SR, Bissetty T, et al. A single surgical unit’s experience with abdominal tuberculosis in the HIV/AIDS era. World J Surg 2007;31: 1088–1097.
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Abdominal tuberculosis in children Etienne de la Rey Nel
INTRODUCTION Abdominal TB is a relatively unusual form of TB that poses significant diagnostic and therapeutic challenges in childhood. The presentation of the disease is non-specific and delays in presentation and diagnosis increase its morbidity and mortality. Abdominal TB accounts for a small proportion of all cases of TB in childhood. Of 102 children seen with extrapulmonary TB in Greece, only two had abdominal TB.1 Similarly Uysal and co-workers found that it was less common than tuberculous meningitis and pleural disease in Turkey. Despite the relative rarity of abdominal TB it remains an important cause of unexplained abdominal complaints in childhood.3
EPIDEMIOLOGY The peak incidence of abdominal TB is in the third and fourth decades of life with the minority of cases occurring during childhood. Of 881 patients diagnosed with abdominal TB in Ibadan, Nigeria, only 10.5% were younger than 10 years.4 This is consistent with earlier observations in Nigeria made by Lewis and Abioye.5 Similarly in India only 21.4% of patients with abdominal TB who required surgery were younger than 15 years.6 Paediatric abdominal TB occurs from the first weeks of life through to adolescence. More than half of children with abdominal TB in South Africa are younger than 5 years old.3,7,8 A similar age distribution was found in the report of a small group of children with abdominal TB in the USA and a larger study from India.9,10 On the other hand the mean age of presentation in a more recent study from India was 9.5 years,11 and in a small series from Tunisia the mean age was 11 years, presumably reflecting the epidemiology of TB in the particular region.12 In developed countries abdominal TB occurs predominantly in immigrants from endemic areas. Twenty-four of 26 children with abdominal TB reported in the USA were Hispanic and the remaining two were of Indo-Chinese origin.9 The experience in other developed countries has been similar.13
PATHOGENESIS INTESTINE Most infections are due to Mycobacterium tuberculosis. Mycobacterium bovis infection has become rare even in developing economies.14 In certain regions, however, it remains an important cause of intestinal TB.9
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Ingestion of infected sputum is the most important suggested origin of intestinal disease. After ingestion the cell wall of the mycobacteria is relatively resistant to gastric acid. This allows passage of the organism into the rest of the intestinal tract. Although any part of the intestine may be involved, the distal ileum with its well-developed lymphoid follicles is the most frequently affected. Bacilli are transported from the intestinal lumen to antigen-presenting cells in lymphoid follicles. This primary focus elicits an inflammatory response that predominantly involves the submucosa and serosa and may extend around the entire circumference of the intestine. Granulomas with caseous necrosis form and may be confluent. Lympho-haematogenous spread may also occur from active pulmonary TB in miliary TB or from a silent bacteraemia during primary TB infection. Direct spread from adjacent organs is a rare cause of intestinal TB.15 When ulcers form, they may be single or multiple with granulomas beneath the ulcer bed. Typically they are transverse and may be circumferential. Endarteritis of submucosal vessels with decreased mucosal perfusion is thought to be important in the development of mucosal ulceration.16,17 Ulcers are usually superficial. Extensive fibrosis may occur as the ulcers heal, leading to stricture formation. It is probable that M cells play an important role during initial intestinal infection by M. tuberculosis.18 M cells are adapted to transport antigens to antigen-presenting cells in the Peyer’s patches and numerous bacteria use this route to gain access to the mucosa. The role of M cells in human intestinal TB is supported by animal studies that have demonstrated transport of Bacillus Calmette–Gue´rin (BCG) and Mycobacterium paratuberculosis in the intestine and M. tuberculosis by M cells in the lung.19–21
PERITONEUM Adult data suggest that reactivation of latent foci formed by haematogenous spread during primary infection of the lung is an important mechanism for the pathogenesis of peritoneal TB.18 Lymphohaematogenous spread from active pulmonary TB or miliary TB is an alternative mechanism. Spread to the peritoneum from mesenteric lymph nodes is another suggested mechanism.10 Less frequently contiguous spread from intestinal TB or the fallopian tubes may be responsible for peritonitis.
PATHOLOGY INTESTINE Tuberculosis may involve any part of the intestine. The terminal ileum and caecum are the most frequently involved; other
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Abdominal tuberculosis in children
frequently involved areas of the intestine in decreasing order of frequency are the ileum and jejunum, colon, anorectum, and rarely the proximal small bowel. Segmental thickening of the intestinal wall (hypertrophic form) may involve all or most of the circumference. This occurs most frequently in the ileocaecal region. An inflammatory mass is formed by the intestine, mesenteric fat, and lymph nodes. Extensive adhesions are usually present. Mucosal changes including a cobblestone appearance or flattening of the mucosal folds with longitudinal grooves leading to the area of constriction may be present. Mucosal ulceration (ulcerative form) is thought to occur less frequently in children. Endoscopic studies, however, suggest that colonic ulceration may be more common than previously believed. The wall of the involved segment is indurated. Mesenteric fat is increased with superficial nodules.22 Ulcers are usually superficial, transverse, with hypertrophic surrounding mucosa. Occasionally ulcers may be deeper, penetrating the intestinal wall. The intervening mucosa is usually normal. In severe cases, however, large segments of the intestinal mucosa may be affected with mucosal bridging and psuedopolyps. Granulomas are found in the base of most ulcers. Ulceration may occur in combination with the hypertrophic form (ulcerohypertrophic form). Tuberculosis may involve mesenteric and other intra-abdominal blood vessels. Vessels are encased in thickened omentum and compressed by enlarged lymph nodes. Pathological features include granulomas in the vessel walls, subintimal fibrosis, and intraluminal thrombi. Intestinal ischaemia contributes to the development of ulcers, strictures, perforation, and rarely massive intestinal bleeding. Pseudoaneurysms of the aorta and mesenteric arteries may also cause catastrophic haemorrhage. Thrombosis of the portal and splenic veins leads to portal hypertension complications such as oesophageal varices and splenomegaly.
PERITONEUM Peritoneal and nodal disease occurs more frequently than intestinal disease in children.8,10,11 Three types of peritoneal TB have been described: a wet type characterized by significant ascites, an encysted type, and a fibrotic type with matted mesentery, omentum, and intestinal loops.14 Widespread tuberculous nodules are found on the parietal and visceral peritoneum. These have the appearance of white nodules. The peritoneum and omentum are thickened and hyperaemic with fibrous bands and adhesions. Peritoneal abscesses with granulomatous necrosis are found at laparotomy.12 Ascites is a common feature.
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Mesenteric and para-aortic lymph nodes are usually enlarged. Glandular enlargement is a common feature of tuberculous peritonitis and glandular disease may occur in the absence of overt intestinal or peritoneal disease.
CLINICAL PRESENTATION The clinical presentation of TB of the abdomen is both varied and non-specific (Table 40.1). Presentation to a healthcare facility and subsequent diagnosis are often delayed.4,11 The resultant delay in treatment increases the morbidity and mortality of the disease. Prognosis is also poor in the presence of severe malnutrition, disseminated disease, and comorbidity.8 Children requiring surgical intervention also have an increased mortality. Patients with multiple strictures or multiple perforations in particular have a high mortality.23 The preoperative condition of children is an important determinant of postoperative mortality.24 Although the onset of abdominal TB is usually insidious, some children may present with an apparent acute onset of symptoms.10 Abdominal TB should be considered in the differential diagnosis of children presenting with an acute abdomen, particularly in areas with a high incidence of TB. The majority will, however, present with a chronic or acute-on-chronic history. Malnutrition is a common feature of abdominal TB. More than half of children with abdominal TB will have growth faltering,7,8,11,25 and some children may present with severe malnutrition. The absence of clear evidence of malnutrition does, however, not exclude the diagnosis of TB. The aetiology of malnutrition in these children is multifactorial: anorexia, increased energy requirements, and malabsorption are important contributing factors. Intestinal villous atrophy has been reported in patients with TB.26 A proteinlosing enteropathy that contributes to the development of malnutrition may occur. Some children develop intestinal lymphangiectasia with large intestinal losses of protein combined with steatorrhoea and electrolyte disturbances. Bacterial overgrowth due to a ‘stagnant loop’ occurs in the presence of intestinal obstruction. Common presenting symptoms are abdominal distension, abdominal pain, and weight loss. Other symptoms include vomiting, anorexia, constipation, and diarrhoea. Rarely the child may present with a gastrointestinal haemorrhage, haematochezia being more common than haematemesis. Most children appear systemically ill at presentation. They are often anaemic and fever, often low grade, is a common finding. Fifty per cent of 110 children described by Sharma and co-workers10
Table 40.1 Clinical presentation of abdominal tuberculosis in children Symptoms and signs (%)
Talwar et al. 11 (2000), n = 125
Johnson et al. 8 (1987), n = 59
Davies 3 (1982), n = 55
Saczek et al. 7 (2001), n = 45
Veeragandham et al. (1996),9n = 26
Abdominal pain Abdominal distension Growth failure, weight loss Fever Loss of appetite Ascites Abdominal mass Extra-abdominal lymph node enlargement
100 38 58 74 54 44 12 N/A
44 92 78
60 42 30 34 24 7
51 64 56 47
71 35 69 50 15 35 23 19.2 (extra-abdominal TB)
44 56 47
18
20 47 49
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SECTION
5
CLINICAL PRESENTATIONS OF TUBERCULOSIS
had a low-grade fever and all were anaemic. Extra-abdominal lymphadenopathy may be present. When present this offers a useful clue to the diagnosis. The most common signs include abdominal distension, clinically detectable ascites, an abdominal mass, and hepatomegaly. The abdominal mass is typically located in the right lower quadrant of the abdomen. A doughy abdomen is present in the minority of patients. Intestinal obstruction is a frequent complication of abdominal TB. Abdominal pain, vomiting, constipation, and abdominal distension are important symptoms. Obstruction may be due to peritoneal and omental adhesions, adhesions to enlarged mesenteric lymph nodes, direct compression of the intestine by a mass of lymph nodes, or intestinal TB of the hyperplastic type with stricture formation. Intestinal strictures may be multiple or single. In addition to obstruction some children present with an acute abdomen due to perforation. Enterocutaneous fistulae, rectal fistulae and ulcers, gastric ulcers, acute appendicitis, tracheo-oesophageal fistulae, and incarcerated inguinal hernias are rare presentations of abdominal TB. Lymphatic complications include chylous peritonitis and intestinal lymphangiectasia. Rectal bleeding and haematemesis are less common in children than in adults. Intestinal TB should, however, be considered in the differential diagnosis of children presenting with an intestinal bleed, particularly in countries with a high incidence of TB.8,27 There are multiple possible causes of intestinal haemorrhage: mucosal ulceration,8 more common in the colon, less frequent in the stomach or duodenum;28 mesenteric artery aneurysms;29 and portal vein thrombosis.30 Radiological evidence of active or previous pulmonary TB may be present. The reported prevalence of pulmonary TB in children with abdominal TB varies from less than 20% to approximately 60%.7,11
DIAGNOSIS A high index of suspicion should be maintained particularly in children with unexplained abdominal disease. In developed countries abdominal TB is more likely to occur in immigrant populations. In endemic areas children from a low socioeconomic background are at higher risk of developing abdominal TB. The disease may, however, occur outside these high-risk groups. A history of close contact with pulmonary TB should alert the clinician to the possibility of TB. Thirty-six per cent of 45 children with abdominal TB reported by Saczek et al., had a TB household contact, as did nine out of 11 children with tuberculous peritonitis in the series published by Gurkan and colleagues.31 Other reports have found a lower proportion of household contacts. This may reflect how actively the presence of a household contact is sought. Most children with abdominal TB will have some evidence of a systemic chronic disease. Weight loss, anaemia, an increased sedimentation rate, and fever frequently occur and should alert the clinician to the possibility of the diagnosis. South African studies have found a positive tuberculin skin test in 44–68% of children with abdominal TB.3,7 A false-negative tuberculin skin test may occur in the presence of severe malnutrition and overwhelming infection, in immunocompromised children, and following faulty administration of the antigen. A positive tuberculin skin test is of particular value in children under the age of 5 years, indicating recent TB infection. Radiological evidence of pulmonary TB disease is highly suggestive but the absence of radiological or clinical signs of active pulmonary TB does not exclude the diagnosis of abdominal TB.
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Abdominal radiographs are of less value. Signs of intestinal obstruction may be present and rarely there may be evidence of frank perforation. The incidental finding of calcified lymph nodes in the abdomen may lead to the diagnosis.9 An abdominal ultrasound investigation may demonstrate enlarged mesenteric and para-aortic lymph nodes, ascites which may be clear or dense with fine strands, loculations, and debris. Thickening of the bowel wall, an omental mass, and focal lesions in the liver and spleen may be seen.32 Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen may demonstrate the same abnormalities as well as intestinal wall thickening. Bacteriological evidence of TB infection may be obtained from gastric aspirates in young children, sputum in older children, and fine needle aspirate or biopsy of superficial lymph nodes.7 These investigations provide supportive but not definitive evidence for the diagnosis. If ascites is present it should be aspirated and analysed. The protein content is usually elevated (> 25 g/L) with a low serum ascites albumin gradient. Although lymphocytes usually are predominant, in some patients neutrophils are dominant.33 An elevated adenosine deaminase (ADA) in the ascitic fluid is found in most children with tuberculous peritonitis. Normal values, however, occur in children with low protein ascites and human immunodeficiency virus (HIV) infection and the diagnosis of tuberculous peritonitis cannot be excluded exclusively on the grounds of a normal ascites ADA. Microbiological examination of the ascites usually has a low yield. Direct examination with a Ziehl–Neelsen stain has a sensitivity of less than 10%.33 Culture rates for M. tuberculosis vary from 10% to 30%. There is also a considerable delay before the result becomes available. Culturing a large volume (at least 1 L) of fluid may improve the yield. It is unusual, however, to obtain such a large volume of fluid from a young child. Numerous studies have confirmed the value of laparoscopy in the diagnosis of abdominal TB with a sensitivity ranging from 85% to 100%.34,35 Direct visualization of the peritoneal space may allow a presumptive diagnosis to be made: in addition to ascites (usually straw-coloured) there may be yellow–white nodules on the visceral and parietal peritoneum, fibrous bands and adhesions of the peritoneum and omentum, hyperaemic oedematous bowel loops, distended bowel loops, and lymph node enlargement.33,36,37 Histology of biopsy material obtained from the peritoneum and lymph nodes may demonstrate caseating granulomas and acid-fast bacilli. Culture of biopsied tissue provides confirmation of the diagnosis. In addition to histopathology and culture for M. tuberculosis, polymerase chain reaction (PCR) performed on tissue obtained may improve the sensitivity.38 Percutaneous peritoneal biopsy has been shown to be of value in adults with peritoneal TB.39 The feasibility of this technique in children is uncertain. The diagnosis is also often confirmed when a laparotomy is indicated for complications such as intestinal obstruction or perforation. Features similar to those observed with laparoscopy are evident. A diagnostic laparotomy should be performed when the diagnosis remains unclear despite other efforts to confirm the diagnosis.11,40–42 Ulcers are the most common colonoscopic finding. Histology of biopsies obtained during this examination demonstrates caseating granulomas. Ulcers are characteristically transverse and superficial, with irregular margins and occur most frequently in the ileocaecal region. Other typical features include an oedematous and deformed ileocaecal valve, pseudopolyps, and strictures. Although the value of colonoscopy is best established in adults, limited data indicate that it is also a valuable investigation in children.8,43
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Abdominal tuberculosis in children
A trial of therapy is frequently adequate to provide presumptive confirmation of the diagnosis. This is particularly valuable in regions with a high incidence of TB and in children with typical features of abdominal TB. Thirty-six out of 125 children described by Talwar and co-workers11 showed a dramatic response to antiTB treatment. This served as adequate confirmation of the diagnosis in the absence of histological and microbiological confirmation. Their experience has been confirmed by other workers in the field.15,44,45 There are, however, a number of caveats. The response to treatment should be closely monitored. Signs of response include resolution of fever, improved general well-being, nutrition, ascites, and disappearance of abdominal masses.11 Lymph nodes should not enlarge significantly during treatment. This is particularly important as lymphoma may mistakenly be diagnosed as abdominal TB in endemic areas. In the absence of improvement a definitive diagnosis should be pursued by laparoscopy or laparotomy. The effect of HIV coinfection on TB abdomen is summarized in Box 40.1.
DIFFERENTIAL DIAGNOSIS The differential diagnosis is determined by the child’s presentation. An abdominal mass must be distinguished from conditions such as non-Hodgkin’s lymphoma, a round worm mass, and retroperitoneal tumuors (e.g. kidney, neuroblastoma). Other causes of intestinal obstruction must be distinguished from TB. Rarely it may lead to a megacolon and mimic Hirschprung’s disease.3 Other surgical conditions that TB may mimic are appendicitis,46 psoas abscess,25 and congenital anomalies of the urachus (in children with enterocutaneous fistula in the umbilicus). Yersinia infection, gastrointestinal histoplasmosis, and Mycobacterium avium complex infections should also be considered in the differential diagnosis. Intestinal TB and Crohn’s disease are frequently difficult to differentiate. Treatment of abdominal TB as Crohn’s disease will aggravate the TB. The differentiation between Crohn’s disease and TB relies on the assessment of clinical features, imaging, Box 40.1 Effect of HIV coinfection on TB abdomen
18,61
Little information on the effect of HIV coinfection on abdominal TB in children is available. The following list summarizes the important findings from some adult studies. 1. Increased number of patients with extrapulmonary TB. 2. Younger. 3. Less alchohol abuse. 4. Fever, night sweats, and weight loss more common. 5. Ascites and jaundice less common. 6. Intra-abdominal lymphadenopathy more common with CT. 7. Disseminated TB more common. 8. Acid-fast smears of stool and abdominal lymph node aspirates more common. 9. Decreased absorption of anti-TB drugs (isoniazid and rifampicin). 10. Atypical mycobacterial infection more common. 11. Increased mortality. 12. Tuberculosis an important cause of acute abdomen in HIV-infected patients.62 Adapted from Field S, Lewis S; Intestinal and Peritoneal Tuberculosis; in Rom WN, Garay SM (Ed.): Tuberculosis. Philadelphia, Lippincott Williams and Wilkins, 2004, pp. 523–535 and Fee MJ, Oo MM, Gabayan AE, et al. Abdominal tuberculosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 1995; 20:938–44.
40
endoscopy, histology, and an estimation of the pretest likelihood of the disease. Bacteriological confirmation of the diagnosis should be aggressively pursued where the diagnosis is in doubt. Unfortunately there are few data from paediatric studies. Some of the distinguishing features recorded in adults are summarized in Table 40.2.
TREATMENT Severely malnourished children with TB have an increased mortality.8,10 Although information on the value of nutritional support for children with abdominal TB is lacking, Paton et al.47 found improved weight gain and grip strength in adults with TB and wasting in those who received nutritional support. Although zinc and selenium deficiency frequently occur in patients with TB the value of supplementing these nutrients has not been established. Intestinal disease complicates the nutritional support of children with abdominal TB. Enteral nutrition is not possible in the presence of intestinal obstruction or perforation and parenteral nutrition will be required. Malabsorption due to intestinal TB, mucosal atrophy, bacterial overgrowth, and rare complications such as intestinal lymphangiectasia require special attention. The majority of children will respond to normal diets with appropriate supplementation. In the presence of severe malabsorption a hydrolysed infant formula or enteral feed may be required. Children with intestinal lymphangiectasia and chylous peritonitis will benefit from a restricted fat intake and a medium chain triglyceride-enriched formula. A dietician skilled in the treatment of malabsorption syndromes in children should be involved at an early stage of these children’s treatment. Enteral antibiotics (e.g. aminoglycosides such as gentamicin and metronidazole) are useful for the treatment of bacterial overgrowth. If bile salt-induced diarrhoea is suspected, a trial of cholestyramine is justified.
MEDICAL Most patients will respond to medical treatment. Even strictures may improve with medical treatment only, and most enterocutaneous fistulae will resolve without surgical intervention.48 Antituberculosis treatment should be guided by local guidelines. Important issues are the number of anti-TB drugs, the appropriate doses, and duration of therapy. Abdominal TB is a severe form of TB disease and should be treated accordingly. Present World Health Organization guidelines recommend the use of four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) during the initial phase for 2 months, followed by two drugs (isoniazid, rifampicin) during the continuation phase for 4 months. Antituberculosis drug doses are calculated according to weight. The metabolism of drugs varies with age and is unpredictable. Given the severity of the disease it is prudent to prescribe drugs in the upper range of the recommended dose. A 6-month course of treatment is adequate in most patients.49
STEROIDS It has been suggested that the use of steroids as adjunct therapy for abdominal TB may decrease the morbidity and mortality.50–52 Experience is limited to case reports and retrospective reviews. At
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Table 40.2 Differences between intestinal tuberculosis and Crohn’s disease Feature
Tuberculosis
Crohn’s disease
Clinical (Kirsch et al. 200655)
Chest radiograph more likely to show signs of previous or active TB
Imaging (CT) (Engin & Balk 2005,56 Pereira et al. 200557)
Perianal fistulae more common in Crohn’s disease Extraintestinal manifestations more common: arthritis, arthralgia, erythema nodosum More uniform and lesser thickening of the bowel wall Mural stratification Vascular jejunization (the comb sign) Mesenteric fibrofatty proliferation
Colonoscopy (adapted from Lee et al. 200658)
Histology (adapted from Pulimood et al. 1999, 2005;59,60 Kirsch et al. 200655)
Preferential thickening of the ileocaecal valve and medial wall of the caecum Few small regional nodes An inflammatory mass that extends into adjacent muscle suggests TB In the sclerotic form, the main reaction is fibrosis with single or multiple short strictures. The caecum classically becomes amputated, conical, shrunken, and retracted. Common features: Involvement of fewer than four segments Patulous ileocaecal valve Transverse ulcers Scars or pseudopolyps Granulomas: Multiple (mean number per section: 5.35, > 10 per biopsy site suggestive of TB) Large (> 0.05 mm2 more likely to be TB), confluent granulomas (often with caseating necrosis) Submucosal granulomas Ulcers lined by conglomerate epithelioid histiocytes and disproportionate submucosal inflammation
this stage there is not enough evidence to recommend the use of steroids in children with abdominal TB.
SURGICAL Surgical intervention, with the exception of a diagnostic laparoscopy or laparotomy, should be avoided unless there is a clear indication. Indications for surgery include obstruction, intestinal perforation, persistent fistula, and severe intestinal bleeding.
REFERENCES 1. Maltezou HC, Spyridis P, Kafetzis DA. Extrapulmonary tuberculosis in children. Arch Dis Child 2000;83:342–346. 2. Uysal G, Gursoy T, Guven A, et al. Clinical features of extrapulmonary tuberculosis in children. Saudi Med J 2005;26:750–753. 3. Davies MR. Abdominal tuberculosis in children. S Afr J Surg 1982;20:7–19. 4. Ihekwaba FN. Abdominal tuberculosis: a study of 881 cases. J R Coll Surg Edinb 1993;38:293–295. 5. Lewis EA, Abioye AA. Tuberculosis of the abdomen in Ibadan: a clinico-pathological review. Tubercle 1975;56:149–155. 6. Wadhwa N, Agarwal S, Mishra K. Reappraisal of abdominal tuberculosis. J Indian Med Assoc 2004;102:31–32. 7. Saczek KB, Schaaf HS, Voss M, et al. Diagnostic dilemmas in abdominal tuberculosis in children. Pediatr Surg Int 2001;17:111–115. 8. Johnson CA, Hill ID, Bowie MD. Abdominal tuberculosis in children. A survey of cases at the Red Cross War Memorial Children’s Hospital, 1976-1985. S Afr Med J 1987;72:20–22.
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Common features: Anorectal lesions Longitudinal ulcers Aphthous ulcers Cobblestone Granulomas: Infrequent (mean number of granulomas per section: 0.75) Small (mean widest diameter: 95 m) microgranulomas (defined as poorly organized collections of epithelioid histiocytes) Mucosal granulomas Focally enhanced colitis. High prevalence of chronic inflammation, even in endoscopically normal appearing areas
Subtotal obstruction due to strictures may resolve with medical treatment and supportive therapy. Similarly many fistulae will resolve with medical treatment alone.53 Persistent obstruction due to strictures may require stricturoplasty. Operative complications, however, are high; notably, perforations with the formation of enterocutaneous fistulae are common. The clinician should consequently avoid early surgical intervention if possible. Delayed surgery in the presence of frank perforation, on the other hand, has a high mortality.54
9. Veeragandham RS, Lynch FP, Canty TG, et al. Abdominal tuberculosis in children: review of 26 cases. J Pediatr Surg 1996;31:170–175; discussion 175–176. 10. Sharma AK, Agarwal LD, Sharma CS, et al. Abdominal tuberculosis in children: experience over a decade. Indian Pediatr 1993;30:1149–1153. 11. Talwar BS, Talwar R, Chowdhary B, et al. Abdominal tuberculosis in children: an Indian experience. J Trop Pediatr 2000;46:368–370. 12. Boukthir S, Mrad SM, Becher SB, et al. Abdominal tuberculosis in children. Report of 10 cases. Acta Gastroenterol Belg 2004;67:245–249. 13. Collado C, Stirnemann J, Ganne N, et al. Gastrointestinal tuberculosis: 17 cases collected in 4 hospitals in the northeastern suburb of Paris. Gastroenterol Clin Biol 2005;29:419–424. 14. Sharma MP, Bhatia V. Abdominal tuberculosis. Indian J Med Res 2004;120:305–315. 15. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 1993;88:989–999. 16. Howell JS, Knapton PJ. Ileo-caecal tuberculosis. Gut 1964;5:524–529. 17. Malik A, Saxena NC. Ultrasound in abdominal tuberculosis. Abdom Imaging 2003;28:574–579. 18. Field S, Lewis S. Intestinal and peritoneal tuberculosis. In: Rom WN, Garay SM (eds).
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Tuberculosis. Philadelphia: Lippincott Williams and Wilkins, 2004: 523–535. Fujimura Y. Functional morphology of microfold cells (M cells) in Peyer’s patches–phagocytosis and transport of BCG by M cells into rabbit Peyer’s patches. Gastroenterol Jpn 1986;21:325–335. Momotani E, Whipple DL, Thiermann AB, et al. Role of M cells and macrophages in the entrance of Mycobacterium paratuberculosis into domes of ileal Peyer’s patches in calves. Vet Pathol 1988;25: 131–137. Teitelbaum R, Schubert W, Gunther L, et al. The M cell as a portal of entry to the lung for the bacterial pathogen Mycobacterium tuberculosis. Immunity 1999;10:641–650. Tandon HD, Prakash A. Pathology of intestinal tuberculosis and its distinction from Crohn’s disease. Gut 1972;13:260–269. Kakar A, Aranya RC, Nair SK. Acute perforation of small intestine due to tuberculosis. Aust NZ J Surg 1983;53:381–383. Dhar A, Bagga D, Taneja SB. Perforated tubercular enteritis of childhood: a ten year study. Indian J Pediatr 1990;57:713–716. Ozbey H, Tireli GA, Salman T. Abdominal tuberculosis in children. Eur J Pediatr Surg 2003;13:116–119.
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Abdominal tuberculosis in children 26. Fung WP, Tan KK, Yu SF, et al. Malabsorption and subtotal villous atrophy secondary to pulmonary and intestinal tuberculosis. Gut 1970;11:212–216. 27. Davalos M, Frisancho O, Cervera Z, et al. Colonoscopia diagnotica y terapeutica en pediatria. Rev Gastroenterol Peru 2000;20:240–246. 28. Gupta SK, Jain AK, Gupta JP, et al. Duodenal tuberculosis. Clin Radiol 1988;39:159–161. 29. Kahn SA, Kirschner BS. Massive intestinal bleeding in a child with superior mesenteric artery aneurysm and gastrointestinal tuberculosis. J Pediatr Gastroenterol Nutr 2006;43:256–259. 30. Caroli-Bosc FX, Conio M, Maes B, et al. Abdominal tuberculosis involving hepatic hilar lymph nodes. A cause of portal vein thrombosis and portal hypertension. J Clin Gastroenterol 1997;25:541–543. 31. Gurkan F, Ozates M, Bosnak M, et al. Tuberculous peritonitis in 11 children: clinical features and diagnostic approach. Pediatr Int 1999;41: 510–513. 32. Sheikh M, Moosa I, Hussein FM, et al. Ultrasonographic diagnosis in abdominal tuberculosis. Australas Radiol 1999;43:175–179. 33. Chow KM, Chow VC, Szeto CC. Indication for peritoneal biopsy in tuberculous peritonitis. Am J Surg 2003;185:567–573. 34. Madhok P, Kapur VK. Abdominal tuberculosis in children. Prog Pediatr Surg 1982;15:173–180. 35. Sotoudehmanesh R, Shirazian N, Asgari AA, et al. Tuberculous peritonitis in an endemic area. Dig Liver Dis 2003;35:37–40. 36. Ibrarullah M, Mohan A, Sarkari A, et al. Abdominal tuberculosis: diagnosis by laparoscopy and colonoscopy. Trop Gastroenterol 2002;23:150–153. 37. Uygur-Bayramicli O, Dabak G, Dabak R. A clinical dilemma: abdominal tuberculosis. World J Gastroenterol 2003;9:1098–1101. 38. Kulkarni S, Vyas S, Supe A, et al. Use of polymerase chain reaction in the diagnosis of abdominal tuberculosis. J Gastroenterol Hepatol 2006;21: 819–823.
39. Vardareli E, Kircali B. A diagnostic approach to abdominal tuberculosis. World J Gastroenterol 2005;11:3328. 40. Katigbak MW, Shlasko E, Klein SM, et al. Peritoneal tuberculosis in a 15-month-old male: surgical diagnosis of an insidious disease. Surg Infect (Larchmt) 2005;6:255–258. 41. Akgun Y. Intestinal and peritoneal tuberculosis: changing trends over 10 years and a review of 80 patients. Can J Surg 2005;48:131–136. 42. Gerhardt T, Wolff M, Fischer H, et al. Pitfalls in the diagnosis of intestinal tuberculosis: a case report. Scand J Gastroenterol 2005;40:240–243. 43. Tam PK, Saing H, Lee JM. Colonoscopy in the diagnosis of abdominal tuberculosis in children. Aust Paediatr J 1986;22:143–144. 44. Misra SP, Misra V, Dwivedi M, et al. Colonic tuberculosis: clinical features, endoscopic appearance and management. J Gastroenterol Hepatol 1999;14: 723–729. 45. Ramanathan M, Wahinuddin S, Safari E, et al. Abdominal tuberculosis: a presumptive diagnosis. Singapore Med J 1997;38:364–368. 46. Gupta S, Kaushik R, Kaur A, et al. Tubercular appendicitis—a case report. World J Emerg Surg 2006;1:22. 47. Paton NI, Chua Y, Earnest A, et al. Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting. Am J Clin Nutr 2004;80:460–465. 48. Anand BS, Nanda R, Sachdev GK. Response of tuberculous stricture to antituberculous treatment. Gut 1988;29:62–69. 49. Balasubramanian R, Nagarajan M, Balambal R, et al. Randomised controlled clinical trial of short course chemotherapy in abdominal tuberculosis: a five-year report. Int J Tuberc Lung Dis 1997;1:44–51. 50. Alrajhi AA, Halim MA, al-Hokail A, et al. Corticosteroid treatment of peritoneal tuberculosis. Clin Infect Dis 1998;27:52–56. 51. Bukharie H. Paradoxical response to anti-tuberculous drugs: resolution with corticosteroid therapy. Scand J Infect Dis 2000;32:96–97.
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52. Demir K, Okten A, Kaymakoglu S, et al. Tuberculous peritonitis–reports of 26 cases, detailing diagnostic and therapeutic problems. Eur J Gastroenterol Hepatol 2001;13:581–585. 53. Rao PL, Mitra SK, Pathak IC. Spontaneous tuberculous enteroumbilical fistulas. Am J Gastroenterol 1979;72:671–675. 54. Talwar S, Talwar R, Prasad P. Tuberculous perforations of the small intestine. Int J Clin Pract 1999;53:514–518. 55. Kirsch R, Pentecost M, Hall PdM, et al. Role of colonoscopic biopsy in distinguishing between Crohn’s disease and intestinal tuberculosis. J Clin Pathol 2006;59:840–844. 56. Engin G, Balk E. Imaging findings of intestinal tuberculosis. J Comput Assist Tomogr 2005;29:37–41. 57. Pereira JM, Madureira AJ, Vieira A, et al. Abdominal tuberculosis: imaging features. Eur J Radiol 2005;55:173–180. 58. Lee YJ, Yang S, Byeon J, et al. Analysis of colonoscopic findings in the differential diagnosis between intestinal tuberculosis and Crohn’s disease. Endoscopy 2006;38:592–597. 59. Pulimood AB, Ramakrishna BS, Kurian G, et al. Endoscopic mucosal biopsies are useful in distinguishing granulomatous colitis due to Crohn’s disease from tuberculosis. Gut 1999;45: 537–541. 60. Pulimood AB, Peter S, Ramakrishna B, et al. Segmental colonoscopic biopsies in the differentiation of ileocolic tuberculosis from Crohn’s disease. J Gastroenterol Hepatol 2005;20:688–696. 61. Fee MJ, Oo MM, Gabayan AE, et al. Abdominal tuberculosis in patients infected with the human immunodeficiency virus. Clin Infect Dis 1995;20: 938–944. 62. Smit SJA, Du Toit RS. The acute AIDS abdomen–a prospective clinical and pathological study. S Afr J Surg 2005;43:88.
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Tuberculosis of the kidney and urinary tract John B Eastwood and Catherine M Corbishley
INTRODUCTION Involvement of the genitourinary tract is a common non-pulmonary manifestation of primary TB and is usually the result of haematogenous dissemination of tubercle bacilli from a primary pulmonary complex. Congenital renal TB and involvement of the kidney by direct spread of disease from intestinal and other intra-abdominal lesions have been described but both are extremely rare. The various clinically evident pulmonary and non-pulmonary forms of primary TB usually appear within 3 years of initial infection,1 but an exception is renal TB, which often develops only after 8 or more years.2 Manifestation of disease may be delayed even longer and, as described in Chapter 15, the kidney is a frequent site of reactivation of TB due to Mycobacterium bovis acquired several decades previously. The kidney and urinary tract may, however, be involved in more acute widely disseminated forms of TB as occur, for example, in immunocompromised patients at any time in the natural history of the disease. For this reason, renal manifestations of TB are relatively more frequent in those infected with human immunodeficiency virus (HIV).3 The prevalence of TB of the genitourinary tract world-wide is uncertain as many cases, particularly in resource-poor regions, are not diagnosed. In the more developed nations, there are considerable variations in prevalence in different ethnic groups. In south-east England, for example, a survey of bacteriologically proven TB in 1995 showed that non-pulmonary manifestations were relatively much more common in patients of Indian subcontinent ethnic origin (46%) than in those of European ethnic origin (19%); yet, among non-pulmonary cases, genitourinary manifestations were significantly less common (8%) in the former than in the latter.4 The mean age of members of the Indian subcontinent ethnic group is somewhat lower than that of the European ethnic group in England and these differences in age distribution are, at least in part, responsible for this variation, since in developed nations genitourinary TB typically presents in the fourth to sixth decades of life.5
PATHOGENESIS The kidney is the usual site of the initial genitourinary lesion, and it is assumed that tubercle bacilli are implanted in this organ during the stage of haematogenous dissemination that occurs early in the natural history of the primary pulmonary complex. Granulomas usually develop initially in the glomeruli of the renal cortex; their development here has been attributed to high blood flow and
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raised oxygen tension, but the reason the disease takes several years to become manifest is unknown. The cortical tuberculous granulomas are unilateral or, more often, bilateral and if they undergo enlargement they may rupture into the proximal tubule, a process that enables bacilli to reach the loop of Henle. Lesions then develop in the renal medulla, and ensuing tissue necrosis may result in destruction of the renal papillae with extension of the disease into the renal calyces. Viable tubercle bacilli then enter the urinary system and cause secondary granulomas in the renal pelvis, ureters and bladder and in the male in the prostate, seminal vesicles and epididymis, although such lesions may also be the result of haematogenous or lymphatic spread from foci of TB elsewhere in the body.6
CLINICAL MANIFESTATIONS ‘CLASSICAL’ URINARY TRACT TUBERCULOSIS As mentioned earlier, overt renal TB occurs late in the ‘timetable’ of this disease, often after any other manifestation of primary disease has resolved. Thus, only around one-third of patients have an abnormal chest radiograph.7 As a result of this and the insidious nature of its development the diagnosis is often missed until the disease process is advanced with significant tissue destruction. In one illustrative study, 18 of 25 physicians found to have renal TB had advanced disease at the time of diagnosis. Despite their medical knowledge, most of them had not considered TB.8 Many patients present with signs and symptoms characteristic of bacterial infection of the bladder, including dysuria, nocturia, frequency and suprapubic pain, but no pathogens are found on standard bacteriological culture. In such symptomatic but culture-negative patients, the presence of many white blood cells in the urine (‘sterile pyuria’; see Box 41.1) should raise the clinical suspicion of genitourinary TB, especially in those patients who fail to respond to a course of antibacterial agents. There may be haematuria, which is occasionally macroscopic. In acquired immunodeficiency syndrome (AIDS) patients, the presence of sterile pyuria, albuminuria or haematuria have been recommended as indicative of a need for further investigation for renal TB.9 The classical features of TB such as fever, night sweats, general malaise, anorexia and loss of weight are unusual but when they occur suggest the presence of foci of TB elsewhere. Some patients report backache or flank pain of a vague ‘orthopaedic’ nature and, occasionally, abdominal pain. According to one report, around 10% of patients develop renal colic.10
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Box 41.1 Causes of a sterile pyuria
Tuberculosis of the urinary tract. Chlamydia trachomatis, Mycoplasma or Ureaplasma infection. Chemical cystitis. Renal calculi, prostatitis. Coliform (or other pathogen) urinary tract infection but antibiotic inhibiting growth. Failure to realize that low numbers of organisms can indicate infection. White blood cells from outside urinary tract, e.g. from foreskin or vulva. Renal parenchymal cause – acute tubulointerstitial nephritis, glomerular disease.
Scientific Foundations of Urology Vol 1, Chapter 30 (eds. D. Innes Williams and G.D. Chisholm), pp 211-217. London, Heinemann. Figure 5.
Advanced and bilateral renal TB with widespread tissue destruction results in reduction of renal function, which is best quantified by measuring glomerular filtration rate (GFR). It is important to prevent further loss of GFR by instituting treatment as soon as possible. Sometimes, a reduced GFR is the result of bilateral urinary obstruction due to secondary tuberculous lesions in the ureters and/or bladder. Scarring and contraction of the bladder reduces bladder capacity, a condition termed ‘thimble bladder’. Occasionally, in advanced cases, a renal mass may be palpable and there may be nephrocutaneous fistulae.
TUBERCULOUS INTERSTITIAL NEPHRITIS Although most patients with TB of the kidney develop the classical form described above, some develop an even more insidious form termed tuberculous interstitial nephritis. This was first described in 1981 in a report of three patients, one from West Africa and two from the Indian subcontinent, with advanced renal failure.11 Radiological examination revealed normal and equal-sized kidneys with smooth outlines, no calcification and no obvious anatomical distortion, but biopsies revealed interstitial infiltrations of chronic
41
inflammatory cells and granuloma formation. In two of them there was caseous necrosis with acid-fast bacilli but such bacilli were neither seen microscopically in the urine nor cultured from it. Two of these patients had radiological features compatible with pulmonary TB, and one had tuberculous peritonitis. The importance of these three patients is that they indicate that TB may involve the kidney, even to the extent of causing renal failure, without inducing any of the usual radiological and pathological features of such involvement, such as gross tissue destruction, calcification and fibrosis with associated urinary tract obstruction. In a subsequent study interstitial granulomas were found in 24 of 3,500 renal biopsies carried out in Paris over a 14-year period.12 Three of these 24 patients had TB and in one case acid-fast bacilli were demonstrated in the kidney. One illustrative case, a Ugandan Asian woman with evidence of impaired renal function (urea, 13.3 mmol/L; creatinine, 260 mmol/L; creatinine clearance, 17 mL/min), emphasizes the diagnostic difficulty. Radiology (intravenous urography) showed that her kidneys were equal-sized and with smooth outlines, and a renal biopsy revealed interstitial fibrosis with epithelioid and giant cell granulomas, one of which showed caseous necrosis.13 Although acid-fast bacilli were not seen in, nor were mycobacteria cultured from, either urine or biopsy material, the Mantoux test was strongly positive and a 12-month course of anti-TB therapy led to improvement in GFR (creatinine, 223 mmol/L; creatinine clearance, 39 mL/min) over the next 3 years, and a stable creatinine level thereafter (Fig. 41.1). The biopsy was the only pointer to the diagnosis of TB, which had not been considered earlier as, in contrast to previously reported cases, there was no other evidence of this disease and leucocytes were only seen in one of six mid-stream urine samples.11 As a result of the cryptic and insidious nature of tuberculous interstitial nephritis, it is, in contrast to classical renal TB, probably greatly underestimated as a cause of end-stage renal failure. In view of this it has been suggested that renal biopsy should be performed in all patients with radiologically normal kidneys in whom there is
70
14
80
12
90
1,000 creatinine
10
100
8
125 150
6
200 250 300
4 Creatinine (mmol/l)
400 500
2
1000 0
0
5
10 15 Years Fig. 41.1 Reciprocal creatinine plot against time, showing arrest of decline of renal function after treatment of renal TB. Grey rectangle indicates treatment with anti-TB drugs and prednisolone for 6 months. Vertical axis: numbers to left refer to 1,000/Creatinine; those to the right the plasma creatinine. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3. Fig. 2.
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no apparent cause – especially in patients from communities at a high risk of TB.11,14
GLOMERULAR DISEASE Various forms of glomerulonephritis have been documented in patients with leprosy, especially in those with long-standing multibacillary (borderline and polar lepromatous) forms of the disease, and are due to secondary immunological phenomena.15 Indeed, renal failure is a common cause of death in such patients. By contrast, evidence for an association between glomerulonephritis and TB is limited to a few case reports. These include a TB patient with ‘dense deposit disease’,16 and another with miliary TB who had focal proliferative glomerulonephritis with granular staining for IgA, IgM, and C3 around capillary loops and in the mesangium.17 In the latter case tuberculous granulomas could not be identified in kidney tissue, suggesting that the glomerular lesions might, as in leprosy, be due to secondary immune phenomena. There is an association between long-standing TB and amyloidosis, with considerable geographical differences in prevalence. In India renal amyloidosis affecting the kidney is a common cause of renal failure in TB patients.18
TUBERCULOSIS IN PATIENTS WITH CHRONIC RENAL FAILURE Chronic renal failure appears to be a risk factor for the development of overt TB as the disease is more frequent in patients with renal failure than in the general population.19 The uraemia associated with chronic renal failure has immunosuppressive effects, manifesting as anergy on skin testing with a range of recall antigens including mumps, tetanus and candida. Two studies revealed anergy on recall skin testing in, respectively, 32% and 40% of patients on dialysis.20,21 In a further study, anergy was demonstrated in 69% of patients at the start of haemodialysis but this level dropped to 50% in patients on dialysis for 1–8 months, and to 24% in those on dialysis for 9–69 months, but rising again to 46% in patients on dialysis for 6 or more years.22 Patients with renal failure are almost always negative on tuberculin skin testing but the significance of this in an individual case cannot be determined unless the tuberculin status of a patient before the onset of renal failure is known.20 Many patients with renal failure have low circulating levels of 25-OH-vitamin D,23 and this may contribute to the risk of developing overt TB after infection as this vitamin is involved in macrophage activation and low levels are a known predisposing factor for this disease. Diabetes, a risk factor for TB,19 is a common cause of end-stage renal disease; in the UK around 20% of patients commencing dialysis are diabetic.
TUBERCULOSIS AS A CAUSE OF END-STAGE RENAL DISEASE Tuberculosis is a cause of progressive renal failure but, in contrast to many other causes of this condition, is potentially treatable.13 Early diagnosis is therefore important. The European Dialysis and Transplant Association (EDTA), covering 35 European countries, reported that 195 (0.65%) of 30,064 new dialysis patients in 1991 had renal failure due to TB, a proportion similar to data from previous years.24 The relative incidence shows geographical variation. In Portugal, for example, a high incidence was reported in the Algarve, with TB being the cause of renal failure in 12 (3.5%) of 345 patients
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commencing dialysis over a 10-year period.25 In addition, TB as the primary cause of renal failure is commoner in Europe (0.7%) than in the United States (0.004%) and Australasia (0.16%).26 Unfortunately, many patients with TB as the primary cause of end-stage renal failure have neither symptoms nor signs of this disease at the time of renal diagnosis. As mentioned earlier, the insidious and cryptic interstitial form of renal TB is especially likely to be overlooked as a cause of end-stage renal failure and, as it is treatable, diagnostic awareness and appropriate investigations, including biopsy, are advisable.11,14
DIALYSIS PATIENTS Haemodialysis, especially in diabetics,19 is a risk factor for the development of TB, particularly reactivation of latent disease.27 In such patients, TB often develops in an insidious manner with non-specific symptoms including anorexia, weight loss and lowgrade fever. The majority of patients have extrapulmonary forms of TB or, occasionally, miliary disease.28,29 In more developed nations a higher proportion of those in ethnic minority groups than in the indigenous majority population require dialysis for end-stage renal disease,30,31 and as many come from countries where infection by tubercle bacilli is common, patients in these minority groups have a higher incidence of TB.32 In a report of 11 dialysis patients with TB seen at the Hammersmith Hospital, London, all were born abroad.19 The annual incidence of TB in these patients was equivalent to 1,187 per 100,000 population, compared with an overall annual incidence in England and Wales of at most 210 (black Africans) and 132 (individuals from the Indian subcontinent) cases per 100,000 population. Accordingly, evidence of TB must be sought carefully in members of ethnic minority groups, especially immigrants, refugees and asylum seekers who have renal failure. There have been fewer reports of TB among patients undergoing continuous ambulatory peritoneal dialysis (CAPD) than in those on haemodialysis, although there is no reason these patients should be at a lower risk.33,37 In one series of eight patients with peritoneal TB seen over a 13-year period, all were undergoing CAPD rather than the automated form (APD).37 Tuberculosis developed soon after dialysis commenced and was indistinguishable from non-acidfast bacterial peritonitis. Tubercle bacilli were isolated from six of the eight patients, mostly from the peritoneal fluid itself.
TRANSPLANT PATIENTS As a result of immunosuppressive therapy, recipients of transplants, including renal transplants, are at risk of various opportunist infections such as those caused by Epstein–Barr virus, cytomegalovirus and Pneumocystis jiroveci. Until recently TB received less attention than other opportunist infections as it appeared to be an uncommon complication. Thus, in 1983 when renal transplantation had been in existence for about 30 years, a review of the literature revealed only 42 cases of TB among recipients of transplanted kidneys.38 Subsequently, 14 cases of TB were reported in a group of 403 renal transplant patients in Saudi Arabia, corresponding to a risk of the disease 50 times that of the general population.39 Miliary TB occurred in 64% of these 14 patients, and in 38% of a total of 130 Saudi Arabian patients reported in other publications. The risk of developing TB was unrelated to tuberculin skin test reactivity. It is therefore necessary to consider TB in renal transplant recipients who develop fever or other suggestive symptoms and signs, especially if the patient is from a community at risk of infection.
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Until recently, the need for routine TB preventive therapy for transplant patients was controversial and there was no consensus opinion and no clear guidelines. The ‘European Best Practice Guidelines for Renal Transplantation’, published in 2002, recommend that those selected for, and receiving, renal transplants who may have latent TB should receive isoniazid prophylaxis, 300 mg daily for 9 months.40 Candidates for preventive therapy are those with one or more of the following:
a history of inadequately treated TB; radiological evidence suggestive of old pulmonary TB; close contact with a person with TB; and induration on Mantoux skin testing of 5 mm for transplant recipients or 10 mm for patients on dialysis awaiting transplantation.
Because patients sometimes acquire TB from the transplanted kidney itself,39,41 tuberculin-negative patients who receive a kidney from a tuberculin-positive donor should also be prescribed preventive therapy. Despite widely held views to the contrary, there is little published evidence that systemic corticosteroid therapy is a risk factor for reactivation of latent TB. Nevertheless, as those with latent TB who are receiving long-term corticosteroid therapy for respiratory disease are often given isoniazid preventive therapy,42 it appears rational to treat renal transplant patients, whose therapy induces a more profound suppression of their immunity, in like manner.
TUBERCULOSIS OF THE GENITAL TRACT These forms of TB are described in Chapters 42 and 43. In relation to TB of the kidney and urinary tract, it is important to note that, while TB of the female genital tract is almost always acquired by haematogenous dissemination from the lung or other site,7 genital TB in the male is almost always, but not exclusively, secondary to disease of the kidney and spread by infected urine.As a result, the urinary tract should be fully investigated in all male patients with genital TB as at least three-quarters of the patients will have lesions elsewhere in the urinary tract,43 compared with only 5% of females.
HYPERCALCAEMIA AND TUBERCULOSIS Hypercalcaemia has been described in haemodialysis patients with both genitourinary and disseminated TB.44–46 It has also been reported in a CAPD patient with tuberculous peritonitis.47 In one case, hypercalcaemia developed in a patient who had been on haemodialysis for 8 months and developed widely disseminated TB with persistent fever;44 circulating levels of calcitriol (1,25-(OH)2 vitamin D3), but not those of parathyroid hormone, were found to be elevated. Indeed, hypercalcaemia has been reported in patients with disseminated TB in the absence of renal disease. In both the examples hypercalcaemia has been attributed to elevated levels of calcitriol due to its synthesis by activated macrophages in the widespread lesions.48
DIAGNOSIS BACTERIOLOGICAL INVESTIGATIONS Acid-fast bacilli are detectable in the urine by microscopy and culture. Microscopy is relatively insensitive as in many cases few bacilli are present in the urine and they may be shed from the lesions
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intermittently. Care should be taken in the interpretation of any acid-fast bacilli seen as the lower urethra may be contaminated with various species of environmental mycobacteria. Centrifuged deposits of mid-stream early morning urine samples collected on 3 consecutive days are suitable for both microscopy and culture. The reported diagnostic sensitivity of urine culture varies greatly from study to study. There have been a few reports of the successful use of the polymerase chain reaction (PCR) to detect Mycobacterium tuberculosis in urine but there is a need for more data as some culture-positive patients are negative on PCR.49 As with microscopy, isolation of an environmental mycobacterium should be interpreted with caution. A literature survey has shown that, apart from occurring as a component of a disseminated infection in an immunocompromised patient, renal disease due to environmental mycobacteria is extremely rare; rigorous criteria for its diagnosis should therefore be applied.50
IMAGING (FIGS 41.2–41.7) Radiological imaging has a central place in the diagnosis of TB of the kidney and urinary tract, with intravenous urography (IVU) being particularly important as it reveals the anatomical structures clearly. Plain films reveal renal calcification in about 30% of cases.51 Calcification may be punctate, speckled or diffuse and in advanced disease the entire pelvicalyceal system and upper ureter may be outlined by calcified tissue. In early TB irregularity of the papillary margins with reduced density of contrast medium is seen in the affected part of the kidney. In more advanced disease cavities, which may be smooth or irregular and which may communicate with the pelvicalyceal system, develop and there is an associated loss of renal parenchyma. Urography also reveals strictures due to fibrosis and when these involve the calyceal infundibula the contrast medium does not fill the calyces and typically the infundibulum shows a ‘pinched-off’ appearance. Fibrosis at the pelviureteric junction can lead to obstruction and calyceal dilatation. A combination of granulomatous lesions and dilated calyces that do not fill with contrast medium may give the appearance of a mass. Extension of the disease process into the perinephric space may lead to formation of abscesses and fistulae that communicate with the skin or intestine and may be revealed in detail by the use of retrograde ureterography or sinography. As discussed earlier, tuberculous lesions of the ureter and bladder are almost always secondary to renal disease, which is usually evident radiologically. The earliest ureteric change, ulceration, is not usually seen on intravenous urography but dilatation due to strictures, and filling defects due to extensive granuloma formation, are more easily identifiable. In more advanced disease with progressive fibrosis the ureter shortens, the wall becomes thickened and incompetence at the vesicoureteric junction leads to urinary reflux. Likewise the bladder wall may be thickened, and large granulomatous lesions may appear as filling defects. As the disease of the bladder becomes generalized, progressive fibrosis leads to a reduction in bladder capacity. With advanced disease the ureters and bladder may become calcified and be visible on plain films, as may the prostate, seminal vesicles and epididymis when these structures are involved in the disease process. Although ultrasonography may reveal features of advanced disease, including pelvicalyceal dilatation, perinephric abscesses and extensive calcification,52 it is less sensitive than intravenous urography.53 Likewise, though computed tomography reveals characteristics of
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Fig. 41.2 Early focal renal TB. The plain radiograph shows calcification in the lower pole of the right kidney. The 5-minute IVU radiograph shows an
abnormal lower pole calyx with loss of adjacent parenchyma. There was sterile pyuria and M. tuberculosis was cultured from the urine. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 3.
Fig. 41.3 Late bilateral renal TB. The IVU radiograph shows bilateral calyceal dilatation with calcification on the right. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 4.
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Fig. 41.4 Early changes of renal TB on a 20-minute IVU radiograph. There are cavities in the parenchyma adjacent to the right upper and interpolar calyces; there is dilatation of the right ureter. The left kidney is normal. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 5.
Fig. 41.5 (A) Calcification in the right hypochondrium. (B) More pronounced calcification in the same area 9 years later. (C) The 20-minute IVU radiograph shows calyceal distortion and stricture – typical appearances of TB. The multifocal strictures and dilated segments of the ureter are typical late features of TB and there is also irregularity of the bladder wall. The left kidney is normal. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 6.
Fig. 41.6 (A) A 30-minute IVU radiograph shows normal left kidney and ureter and a lack of excretion on the right. (B) A 1-hour radiograph shows that contrast medium is no longer seen in the collecting system on the left side and there is opacification of a grossly distorted kidney on the right. This appearance is typical of ‘autonephrectomy’ that sometimes occurs in very advanced disease but the lack of calcification is unusual. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 7.
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Fig. 41.7 Two 10-minute IVU radiographs taken 1 month apart. Note the mural abnormalities in the ureter (A) that have progressed to frank strictures 1 month later. The right kidney shows widespread calyceal dilatation. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 8.
advanced disease including renal parenchymal masses, scarring, thickening of the wall of the urinary tract and extrarenal lesions more often than intravenous urography,54,55 it appears, though not assessed in detail, to be less sensitive than the latter in early disease as it does not give such a detailed picture of the pelvicalyceal anatomy. Imaging is required in the early months of anti-TB therapy since ureteric strictures may develop; limited intravenous urography has always been used to reveal these strictures as well as any dilatation of the proximal urinary tract. Strictures may develop at sites apparently normal at the time of the initial investigation as mucosal ulceration present before treatment may not be readily seen radiologically. In practice nowadays ultrasonography is used for early detection of strictures and hold-up as it is less invasive than urography, does not require intravenous contrast and is easy to repeat.
PATHOLOGY The morphology of the lesions in TB of the kidney and urinary tract depend, as in other forms of TB, on the virulence of the organism and the immune status of the patient. As in other anatomical sites, the characteristic lesion is the caseating epithelioid granuloma (Fig. 41.8), although caseation is not always seen, especially in the lesions of cryptic disseminated disease in immunocompromised persons and in those due to Bacillus Calmette–Gue´rin (BCG). Acid-fast bacilli are usually demonstrable in early active foci of disease and may be particularly abundant in the lesions of immunocompromised patients (Fig. 41.9),56 but they may be scanty or impossible to find in lesions of immunocompetent or treated patients or in old lesions.57 Fluorescence microscopy and
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Fig. 41.8 Caseating epithelioid granuloma, the classical histological hallmark of TB.
nucleic acid technology such as in situ PCR are more sensitive for the detection of tubercle bacilli in tissues and are thus becoming more widely used. Examination of formalin-fixed and paraffinprocessed tissue sections by in situ PCR yields both false-positive and -negative results and so its use in primary diagnosis is limited. There are several causes of granulomas in the kidney and urinary tract that must be differentiated from TB. Fungal infections and Wegener’s granulomatosis may be the cause of necrotizing granulomas and non-caseating granulomas may be due to sarcoidosis,
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Fig. 41.9 Large numbers of acid-fast bacilli in the tissues of an immunocompromised patient with overwhelming infection. Ziehl-Neelsen stain. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 10.
leprosy and brucellosis. ‘Foreign body type’ granulomas occasionally develop as responses to amyloid, ruptured tubules, myeloma protein and therapeutic embolization and usually have features quite different from those of infectious granulomas. A condition termed xanthogranulomatous pyelonephritis may resemble renal TB both clinically and radiologically but it is readily distinguishable on histological examination.
Fig. 41.10 Tuberculous involvement of the renal papillae with papillary necrosis and cystic changes.
PATTERNS OF RENAL TUBERCULOSIS Localized disease Although TB of the kidney is almost always due to haematogenous spread from a primary lesion, usually in the lung, evidence of active pulmonary TB is uncommon at the time that renal disease becomes clinically evident. This may be due to the long time interval before the emergence of renal lesions, in contrast to other forms of nonpulmonary TB. There may, however, be radiological evidence of old, healed, pulmonary lesions.58,59 At the time of diagnosis, renal TB is usually unilateral but in the absence of treatment, as in the prechemotherapeutic era, the disease is often bilateral at autopsy.60,61 Most tuberculous lesions in the kidney are in the medulla and often manifest as confluent caseating epithelioid cell granulomata. Local damage to blood vessels by the disease process leads to vascular insufficiency of, and ultimately necrosis of, the papillae (Fig. 41.10). Spread to the renal pelvis may result in tuberculous pyelonephritis and, in some cases, progression to gross and widespread renal necrosis resembling pyonephrosis. This condition is termed ‘cement kidney’, ‘putty kidney’ or ‘mortar kidney’ (Fig. 41.11). Complete isolation of a grossly diseased and nonfunctional kidney from surrounding tissues is termed ‘autonephrectomy’.62 Spread of the disease process outside the renal capsule may produce a space-occupying mass that may mimic a cancer,63 or xanthogranulomatous pyelonephritis.64 Calcification secondary to fibrosis in the renal pelvis occurs in 24% of cases, with the development of renal or ureteric calculi in up to 19% of cases.65 The pathogenesis of tuberculous interstitial nephritis is poorly understood. Granulomata are detectable in some, but not all, cases
(Fig. 41.12), and there may be an immunological component as recovery is enhanced by the use of corticosteroids as well as anti-TB agents.11 Proliferative glomerulonephritis due to immune complex deposition as a complication of miliary TB has also been reported.17
Disseminated disease The kidney is often involved in widely disseminated TB which, depending on the immune status of the patient, may be of the miliary or cryptic disseminated forms. In miliary TB, tubercles up to 3 mm in diameter and usually pale or white are present throughout the kidney, principally in the cortex. There are epithelioid cell granulomata, with or without caseation and both Langhans-type giant cells and acid-fast bacilli are usually seen. Renal function is usually within normal limits. The lesions in immunocompromised patients with cryptic disseminated TB are more diffuse and less well formed than in classical miliary disease and contain histiocytic cells with abundant pale cytoplasm and numerous acid-fast bacilli (‘multibacillary histiocytosis’). A similar appearance is seen in immunocompromised patients with disease caused by an environmental mycobacterium, such as a member of the Mycobacterium avium complex.66 LOWER URINARY TRACT INVOLVEMENT Tubercle bacilli released into the pelvicalyceal system from necrotic lesions pass down the ureters and, after implantation, may cause secondary lesions in the ureters and bladder involving the mucosae
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Fig. 41.13 Tuberculous stricture of the ureter with inflammation and thickening of the mucosa and ureteral wall.
Fig. 41.11 ‘Cement’ or ‘putty’ kidney. Tuberculous ‘pyonephrosis’ with extensive confluent caseous necrosis and renal parenchymal destruction. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 14.
dilatation and/or reflux. Large amounts of keratin are sometimes produced by tuberculous lesions in the renal pelvis and may cause renal colic. Early diagnosis of TB and commencement of anti-TB therapy and, if indicated, surgical relief of obstruction may prevent loss of renal function, gross pathology and the possible need for nephrectomy.58,67 Contraction of the bladder due to scarring may continue after successful treatment of TB and may severely reduce capacity and require bladder augmentation or, in severe cases, cystectomy.68 Secondary bacterial infection of the urinary tract is a common complication of TB and, as a late complication, chronic inflammation and infection of the renal pelvis or bladder may result in the development of keratinizing squamous metaplasia (previously known as leucoplakia) (Fig. 41.14). Keratinizing squamous metaplasia may persist after successful treatment of tuberculous cystitis,69 and is a risk factor for the development of squamous carcinoma. Although, by reducing the inflammation, anti-TB therapy reduces
Fig. 41.12 Granulomatous interstitial nephritis; note that one of the glomeruli is normal.
and walls of these structures. An uncommon cause of TB of the bladder is spread from a lesion in the epididymis resulting directly from haematogenous dissemination from disease elsewhere in the body. Ureteric involvement may induce scarring which, in turn, results in irregular strictures (Fig. 41.13), urinary obstruction, segmental
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Fig. 41.14 Keratinizing squamous metaplasia of the bladder. There is no epithelial dysplasia but such cases carry an increased risk of developing squamous cell carcinoma in both the bladder and renal pelvis where similar metaplasia may be present. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). 3rd edn. Oxford: Oxford University Press, 2005: 7.3, Fig. 16.
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this risk, long-term follow-up is required to detect early and treatable malignant transformation.
BCG-INDUCED URINARY TRACT INFECTION In many centres, instillation of BCG is the method of choice for treatment of transitional carcinoma in situ and superficial cancer of the bladder. Patients usually develop a self-limiting low-grade superficial cystitis which may be essential to the success of this treatment, but more severe inflammatory reactions sometimes occur. BCG infection, usually asymptomatic, of the prostate frequently occurs. A few cases of disseminated BCG disease (‘BCG-osis’) have been reported,70 but a more common complication is ascending infection by reflux leading to development of ureteric lesions which, in one survey, led to ureteric obstruction in 0.3% of 2,602 treated patients.71 In addition, renal lesions were detected in 0.1% of these patients and this was also attributed to ascending infection. The lesions caused by BCG are identical to those caused by virulent tubercle bacilli (Fig. 41.15) and caseation is more often seen in lesions of the prostate than in those in the bladder. Although acid-fast bacilli may be demonstrated in the lesions, diagnosis is usually based on a history of BCG treatment. Balanoposthitis due to BCG occasionally occurs and is probably due to local trauma of the urethra during insertion of the catheter used to instil the BCG.72
TREATMENT The short-course anti-TB regimens advocated by the World Health Organization (WHO) and described in Chapters 61 and 62 are suitable for all forms of TB, including those involving the kidney and urinary tract.73 In practice, most patients will receive a 2-month intensive phase of rifampicin, isoniazid, pyrazinamide and ethambutol, followed by a 4-month continuation phase of rifampicin and isoniazid. Three of the drugs in this regimen – rifampicin, isoniazid, pyrazinamide – as well as the closely related second-line drugs ethionamide and protionamide – are either directly metabolized or excreted in the bile. They may thus usually be given safely in the
Fig. 41.15 BCG-induced granulomatous prostatitis around prostatic ducts in a cysto-prostatectomy specimen. The patient had been treated with intravesical BCG for transitional carcinoma in situ of the bladder.
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standard doses to patients with reduced renal function. Care is, however, required with isoniazid in patients with impaired renal function as the rare complication of encephalopathy occurs more frequently in such patients. Although the incidence of encephalopathy is reduced by giving pyridoxine, 25–50 mg/day, this complication has occasionally been reported in dialysis patients, even those receiving pyridoxine, although the condition has resolved when isoniazid was withdrawn.74 Hepatotoxicity is a recognized adverse effect of isoniazid but data on its occurrence in renal transplant recipients are limited and are discussed in the ‘European Best Practice Guidelines for Renal Transplantation’, published in 2002.40 The available data indicate that the risk of serious hepatotoxicity is low when isoniazid is given alone for preventive therapy but the risk rises when other anti-TB agents are given. Accordingly, the hepatic function of renal transplant recipients being treated for TB should be regularly monitored. The presence of viral hepatitis does not appear to enhance the risk of isoniazid-related hepatotoxicity. Unlike the other three first-line anti-TB agents mentioned earlier, ethambutol is principally eliminated by the kidney and, if renal function is impaired, the dose should be reduced. Thus, if the glomerular filtration rate is between 50 and 100 mL/min 25 mg should be given three times a week, and if it is between 30 and 50 mL/min the same dose should be given twice a week.75,76 As streptomycin, in common with other aminoglycosides, is excreted entirely by the kidney and can cause severe renal toxicity it should be avoided whenever possible in patients with renal failure, whether or not they are on dialysis. If it is considered necessary to treat such patients with an aminoglycoside, they should only be used if frequent assays can be conducted so that the plasma levels can be kept within safe limits and a suitable dosage established. Renal transplant patients require several agents to induce immunosuppression, including corticosteroids, azathioprine, ciclosporin, sirolimus and tacrolimus. Care is required with the use of rifampicin which, as described in Chapter 59, increases the catabolism of these and many other drugs, such as diazepam, digoxin, opioids, oral contraceptives, phenytoin and warfarin, that transplant patients may require.77 Streptomycin increases the available level of ciclosporin, resulting in nephrotoxicity, so use of this aminoglycoside should be avoided. Although there were concerns that the use of isoniazid in preventive therapy in transplant patients might likewise induce ciclosporin nephrotoxicity by increasing the plasma level of this agent, a detailed study on seven renal transplant recipients of slow isoniazid acetylation status showed that the pharmacokinetic behaviour of ciclosporin was not adversely affected by isoniazid and it was thus concluded that the simultaneous use of these agents is safe.78 At the time of writing, there is little information on the effect of isoniazid on the pharmokinetics and metabolism of tacrolimus or sirolimus so no recommendations with regard to their concomitant use can be made. The particular problems of drug interactions between anti-TB and antiretroviral agents given simultaneously to those with TB and HIV disease are discussed in Chapter 60. In some patients with HIV disease, antiretroviral therapy induces a condition termed immune restoration inflammatory syndrome (IRIS, Chapter 67), which can have serious adverse effects on the patient, including a few cases of acute renal failure in patients with localized or disseminated TB or disease due to environmental mycobacteria.79
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SURGERY A detailed account of surgical procedures is beyond the scope of this book. Emergency surgical procedures, including percutaneous nephrostomy and endoscopic stenting of the ureter, are required for the relief of urinary tract obstruction in cases of diminishing renal function.80 Reconstructive surgery may be required for correction of strictures and to augment the capacity of a shrunken bladder. The European Association of Urology advises that both radical and reconstructive surgery should be carried out during the initial intensive 2-month period of anti-TB therapy.73 Surgery may be subsequently required to relieve strictures that develop during or after anti-TB therapy. In this context, corticosteroids are sometimes added to the therapeutic regimen on the assumption that this will reduce scarring, strictures and contractures but there is no firm evidence of beneficial effects. In general the need for open surgery has declined in recent years, and a non-functioning kidney giving rise to no symptoms would not normally be removed. On the other hand, surgery might be contemplated in the presence of complicating factors such as abscesses or fistulae.
and eventually end-stage renal failure. Second, patients with renal failure, especially those treated by one of the various forms of dialysis and recipients of renal transplantation, are more susceptible to the development of overt TB, following either primary infection or reactivation of latent TB. Likewise, patients with certain renal diseases, particularly vasculitides and some forms of glomerulonephritis, are treated with immunosuppressive agents that render them more susceptible to activation of TB and other mycobacterial diseases. Unexplained fever, malaise and weight loss in patients with renal disease, especially in those treated with immunosuppressive agents including recipients of renal transplants, should lead one to consider a diagnosis of TB. In patients with TB and chronic renal insufficiency, including those on dialysis, the former can usually be treated successfully by the agents used in standard short-course anti-TB regimens, although attention to drug dosages and adverse effects is required. Interactions between agents used to treat TB, notably rifampicin, and ciclosporin, tacrolimus and other immunosuppressive agents also require careful management.
ACKNOWLEDGEMENTS CONCLUSIONS There are two principal associations between disease of the kidneys and urinary tract and TB. First, TB may directly affect these structures and, by either destruction of renal tissue or the development of urinary tract obstruction, lead to impairment of renal function
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Tuberculosis of the kidney and urinary tract 32. Kwan JT, Hart PD, Raftery MJ, et al. Mycobacterial infection is an important infective complication in British Asian dialysis patients. J Hosp Infect 1991;19:249–255. 33. Cheng IK, Chan PC, Chan MK. Tuberculous peritonitis complicating long-term peritoneal dialysis. Am J Kidney Dis 1989;9:155–161. 34. Tan D, Fein PA, Jorden A, et al. Successful treatment of tuberculous peritonitis while maintaining patient on CAPD. Adv Perit Dial 1991;7:102–104. 35. Ahijado F, Luno J, Soto I, et al. Tuberculous peritonitis on CAPD. Contrib Nephrol 1991;89: 79–86. 36. Ong AC, Scoble JE, Baillod RA, et al. Tuberculous peritonitis complicating peritoneal dialysis: a case for early diagnostic laparotomy. Nephrol Dial Transplant 1992;7:443–446. 37. Quantrill SJ, Woodward MA, Bell CE, et al. Peritoneal tuberculosis in patients receiving continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2001;16:1024–1027. 38. Lichtenstein IH, MacGregor RR. Mycobacterial infections in renal transplant recipients: report of five cases and review of the literature. Rev Infect Dis 1983;5:216–226. 39. Qunibi WY, Al-Sibai MB, Taher S, et al. Mycobacterial infection after renal transplantation: a report of 14 cases and review of the literature. QJM 1990:77:1039–1060. 40. European Best Practice Guidelines for Renal Transplantation. Part 2. Tuberculosis. Nephrol Dial Transplant 2002;17(Suppl 4):39–43. 41. Peters FT, Reiter CG, Boswell RL. Transmission of tuberculosis by kidney transplantation. Transplantation 1984;38:514–516. 42. American Thoracic Society. Preventative therapy of tuberculosis infection. Am Rev Respir Dis 1974; 110:371–374. 43. Ferrie BG, Rundle JSH. Tuberculous epididymoorchitis. A review of 20 cases. Br J Urol 1983; 55:437–439. 44. Felsenfeld AJ, Drezner MK, Llach F. Hypercalcaemia and elevated calcitriol in a maintenance dialysis patient with tuberculosis. Arch Intern Med 1986; 146:1941–1945. 45. Peces R, Alvarez J. Hypercalcemia and elevated 1,25 (OH)2D3 levels in a dialysis patient with disseminated tuberculosis. Nephron 1987;46:377–379. 46. Peces R, de la Torre M, Alcazar F, et al. Genitourinary tuberculosis as the cause of unexplained hypercalcaemia in a patient with preend-stage renal failure. Nephrol Dial Transplant 1998;13:488–490. 47. Lye WC, Lee EJ. Tuberculous peritonitis in CAPD— a cause of hypercalcaemia. Perit Dial Int 1990; 10:307–308.
48. Rook GAW. The role of vitamin D in tuberculosis. Am Rev Respir Dis 1988;138:768–770. 49. Madkour MM. Genitourinary tuberculosis. In: Madkour MM (ed). Tuberculosis. Berlin: Springer, 2004: 699–729. 50. Eastwood JB, Corbishley CM, Grange JM. Renal tuberculosis and other mycobacterial infections. In: Davidson AM, Cameron JS, Grunfeld J-P, et al (eds). Oxford Textbook of Nephrology, 3rd edn. Oxford: Oxford University Press, 2005: 7.3. 51. Roylance J, Penry JB, Davies ER, et al. The radiology of tuberculosis of the urinary tract. Clin Radiol 1970;21:163–170. 52. Schaffer R, Becker JA, Goodman J. Sonography of tuberculous kidney. Urology 1983;22:209–211. 53. Premkumar A, Latimer M, Newhouse JH. CT and sonography of advanced urinary tract tuberculosis. Am J Roentgenol 1987;148:65–69. 54. Goldman SM, Fishman EK, Hartman DS, et al. Computed tomography of renal tuberculosis and its pathological correlates. Comput Assist Tomogr 1985;9:771–776. 55. Wang LJ, Wu CF, Wong YC, et al. Imaging findings of urinary tuberculosis on excretory urography and computerized tomography. J Urol 2003;169:524–528. 56. Ridley DS, Ridley MJ. Rationale for the histological spectrum of tuberculosis. A basis for classification. Pathology 1987;19:186–192. 57. Trasca E, Trasca ET, Buzulica R, et al. The place and role of histological examination in diagnostic algorithm of urinary system tuberculosis. Rom J Morph Embryol 2005;46:105–108. 58. Christensen WI. Genitourinary tuberculosis: Review of 102 cases. Medicine 1974;53:377–390. 59. Narayana AS. Overview of renal tuberculosis. Urology 1982;19:231–237. 60. Kretschmer HL. Tuberculosis of the kidney, a critical review based on a series of 221 cases. N Engl J Med 1930;202:660–671. 61. Greenberger ME, Wershub LP, Auerbach O. The incidence of renal tuberculosis in five hundred autopsies for pulmonary and extrapulmonary tuberculosis. JAMA 1935;104:726–730. 62. Muttarak M, Pattamapaspong N. Clinics in diagnostic imaging (97). Right renal tuberculous autonephrectomy. Singapore Med J 2004;45:239–241. 63. Njeh M, Jemni M, Abid R, et al. La tuberculose renale a forme pseudo tumorale. J Urol (Paris) 1993;99:150–152. 64. Shah HN, Jain P, Chibber PJ, et al. Renal tuberculosis simulating xanthogranulomatous pyelonephritis with contiguous hepatic involvement. Int J Urol 2006;13:67–68. 65. Ross JC. Calcification in genito-urinary tuberculosis. Br J Urol 1970;42:656–660.
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66. Horsburgh CR. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:1332–1338. 67. Ramanathan R, Kumar A, Kapoor R, et al. Relief of urinary tract obstruction in tuberculosis to improve renal function. Analysis of predictive factors. Br J Urol 1998;81:199–205. 68. Laidlaw M. Renal tuberculosis. In: Chisholm GD, Innes Williams D (eds). Scientific Foundations of Urology, 2nd edn. London: Heinemann, 1982: 222–227. 69. Byrd RB, Viner NA, Omell GA, et al. Leukoplakia associated with renal tuberculosis in the chemotherapeutic era. Br J Urol 1976;48:377–381. 70. Ersoy O, Aran R, Aydinli M, et al. Granulomatous hepatitis after intravesical BCG treatment for bladder cancer. Indian J Gastroenterol 2006;25:258–259. 71. Lamm DL. Complications of Bacillus CalmetteGue´rin immunotherapy. Urol Clin North Am 1992;19: 565–572. 72. Yusuke H, Yoshinori H, Kenichi M, et al. Granulomatous balanoposthitis after intravesical Bacillus Calmette-Gue´rin instillation therapy. Int J Urol 2006;13:1361–1363. 73. Cek M, Lenk S, Naber KG, et al. Members of the Urinary Tract Infection (UTI) Working Group of the European Association of Urology (EAU) Guidelines Office. EAU guidelines for the management of genitourinary tuberculosis. Eur Urol 2005;48: 353–362. 74. Cheung WC, Lo CY, Lo WK, et al. Isoniazid induced encephalopathy in dialysis patients. Tuberc Lung Dis 1993;74:136–139. 75. Mitchison DA, Ellard GA. Tuberculosis in patients having dialysis. BMJ 1980;1:1186 and 1533. 76. Girling DJ. The chemotherapy of tuberculosis. In: Ratledge C, Stanford JL, Grange JM (eds). The Biology of the Mycobacteria, Vol. 3. London/New York: Academic Press, 1989: 285–323. 77. Finch CK, Chrisman CR, Baciewicz AM, et al. Rifampin and rifabutin drug interactions: an update. Arch Intern Med 2002;162:985–992. 78. Sud K, Muthukumar T, Singh B, et al. Isoniazid does not affect bioavailability of cyclosporine in renal transplant recipients. Method Find Exp Clin Pharmacol 2000;22:647–649. 79. Daugas E, Plaisier E, Boffa JJ, et al. Acute renal failure associated with immune restoration inflammatory syndrome. Nat Clin Pract Nephrol 2006;2:594–598. 80. Shin KY, Park HJ, Lee JJ, et al. Role of early endourologic management of tuberculous ureteral strictures. J Endourol 2002;16:755–758.
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Male genital tuberculosis Mete C ¸ ek
BACKGROUND/INTRODUCTION The high incidence of TB in developing countries makes this a health problem of large proportions world-wide. Genitourinary TB is one of the most frequent non-pulmonary manifestations of TB. Other bacterial (including non-tuberculous mycobacterial) infections, tumours, cysts, fungal diseases and some less common illnesses (parasitic, tropical, granulomatous diseases) may be confused with tuberculous genital infection. The prostate and the epididymis are the most frequently affected genital sites of TB.1 Testicles are less frequently infected. Haematogenous seeding, intracanalicular or direct extension from neighbouring foci in the genital tract and infection descending from the kidneys are the normal routes of infection.
EPIDEMIOLOGY In developing countries, the percentage of cases of TB with genitourinary involvement is approximately double that in developed areas. The incidence of TB in some developing countries is 30 times greater than that in the United States. In the northern hemisphere, the TB incidence varies from 5 per 100,000 population in Sweden to 181 per 100,000 population in Kazakhstan.2 Epididymal TB most commonly develops in sexually active young men. Before the development of anti-TB treatment, the typical patient was aged 16–40 years. Now, more than 70% of men with genital TB are older than 35, and 15–20% are older than 65.3 Almost four-fifths of the 243 patients with prostatic TB in Moore’s historical 1937 paper were under the age of 50. This finding convinced him that this was ‘a disease of young adults’. However, in a recent series of 100 patients reported by Kulchavenya and Khomyakov,4 the mean age of patients with prostatic TB was 49 and the mean age of patients with TB of the intrascrotal organs was 45.4. Tzvetkov and Tzvetkov5 reported 69 male patients with genital TB with an average age of 40.3 years. On the other hand, case reports and small series of prostatic TB report patients of older ages, probably because they either are incidentally diagnosed after a transurethral resection of the prostate (TUR-P) for prostatic enlargement,6 or are complications of intravesical instillations of Bacillus Calmette–Gue´rin (BCG) for the treatment of superficial bladder tumour. Reported cases of prostatic TB in men with human immunodeficiency virus (HIV) document presentation in men aged 30–47 years.7
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Other genital organs such as testis, vas deferens, scrotal skin, seminal vesicles, urethra and penis may also develop TB, but they are much rarer than prostatitis and epididymitis tuberculosa. Nosocomial transmission of TB after manipulation of infected tissues of the genitourinary tract has been reported.8 Venereal acquisition of male genital TB is unlikely, although cases of male-to-female transmission of genital TB have been reported.9
SYMPTOMS AND SIGNS EPIDIDYMIS The typical presentation of tuberculous epididymitis is the gradual onset of swelling, which is followed by pain. Complaints about voiding are usually absent as long as only external genitalia are involved. Associated renal, vesical or prostatic TB may contribute to irritative voiding symptoms. Malaise, fevers and chills are common. Acute onset is not infrequent. In a recent series 66.7% of 42 patients with TB of the scrotal organs had an acute onset of the disease.4 One of the local findings is tethering to scrotal skin, together with the later development of discharging scrotal fistulae. Involvement of the testis is usually a late feature. Occasionally, a draining sinus may be based posterior upon the epididymis. Physical examination may reveal an enlarged, irregular, nodular and tender epididymis. Involvement is usually unilateral; however, bilateral involvement in up to 30.9% of these patients has been reported.4 Bilateral involvement is frequently associated with male factor infertility due to the obstruction of epididymal tubules. Secondary tuberculous involvement of the testicle can be observed in advanced cases; this situation should especially be suspected when large epididymal masses or abscesses are discovered during physical examination. Digital rectal evaluation of the prostate must be performed to find out if prostatic involvement is present. The vas deferens may be found to be enlarged and beaded. Another finding is a decrease in the volume of ejaculate, which has been reported to be as high as 40.5% in patients with genital TB.5
PROSTATE Tuberculous involvement of the prostate may manifest with irritative voiding symptoms such as dysuria and frequency. Haematuria, haemospermia and male factor infertility may be other presenting symptoms. However, the often incidental finding of TB in
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TUR-P chips suggests that many men may not have symptoms attributable to prostatic TB. Examination may reveal firm, irregular enlargement and/or nodularity. Soft areas, which might reflect necrosis, may be noted. Confirmation of the diagnosis may be made by detection of acid-fast bacilli or positive cultures from urine, semen, pus and biopsy specimen or by surgical specimen. Common additional findings include a sterile pyuria and the demonstration of focal calcification by ultrasound or radiology. Perineal pain, swelling and drainage can account for a less common but more overt presentation. Tuberculous infection of the prostate in men with acquired immunodeficiency syndrome (AIDS) most often manifests as prostatic abscess.10 Unlike the more insidious presentations noted in men who are immunocompetent, these patients present with fever, perineal pain and urinary hesitancy. Prior infection with TB is the most important risk factor. Historically, 10–12% of men with TB had pathological evidence of prostatic involvement during autopsy.7 On the other hand, HIV infection increases the risk for active TB of the genital organs. Prolonged steroid use and immunosuppressive therapy may increase the risk of reactivation of dormant foci.
OTHER GENITAL ORGANS Tuberculosis of the penis may present in many different forms such as a subcutaneous nodule, tuberculous ulceration, cavernosal cold abscess or erectile failure.11–14 Although rare, tuberculous infection of the vas deferens may lead to nodular or pipestem thickening of the vas. Tuberculous infection of seminal vesicles may present as calcification or cold abscess.15
TUBERCULOSIS AND FERTILITY Mycobacterium tuberculosis does not decrease sperm motility and viability;16 nevertheless, it may cause infertility by obstructing the genital ducts at any level. Testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) in the treatment of male infertility secondary to TB has been suggested.17 The outcome of sperm retrieval and intracytoplasmic sperm injection in patients with obstructive azoospermia (non-tuberculous and tuberculous) and the impact of previous tuberculous epididymitis was evaluated by Moon and co-workers.18 They found that embryo quality and pregnancy outcome in sperm retrieval and ICSI were comparable in both tuberculous and non-tuberculous obstructive azoospermia patients. The results suggest that previous tuberculous epididymitis in patients with obstructive azoospermia does not affect the outcome of sperm retrieval and ICSI. On the other hand, combined antituberculous therapy does not cause any significant change in the basic indices of a sperm count in patients with different forms of TB.19 Tuberculosis of seminal vesicles has been reported to cause aspermia.20
INTRAVESICAL BCG ADMINISTRATION AND GENITAL TUBERCULOSIS Intravesical instillations of BCG are frequently performed by urologists for the treatment of urothelial carcinoma in situ and superficial bladder cancer. This usually causes an acute mycobacterial cystitis, which is only a self-limiting, low-grade, superficial cystitis, but sometimes the inflammatory reaction is more severe. Cases of disseminated infection and solitary genitourinary organ involvement have been recorded.
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Tuberculous epididymo-orchitis following intravesical BCG therapy for superficial bladder carcinoma has been reported occasionally.21 Tuberculous infection of the epididymis may be clinically detectable as early as 2 weeks after intravesical BCG instillation,22 or as late as 3 years afterwards.23 Other reported complications include tuberculous prostatic abscess and TB of the penis.24,25 Although the complication rates seem to be low, awareness of the possibility of TB infection, even months or years after BCG has been given, is important.26 Occasionally lethal complications occur, and reports of genitourinary TB infections after intravesical instillation of BCG continue to be published. In patients with bladder carcinoma treated with intravesical BCG therapy, the presence of scrotal swelling with scrotalskin thickening and epididymal involvement suggests tuberculous epididymo-orchitis rather than testicular tumour.
DIFFERENTIAL DIAGNOSIS The typical presentation of acute tuberculous epididymitis may resemble acute bacterial epididymo-orchitis, which might prompt immediate antibiotic treatment. Even when the symptoms are not suggestive of acute bacterial epididymo-orchitis, the same therapy could be started, especially when TB is not usually considered by the treating physician. If no improvement occurs after 2–3 weeks, a scrotal ultrasonogram is useful for assessing for complications of inadequately treated bacterial epididymo-orchitis. The ultrasonogram can also assist in diagnosing other elements in the differential diagnosis, including hydrocele, spermatocele, scrotal trauma, testicular malignancy and neoplasms of the epididymis. If no such findings are noted, tuberculous epididymitis or a resistant bacterial infection should be considered. Obtaining a purified protein derivative (PPD) skin test, serial first morning urine cultures for acid-fast bacilli, a chest radiograph and an abdominal radiograph would be reasonable at this point. Additionally, a higher index of suspicion for epididymal TB is appropriate in men with HIV infection due to its increased incidence in these circumstances. Fine needle aspiration (FNA) of the epididymis may be useful for diagnosing epididymal TB;27 however, because of the risk of tumour spillage, FNA should be avoided if neoplasm is suspected. Lower urinary tract symptoms, which may accompany tuberculous infections of the prostate, may require differential diagnostic work-up with benign prostatic enlargement, prostatic inflammation and chronic pelvic pain syndrome, postsurgical granulomatous prostatitis and prostate cancer. Non-specific symptoms, including irritative voiding, may be the only complaints. A history of exposure to or infection with TB should guide the clinician in this situation.
INVESTIGATIONS The difficulty of diagnosing extrapulmonary TB due to the lower bacillary counts present in almost all extrapulmonary presentations and the problems associated with obtaining valid samples for analysis is well known. Fortunately, bacteriological investigations and molecular methods (polymerase chain reaction, PCR) yield successful results in genitourinary TB.
LABORATORY STUDIES Blood studies should include erythrocyte sedimentation rate. Elevation in erythrocyte sedimentation rate is common, and it should
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be checked regularly because it may indicate the response to medical treatment.28 Normalization can be used to follow the course of therapy. Urinalysis findings that demonstrate microscopic haematuria or sterile pyuria should raise suspicion for genitourinary TB but they do not definitively establish the diagnosis. Standard microbiological identification of prostatic involvement of M. tuberculosis relies on culture and acid-fast bacilli (AFB) staining results of semen and 3–5 early morning urine specimens. AFB staining, while rapid, has a reported sensitivity of only 52%. If genitourinary TB is suspected, 3–5 consecutive early morning urine samples should be cultured for AFB and their sensitivities obtained. FNA has an important role in the differential diagnosis of epididymal nodules as it can rule out malignancy and other benign cytological diagnoses such as TB and acute and chronic epididymo-orchitis.27 Distinction of spermatic granulomas from the more common tuberculous granulomatous infection is important from the cytopathologist’s point of view. By providing an accurate and rapid diagnosis, FNA prevents aggressive and potentially inappropriate surgical procedures.29 Molecular probes also are available for more rapid identification of organisms in urine. PCR is becoming a useful diagnostic tool because of its rapid detection and high sensitivity and specificity. Moussa et al.30 reported the sensitivity and specificity of the PCR assay of urine to be 95.59% and 98.12%, respectively. Results can be available within 48 hours.30 Further, one of the disadvantages of PCR is its inability to detect whether the TB infection is biologically active or in its latent phase. Most investigators suggest using PCR in combination with cultures and Ziehl–Neelsen staining when making a diagnosis and developing a treatment plan. Thus, PCR is recommended for instant diagnosis and screening before further examination and cannot be the only method in identification of urogenital TB.31,32 Kamyshan et al.32 reported that, of 16 patients with TB of the male sexual organs, M. tuberculosis DNA was detected by PCR in prostatic secretions in 43.7% and in ejaculate in 93%. Treatment for 1 month and longer transformed the positive result into a negative one. Although it is not a required test, semen analysis may be useful in the evaluation of male infertility associated with prostatic TB. The reported semen analyses of 53 patients with genital TB revealed low volume in 89% of patients and azoospermia or oligospermia in 53% of patients.7 Significant leucocytospermia has also been described in patients with prostatic TB. In a recent study of 18 patients with prostatic TB, where the median prostate-specific antigen (PSA) was 2.7 ng/mL (range 0.3–31), levels were elevated in only one-third of patients.33
OTHER TESTS Intradermal injection of tuberculin purified protein derivative When a patient without previous diagnosis of TB is suspected of having prostatic involvement, a PPD test is the standard means of documenting exposure (see Chapter 19). IMAGING STUDIES A chest radiograph should be obtained to assess for evidence of pulmonary TB. A plain abdominal radiograph is useful for searching for evidence of renal or ureteral TB (i.e. renal or ureteral calcifications). A renal ultrasound to evaluate the upper tracts for evidence of hydronephrosis is
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also warranted. An intravenous urogram (IVU) or computed tomography (CT) scan should be obtained to determine the presence of concurrent renal TB. Of patients with prostatic TB, 72% have pathological evidence of renal TB during autopsy. Scrotal ultrasonography is helpful in assessing for complications of epididymal TB, such as fistula or abscess formation; however, the appearance of epididymal TB on ultrasonography is not distinct from that of bacterial epididymo-orchitis. A heterogeneously hypoechoic pattern of epididymal enlargement favours TB epididymitis over non-TB epididymitis, in which the epididymis is more likely to be homogeneous. Sonography is helpful for follow-up of treated lesions.34 Other associated sonographic findings include thickened scrotal skin, hydrocele (Figs 42.1 and 42.2), intrascrotal extratesticular calcification, scrotal abscesses and scrotal sinus tract. Thickening of the scrotal skin is best seen when comparison is made with the unaffected side. Intrascrotal extratesticular sites of calcification affect the epididymis and the tunica vaginalis testis.34 Table 42.1 summarizes statistically significant differences between tuberculous epididymal abscess and pyogenic epididymal abscess.35 At transrectal ultrasonography, the most common finding of tuberculous prostatitis is hypoechoic areas with an irregular pattern in the peripheral zone of the prostate.36 In persons with a soft or fluctuant prostate in whom abscess is considered, transrectal ultrasonography (TRUS) is particularly useful. TRUS allows demonstration and localization of the collection and can then guide transrectal aspiration and drainage of any fluid for culture and microscopic examination. However, the findings of diffuse hypoechoic lesions within the peripheral zone of the prostate often make the distinction between prostatic cancer and TB difficult.37 Contrast-enhanced CT shows hypoattenuating prostatic lesions, which probably represent foci of caseous necrosis and inflammation (Fig. 42.3A). Non-tuberculous pyogenic prostatic abscesses have a similar CT appearance. At magnetic resonance imaging (MRI), a prostatic abscess demonstrates peripheral enhancement (Fig. 42.3B and C). This finding helps differentiate an abscess from prostatic malignancy. In addition, MRI shows diffuse, radiating, streaky areas of low signal intensity in the prostate (‘watermelon skin’ sign) on T2-weighted images (Fig. 42.3D). Cystourethrography can be performed to confirm and delineate the extent of a vesicoperineal fistula associated with prostatic TB. Transrectal ultrasound-guided needle biopsies have been used to obtain tissue for a definitive diagnosis of the disease, to monitor response to therapy and to ensure eradication of the prostatic disease.33
PATHOLOGY PATHOPHYSIOLOGY The spread of TB to the epididymis is thought to occur haematogenously or by retrocanalicular descent of organisms from the haematogenously infected prostate. Because epididymal TB is more common than prostatic TB, the former mechanism is probably the more common one. Distal spread through the genitourinary tract from a renal source may also occur. Pathologically, the characteristic finding of tuberculous epididymitis is caseating granuloma(s), which may form the abscess cavity and contain yellow–green caseous materials. The formation of granulomas in the epididymis is responsible for the clinical manifestations of epididymal TB, as in other organ systems. At pathology, the earliest lesions are seen as discrete or conglomerate yellowish,
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Fig. 42.1 A 73-year-old man with TB epididymitis. Longitudinal sonogram of right hemiscrotum shows diffusely enlarged heterogeneously hypoechoic epididymis (E) (solid arrows) adjacent to multiseptated hydrocele (open arrows). Right testis (RT T) is of normal size and echogeneity. Muttarak M, Peh WC, Lojanapiwat B, et al.: Tuberculous epididymitis and epididymo-orchitis: sonographic appearances. AJR 2001;176:1459–1466. Reprinted with permission from the American Journal of Roentgenology
Table 42.1 Statistically significant differences between tuberculous epididymal abscess and pyogenic epididymal 39 abscess Tuberculous epididymal abscess
Pyogenic epididymal abscess
Clinical
Longer duration of Shorter duration of symptoms and absence symptoms and Rights wereofnot granted to include thispresence content in scrotal tenderness of scrotal electronic media. Please refer to the printed book. tenderness Grey-scale Larger size Smaller size ultrasonography Colour Doppler Lower degree of blood Higher degree of blood ultrasonography flow in the peripheral flow in the peripheral portion of the abscess portion of the abscess Dal Mo Yang1, Myung Hwan Yoon1, Hak Soo Kim1, et al. Comparison of Tuberculous and Pyogenic Epididymal Abscesses Clinical, Gray-Scale Sonographic, and Colour Doppler Sonographic Feature. AJR 2001; 177:1131–1135).
Fig. 42.2 A 75-year-old man with TB epididymitis. Longitudinal sonogram of left hemiscrotum shows enlarged nodular heterogeneously hypoechoic epididymal tail (arrows).
necrotic areas in the tail of the epididymis (Fig. 42.4A). Either the disease regresses and heals, often with calcifications, or, more commonly, the inflammatory process progresses to involve the entire epididymis. In the past, TB epididymitis was more commonly bilateral, but, currently, the disease appears to be more frequently unilateral.34 The tuberculous lesions are typically located in the peripheral part of the posterior and lateral lobes of the prostate. Upon microscopic examination of prostatic TB samples, characteristic granulomas composed of Langhans multinucleated giant cells and epithelioid cells are noted, usually in association with central
regions of caseous necrosis. Note that similar histological changes can be seen in the prostates of patients treated with BCG vaccine for transitional cell carcinoma of the bladder (Fig. 42.4B).
MANAGEMENT MEDICAL Standard 6-month anti-TB drug treatment is the first-line therapy in genital TB. A 9- to 12-month course of therapy is necessary only in complicated cases (recurrences of TB, immunosuppression and HIV/ AIDS).
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Rights were not granted to include this content in electronic media. Please refer to the printed book.
Fig. 42.3 (A) Contrast-enhanced CT scan shows an amorphous calcification (arrowhead) and diffuse low-attenuation areas in the peripheral zone of the prostate (arrows). (B) Axial T2-weighted endorectal MR image (4,700/112) shows a focal, heterogeneous area of high signal intensity, which corresponds to an abscess (arrow). (C) Contrast-enhanced axial T1-weighted endorectal MR image (600/15) shows peripheral enhancement of the abscess (arrow). (D) Axial T2-weighted endorectal MR image (4,700/112) shows diffuse, radiating, streaky areas of low signal intensity in the peripheral zone of the prostate (watermelon skin sign) (arrowheads). Engin G, Acunas B, Acunas G, et al. Imaging of extrapulmonary tuberculosis, Radiographics. 2000 Mar-Apr; 20(2):471–88.
Fig. 42.4 A 75-year-old man with TB epididymitis. (A) The resected specimen shows marked enlargement of the tail of the epididymis (straight arrows). The testis is normal (curved arrow). Gross pathological findings correlate well with sonographic appearances. (B) Photomicrograph of a histological section shows multiple granulomas (large arrows) surrounded by layers of fibroblasts (arrowheads). Granulomas consist of chronic inflammatory cells including lymphocytes, plasma cells, epithelioid histiocytes and a few multinucleated Langhans giant cells (small arrows) (haematoxylin and eosin 100). Muttarak M, Peh WC, Lojanapiwat B, et al.: Tuberculous epididymitis and epididymo-orchitis: sonographic appearances. AJR 2001; 176:1459-1466. Reprinted with permission from the American Journal of Roentgenology (See colour insert.)
A serious problem at present is the high percentage of primary drug resistance in patients with TB. Resistance to primary antituberculous agents is increased in immigrants from Southeast Asia, China, the Indian subcontinent and Central America. This has led to more
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complex empiric regimens. Risk factors for multidrug-resistant (MDR) TB include prior treatment and residence in countries with known high MDR-TB rates. In cases with MDR-TB as defined by the World Health Organization i.e. caused by bacilli resistant to
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rifampicin and isoniazid, with or without resistance to other drugs, therapy requires the use of at least four drugs selected on the basis of a drug susceptibility test (ethionamide, prothionamide, quinolones, clarithromycin, cycloserine, kanamycin, viomycin, capreomycin, thiacetazone and para-amino-salicide acid). These drugs are less effective and often more toxic than the first-line drugs. A 6-month short-course antituberculous drug regimen is also effective in uncomplicated genitourinary TB.38 Special considerations apply to the treatment of TB in patients with impaired renal function. Rifampicin, isoniazid, pyrazinamide, prothionamide and ethionamide may be given in normal dosage. They are eliminated in the bile or broken down to metabolites not excreted by the kidney. Care is required in the use of streptomycin, other aminoglycosides and ethambutol. These are wholly excreted via the kidney. Ethambutol causes optic neuritis, which may be irreversible, and a reduced dose should be given according to the glomerular filtration rate (GFR). Streptomycin and other aminoglycosides are ototoxic and nephrotoxic, and should not be given to patients with renal failure and especially after renal transplantation because ciclosporin involves a high risk of nephrotoxity. Encephalopathy is an uncommon complication of isoniazid and can be prevented by pyridoxine (25–50 mg per day). Rifampicin increases the rate of metabolism of corticosteroids, ciclosporin and tacrolimus. Regular measurement of the concentration of ciclosporin and tacrolimus in the blood of such patients (mostly patients after transplantation) is recommended. In HIV-infected patients, the antiretroviral therapy interacts adversely with rifampicin. When rifabutin is given instead of rifampicin the therapy must be extended to 9–12 months. Once the diagnosis of tuberculous infection of the genitalia is confirmed, the treatment is similar to that of other tuberculous infections. Surgery may be required to deal with abscesses, obstructive symptoms or failures of chemotherapy.
SURGICAL EPIDIDYMITIS TUBERCULOSIS Surgery remains an important part of the treatment plan of genitourinary TB, especially because TB may have been present for years before diagnosis, and because abscesses often form between the epididymis and testis on the affected side. Additionally, extensive epididymal and testicular involvement may be resistant to chemotherapy. During the course of treatment, if the lesion loses its tenderness while maintaining nodularity, testicular malignancy should be considered. In this case, operative exploration is indicated. As tuberculous epididymitis often is not suspected in the management of refractory epididymo-orchitis in developed countries, the ultimate diagnosis of tuberculous epididymitis is usually made when examining the pathological specimen from epididymoorchiectomy. Alternative techniques, such as epididymectomy or FNA of the epididymis, can be offered if TB is suspected preoperatively. Although antituberculous chemotherapy must be the initial course of action in tuberculous epididymitis, surgery is required when an intrascrotal abscess is identified because this condition does not respond to antituberculous chemotherapy. In contrast,
42
pyogenic epididymal abscess usually responds to antibiotic therapy. Therefore, the differentiation of tuberculous epididymal abscess and pyogenic epididymal abscess is important in determining the appropriate treatment. There are two indications for epididymectomy: 1. a caseating abscess not responding to chemotherapy; 2. a firm swelling that has remained unchanged or has slowly increased in size despite the use of antibiotics and antituberculous chemotherapy. Orchidectomy is seldom required. Ligation of the contralateral vas is not needed. Epididymectomy should be performed through a scrotal incision.3 If epididymectomy is indicated and the testis seems not to be affected, care should be taken to avoid damaging the surrounding vascular structures during dissection. Early ligation and removal of the distal vas deferens may be performed via a primary approach to the external inguinal ring. Dissection of the epididymis is then started at the head of epididymis until the epididymis is completely removed.39
PROSTATIC TUBERCULOSIS Some urologists advocate resection of the prostate, but, usually, only medical therapy is needed. In patients with obstructive symptomatology, resecting the prostate is reasonable. In addition, in resistant TB, prostate resection can theoretically lessen the infected tissue burden. Surgical treatment should be undertaken only once antituberculous therapy has been initiated to reduce the risk of exposure to the surgical team. In persons infected with HIV, prostatic TB can present as an abscess. Surgical drainage of an abscess collection is required. TRUS-guided needle drainage is an effective method.40,41 Transurethral unroofing of the collection may be another method of treatment.37 The surgeon should obtain intraoperative samples of any abscess fluid for AFB staining, culture and PCR to further confirm the diagnosis of TB. Successful treatment, documented with negative prostatic biopsy results upon follow-up following a triple-drug regimen of rifampicin, ethambutol and isoniazid for a duration of 6 months, has been reported.
COMPLICATIONS Formation of scrotal or perineal fistulae and abscesses is not infrequent. Especially immunocompromised patients are more prone to the formation of prostatic abscess with no evidence of disease elsewhere.42 Infertility is a major problem for young patients who have contracted tuberculous epididymitis. Sexual transmission, although reported occasionally and only from male to female, should also be regarded as a complication of genital TB.
PREVENTION Condom use should be encouraged to prevent possible transmission to sexual partners. Sexual transmission of TB via infected semen has been reported to result in a vaginal tuberculous ulcer.
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It is useful to check semen cultures periodically to monitor treatment, and, if results are positive after 3 months, bacterial resistance to the current drug regimen or patient non-compliance should be strongly suspected. Histological follow-up via repeat transrectal ultrasound-guided prostate biopsies has been recommended to ensure the efficacy of treatment.33
REFERENCES 1. Gorse GJ, Belshe RB. Male genital tuberculosis: a review of the literature with instructive case reports. Rev Infect Dis 1985;7(4):511–524. 2. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. WHO/ CDS/TB/2003.313. Geneva: World Health Organization, 2003. Available at URL:http://www. who.int/docstore/gtb/publications/ttgnp/pdf/ 2003.313.pdf 3. Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979;109(2):205–217. 4. Kulchavenya E, Khomyakov V. Male genital tuberculosis in Siberians. World J Urol 2006;24(1):74–78. 5. Tzvetkov D, Tzvetkova P. Tuberculosis of male genital system—myth or reality in 21st century. Arch Androl 2006;52:375–381. 6. Kostakopoulos A, Economou G, Picramenos D, et al. Tuberculosis of the prostate. Int Urol Nephrol 1998; 30(2):153–157. 7. Pais V, Wagner A, Dahl D. Prostatitis, tuberculous. [online]. November 11, 2005. Available at URL: http://www.emedicine.com/med/topic1921.htm 8. D’Agata EM, Wise S, Stewart A, et al. Nosocomial transmission of Mycobacterium tuberculosis from an extrapulmonary site. Infect Control Hosp Epidemiol 2001;22(1):10–12. 9. Angus BJ, Yates M, Conlon C, et al. Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect Dis 2001;33:e132–e134. 10. Wolf LE. Tuberculous abscess of the prostate in AIDS. Ann Intern Med 1996;125(2):156. 11. Baskin LS, Mee S. Tuberculosis of the penis presenting as a subcutaneous nodule. J Urol 1989;141:1430–1431. 12. Burns DA, Sarkany I. Tuberculous ulceration of the penis. Proc R Soc Med 1976;69:883–884. 13. Murali TR, Raja NS. Cavernosal cold abscess: a rare cause of impotence. Br J Urol 1998;82:929–930. 14. Pal DK. Erectile failure and destruction of glans penis by tuberculosis. Trop Doct 1997;27:178–179. 15. Fraietta R, Mori MM, De Oliveira JM, et al. Tuberculosis of seminal vesicles as a cause of aspermia. J Urol 2003;169(4):1472. 16. Liu JH, Li HY, Cao ZG, et al. Influence of several uropathogenic microorganisms on human sperm
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18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
ACKNOWLEDGEMENT I wish to thank Ms Kay Oosthuizen for proofreading, commenting on and editing the initial drafts of this chapter, for further commenting on the revised texts received from the editors and for general assistance in making this chapter a reality.
motility parameters in vitro. Asian J Androl 2002; 4(3):179–182. Briceno Mayz O, Egozcue Vilarasau S, Puigvert Martinez A. [TESE-ICSI in the treatment of male infertility secondary to tuberculosis. Report of a case]. Arch Esp Urol 2000;53(1):39–42. [In Spanish] Moon SY, Kim SH, Jee BC, et al. The outcome of sperm retrieval and intracytoplasmic sperm injection in patients with obstructive azoospermia: impact of previous tuberculous epididymitis. J Assist Reprod Genet 1999;16(8):431–435. Kulchavenya YV, Brizhatyuk YV, Medvedev SA. Toxic effect of antituberculous drugs on spermatogenesis. Probl Tuberk 2002;5:29–32. Fraietta R, Mori MM, De Oliveira JM, et al. Tuberculosis of seminal vesicles as a cause of aspermia. J Urol 2003;169(4):1472. Muttarak M, Lojanapiwat B, Chaiwun B, et al. Preoperative diagnosis of bilateral tuberculous epididymo-orchitis following intravesical Bacillus Calmette-Guerin therapy for superficial bladder carcinoma. Australas Radiol 2002;46(2): 183–185. Shigehara K, Kobori Y, Amano T, et al. Bilateral tuberculous epididymitis after intravesical Bacillus Calmette-Guerin therapy. Hinyokika Kiyo 2005; 51(12):839–842. Falkensammer C, Gozzi C, Hager M, et al. Late occurrence of bilateral tuberculous-like epididymoorchitis after intravesical bacille Calmette-Guerin therapy for superficial bladder carcinoma. Urology 2005;65(1):175. Aust TR, Massey JA. Tubercular prostatic abscess as a complication of intravesical bacillus Calmette-Guerin immunotherapy. Int J Urol 2005;12(10):920–921. Latini JM, Wang DS, Forgacs P, et al. Tuberculosis of the penis after intravesical bacillus Calmette-Guerin treatment. J Urol 2000;163(6):1870. Lamm DL. Complications of bacillus CalmetteGuerin immunotherapy. Urol Clin North Am 1992; 19(3):565–572. Sah SP, Bhadani PP, Regmi R, et al. Fine needle aspiration cytology of tubercular epididymitis and epididymo-orchitis. Acta Cytol 2006;50(3):243–249. Gow J. The current management of patients with genitourinary tuberculosis. AUA Update Series 1992;11(26):201–208.
29. Kumar V, Gupta N, Srinivasan R, et al. Spermatic granuloma presenting as an epididymal nodule: fine needle aspiration cytological findings and differential diagnosis. Indian J Pathol Microbiol 2004;47(4): 509–510. 30. Moussa OM, Eraky I, El-Far MA, et al. Rapid diagnosis of genitourinary tuberculosis by polymerase chain reaction and non-radioactive DNA hybridization. J Urol 2000;164(2):584–588. 31. Lenk S, Schoereder J. Genitourinary tuberculosis. Curr Opin Urol 2001;11(1):93–96. 32. Kamyshan IS, Stepanov PI, Ziablitsev SV, et al. Role of polymerase chain reaction in diagnosing tuberculosis of the bladder and male sex organs. Urologiia 2003;(3):36–39. 33. Lee Y, Huang W, Huang J, et al. Efficacy of chemotherapy for prostatic tuberculosis—a clinical and histologic follow-up study. Urology 2001; 57(5):872–877. 34. Muttarak M, Peh WC, Lojanapiwat B, et al. Tuberculous epididymitis and epididymo-orchitis: sonographic appearances. AJR Am J Roentgenol 2001;176:1459–1466. 35. Yang DM, Yoon MH, Kim HS, et al. Comparison of tuberculous and pyogenic epididymal abscesses clinical, gray-scale sonographic, and colour Doppler sonographic features. AJR Am J Roentgenol 2001;177:1131–1135. 36. Engin G, Acunas B, Acunas G, et al. Imaging of extrapulmonary tuberculosis. Radiographics 2000; 20(2):471–488; quiz 529–530, 532. 37. Trauzzi SJ, Kay CJ, Kaufman DG, et al. Management of prostatic abscess in patients with human immunodeficiency syndrome. Urology 1994;43(5): 629–633. 38. C ¸ ek M, Lenk S, Naber KG, et al. EAU guidelines for the management of genitourinary tuberculosis. Eur Urol 2005;48(3):353–362. 39. Carl P, Stark L. Indications for surgical management of genitourinary tuberculosis. World J Surg 1997; 21:505–510. 40. Wolf LE. Tuberculous abscess of the prostate in AIDS. Ann Intern Med 1996;125(2):156. 41. Moreno S, Pacho E, Lopez-Herce JA, et al. Mycobacterium tuberculosis visceral abscesses in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;109(5):437. 42. Skoutelis A, Marangos M, Petsas T, et al. Serious complication of tuberculous epididymitis. Infection 2000;28(3):193–195.
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43
Female genital tuberculosis Matthys H Botha and Frederick H van der Merwe
INTRODUCTION Mycobacterium tuberculosis and Mycobacterium leprae have been causing disease for many centuries in the form of TB and leprosy. The term ‘consumption’ was first used in the fourteenth century to describe a fatal wasting disease. A condition called ‘tuberculosis’ was first described in 1860 and a few years later, in 1882, Robert Koch identified the causative agent in the form of rod-shaped bacteria. It is estimated that a third of the world’s population is infected with TB. Reference to TB is widely represented in the arts and one of the most tragic references in opera is by Verdiin La Traviata, which describes the eventual death of the heroine Violetta. M. tuberculosis is a slow-growing bacterium and doubles its population only every 18–24 hours. This slow doubling time for a bacterium partly explains the chronic nature of the disease and may allow dissemination of the disease before acute symptoms develop. Transmission usually occurs when infectious people cough, sneeze, talk or spit, and they propel TB bacilli. It is necessary to inhale only a small number of these mycobacteria to be infected and it is estimated that someone in the world is newly infected with TB every second. During primary infection organisms may spread systemically which, at a later stage, may be activated in a genital site. Genital TB may be spread through sexual transmission, and restriction fragment length polymorphism (RFLP) analysis confirms this route of spread.1 The most common way of transmission to the genital tract is through haematogenous spread from pulmonary or other sites of TB.
PREVENTION Primary prevention of a disease includes strategies to reduce the risk of exposure to disease-causing organisms. It is therefore important to educate and inform those with known TB to be cautious with spitting, coughing, or sneezing in public places because it may spread TB. A well-meaning kiss of affection may spread mycobacteria to uninfected individuals. In the specific scenario of genital TB, safe sexual practice may reduce the incidence of genital infection.
INCIDENCE Over a 10-year period Hassoun et al.2 reported that 1.8% of all TB cases may have a genitourinary site. A study from South Africa found an incidence of 6% culture-positive TB in an infertile
population.3 The reported incidence of genital TB and age distribution of such cases varies by geographic area. Cases occur more frequently (62%) in postmenopausal women in developed countries than in developing countries where only 28% of cases were in the postmenopausal category.4 The prevalence of genital TB is directly proportional to the incidence of pulmonary TB in an area. An interesting observation from Spain showed that very high incidences of pulmonary TB during the Spanish Civil War and Second World War declined very quickly after 1961 followed only years later by a corresponding decline in genital TB.5 The delay in the decline of genital TB incidence was possibly due to the late diagnosis of this asymptomatic condition.
SYMPTOMS Genital TB is a chronic disease and often has low-grade symptomatology with very few specific complaints. However, Sutherland6 reported that 44% of patients with genital TB reported infertility. Pelvic pain was present in 25% and abnormal vaginal bleeding in 18%. Amenorrhoea and vaginal discharge was present in about 5% of cases while postmenopausal bleeding accounted for 2% of patients presenting with genital TB. Rare symptoms included an abdominal mass or unexplained ascites. Genital TB may mimic a tumour or ovarian abscess and may also present with vague abdominal distension.
PHYSICAL EXAMINATION Most cases of confirmed genital TB will have a perfectly normal clinical examination (43%) while about a quarter will present with an adnexal mass (23.6%).7 Other common findings are the presence of pelvic tumour on imaging which may look like fibroids (23.6%) or an irregular uterus (1.4%). On gynaecological examination, adnexal tenderness is found in less than 5% while uterine prolapse or a cervical polyp-like lesion may be present (1.4%).
DIAGNOSIS Genital TB is an elusive diagnosis and a high index of suspicion is the first step of the diagnostic process. A careful history with specific mention of previous exposure to or active TB is of importance. Taking a detailed drug and treatment history in patients
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who had previous treatment for active TB is important for establishing compliance and possible resistance patterns. A high erythrocyte sedimentation rate (ESR) may help in the diagnosis while a test for human immunodeficiency virus (HIV) may identify a high-risk population. Many patients present with a symptom complex similar to that of ovarian carcinoma, i.e. abdominal distension, pelvic tumour, and ascites, and a CA125 level may be done in the diagnostic work-up. CA125, however, is very often raised above an empiric cut-off point of 35 IU/mL in patients with any peritoneal infectious process such as TB. The CA125 is often falsely raised in patients with active TB. A chest radiograph may be suggestive of pulmonary TB but is very often normal in patients with active genital TB. A Mantoux tuberculin skin test may be useful in populations where TB is a rare disease. If the incidence figures in a particular population are very low, the Mantoux test may show sensitivity for the accurate diagnosis of genital TB of up to 55%. Raut et al.8 reported specificity as high as 80%. The diagnosis of genital TB for this study was made on the laparoscopic findings only. The Mantoux test may be negative in patients with active TB if the patient has overwhelming clinical disease, is severely immune compromised, has coincidental viral infection, or is malnourished. The validity of the Mantoux test, therefore, is variable. In populations with a high incidence of TB and where Bacillus Calmette–Gue´rin (BCG) is given routinely, the Mantoux test is often falsely positive. The Mantoux test may, in rare cases, elicit a systemic reaction where a local abdominopelvic reaction in the form of pain in the lower abdomen, tender adnexae, and increased discharge from the cervix may be noted for 24–48 hours after the injection of tuberculin. More than 75% of the patients with active, culture-proven genital TB have a normal chest radiograph. It is important not to use a chest radiograph as exclusion for the diagnosis of genital TB. The gold standard remains the proof of acid-fast bacilli in biological specimens or culture. In the case of patients presenting with subfertility and/or abnormal bleeding, a culture of menstrual fluid may be the most useful strategy.9 Getting menstrual fluid for culture need not be a difficult procedure. The patient is invited to attend the outpatient clinic during the second day of her normal menstruation when the patient is put in the lithotomy position and a sterile speculum is passed. About 10–20 mL of normal saline is instilled into the vagina with a sterile syringe and the normal saline is mixed with the menstrual blood. It is then aspirated and sent for culture. This approach has a good yield for positive cultures. Culture of M. tuberculosis on Lo¨wenstein–Jensen (LJ) medium is the most accurate form of diagnosis. Microscopic examination of acid-fast bacilli (AFB) requires the presence of at least 10,000 organisms per millilitre in the sample. Culture is more sensitive, requiring only 100 organisms per millilitre. However, culture may take up to 8 weeks to grow on LJ medium. Polymerase chain reaction (PCR) is a rapid and sensitive molecular biological method for detecting TB DNA.10 A commercial PCR assay, COBAS Amplicor MTB, is US Food and Drug Administration-approved for sputum but may be used on a variety of specimen types. The assay detects the M. tuberculosis complex. In patients with active genital ulceration, particularly on the vulva, a simple impression on a glass slide may reveal AFB. In patients who undergo a laparotomy and the diagnosis is that of suspected TB, several biopsies should be taken for histology and swabs should be taken with fluid washings for the culture of bacilli. Biopsies may show the typical histology that includes granulomas and
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positive acid-fast stain. Other typical features of TB on histology are epithelioid cell granulomas with or without Langerhans giant cells. Caseating necrosis is rare in specimens from the genital tract. Laparoscopy may be a very good way of diagnosing active genital TB. In a study reported from India, Tripathy and Tripathy11 showed that 59% of patients with pulmonary TB may have tubal damage, while 24% had tubercles on the genital organs. In a study reported from South Africa, laparoscopy done in patients for genital TB showed 53% of patients with abnormal tubes.9 Other imaging techniques may be of great importance and a hysterosalpingogram is a fairly simple test with a high yield. Hysterosalpingogram showed in more than 70% of patients:
coronal or fimbrial block; beaded tube; hydrosalpinx;
whereas ultrasound showed:
adnexal mass; thickened omentum; and ascites.
Other endoscopic investigations such as hysteroscopy may improve the diagnostic yield and an endometrial biopsy may be cultured for AFB.
PATHOLOGY The fallopian tube is affected in nearly all patients with active genital site TB. The endometrium is involved in 50–60% of all patients and the ovary in 20–30% of cases. Cervical, vulval, and vaginal disease are rare but with very careful investigation it may be found that TB from these sites is underdiagnosed.7 In a large descriptive study of 1,426 cases collected at a pathology laboratory over a 31-year period, Nogales-Ortiz and colleagues5 reported that in all the cases studied the fallopian tubes were involved (Table 43.1). In this series all the patients had bilateral fallopian tube involvement. Epithelioid granulomas were found throughout the endometrium; however, the density was higher in the superficial layers and decreased towards the myometrium. Acid-fast bacilli were only demonstrated in less than 2% of these lesions. The myometrium was involved in only 20% of cases and cervical involvement was a rare occurrence. If the cervix was involved it was mainly in the endocervical canal (72.5%) and when the ectocervix was involved the changes were mostly hyperplastic mucosal changes. Vaginal and vulval TB presented with ulcers with a rolled edge. Table 43.1 Involvement of surgical specimens Organ
Cases
No. involved
%
Fallopian tubes Endometrium Myometrium Cervix Ovaries (parenchyma)
331 210 210 41 335
331 153 40 10 37
100 79 20 24 11
Adapted from Nogales-Ortiz F, Tarancon I, Nogales FF Jr. The pathology of female genital tuberculosis. A 31-year study of 1436 cases. Obstet Gynecol. 1979;53(4):422–8.
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PREGNANCY Female genital TB is usually associated with infertility; however, a small number of cases where there is the presence of an intrauterine or ectopic pregnancy together with female genital TB are reported in the literature.5 Congenital transmission of TB has also been reported.2
TUBERCULOSIS OF THE VULVA Tuberculosis of the skin presents in many different ways. On the vulva TB is usually associated with ulceration and has an appearance very similar to that of a chancre (tuberculous chancre). The lesion may appear brown or red and may have a surrounding area of induration. There is often a slightly raised edge around the central ulcer (Figs 43.1 and 43.2). There may, however, be many different forms of skin lesions on the vulva including the following:
TB verrucosa cutis; lupus vulgaris; scrofuloderma (inguinal lymph nodes); and erythema indurata.
These conditions are described in Chapter 47 on TB dermatitis. If chronic ulceration on the vulva does not respond to adequate antibiotic therapy, a biopsy should be taken for histological investigation. A simple impression on a glass slide may reveal AFB.
Fig. 43.2 Biopsy-proven TB of the vulva. An example of an ulcer resembling malignancy.
CERVICAL TUBERCULOSIS Cervical TB is a rare disease but underdiagnosis is very likely. Of those cases with genital TB 2–24% have cervical involvement.2,5 The patients present with postmenopausal bleeding and/or chronic discharge (Figs 43.3 and 43.4). On inspection of the cervix there is often ulceration and necrosis that can easily be confused with a cervical carcinoma. The histology, however, is very typical with granulomas and possibly AFB. Growths on the cervix are often assumed to be cervical cancer but histological proof is of utmost importance. Other conditions that may cause granulomatous disease of the cervix are summarized in Table 43.2.12
ENDOMETRIAL TUBERCULOSIS
Fig. 43.1 Biopsy-proven TB of the vulva. Note the raised edges of the ulcer.
Endometrial TB often goes undiagnosed because in most affected women it is either asymptomatic or presents with non-specific symptoms. In women of reproductive age the most common presenting symptoms are menstrual disturbance, oligo-amenorrhoea, or pelvic pain. Postmenopausal women may present with postmenopausal bleeding, pyometra, or leucorrhoea.13,14 Although imaging is not diagnostic it may raise the index of suspicion. Transvaginal ultrasound may illustrate a thickened endometrium or pyometra.13 Features on hysterosalpingogram include a distorted contour of the uterine cavity due to scarring, venous and lymphatic intravasation, or synechiae with well-demarcated borders.15 Hysteroscopy can allow visualization of granulomas in cases of non-caseating granulomatous endometritis.13,16 Biopsy of such lesions is mandatory to obtain histological confirmation of the
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Table 43.2 Differential diagnosis of granulomatous 12 disease of the cervix Amoebiasis Sarcoidosis Schistosomiasis body Rights were not granted Foreign to include thisreaction content in Brucellosis electronic media. Please Tuberculosis refer to the printed book. Tularaemia Koller AB. Granulomatous lesions of the cervix uteri in Black patients. S Afr Med J. 1975 16;49(30):1228–32
typical non-caseating lesion consistent with TB. Recovery of mycobacteria from granulomas or other endometrial biopsies is highly specific but culture from menstrual fluid, as described earlier, is more sensitive in identification of genital tract TB.3,17
TUBERCULOSIS OF THE FALLOPIAN TUBES AND INFERTILITY
Fig. 43.3 Biopsy-proven TB of the cervix. An example of an exophytic tumour resembling malignancy.
Infertility is one of the leading presenting symptoms of patients with genital TB.18 The fallopian tubes are involved in most cases of genital TB and together with endometrial involvement cause these patients to become infertile. It is reported that 44–78% of women with genital TB will be infertile.3,7,18,19 The prevalence of genital TB in the infertile population in developing countries is between 5% and 20% and is even higher among patients with tubal factor infertility (39–41%).3,5,7,9,17–20 Genital TB should therefore always be considered as the probable cause in the diagnostic work-up of infertile couples, especially in populations with a high prevalence of TB–even in the absence of a previous history of TB.18 As the diagnostic work-up of infertile women includes a hysterosalpingogram and/or hysteroscopy and laparoscopy with chromopertubation, clinicians should be familiar with the features associated with genital TB on these investigations. Tubal involvement has a variety of hysterosalpingographic appearances.15,19 The various features illustrated in a pictorial review include the following:
calcifications showing up as linear streaks; tufted tubal outline or tubal diverticula; tubal occlusion, especially at the transition between the isthmus and ampulla, multiple occlusions causing a beaded appearance or a rigid pipe stem appearance; hydrosalpinx showing up as tubal dilatation with thick mucosal folds; peritubal adhesions giving the tube a ‘corkscrew’ appearance, a peritubal halo, or loculated spillage of contrast medium;15 and the rare finding of enterotubal fistulae–most common between the sigmoid colon and fallopian tube.21
Although laparoscopy is a more invasive procedure, it not only allows for visualization of the fallopian tubes, ovaries, and peritoneal cavity, but also gives the opportunity to biopsy tuberculous lesions and to restore the anatomy in the pelvis where appropriate. One or more of the following features may be found on laparoscopy:
Fig. 43.4 Biopsy-proven TB of the cervix. Ulceration and chronic discharge.
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tubercles on the peritoneal surface; inflamed or blue-coloured uterus; salpingitis, oophoritis or a tubo-ovarian mass; tubal occlusion with hydrosalpinx; dye dripping (instead of free flowing) from the fimbrial opening on chromopertubation;
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Female genital tuberculosis
free peritoneal fluid looking like blood; caseation in the pouch of Douglas; ‘frozen pelvis’; and omental adhesions.
Many of the aforementioned laparoscopic findings may be caused by non-tuberculous pelvic infections. Therefore, laboratory confirmation of the diagnosis is essential. Although many would argue that microbiological proof is essential, most authorities now accept histopathological proof of the typical granuloma to confirm the diagnosis.18 Hysteroscopy should be combined with laparoscopy to exclude/ confirm endometrial involvement. Synechiae formed after endometrial TB or destruction of the endometrium by tuberculous infection may require intervention in the form of lysis of the synechiae and priming of the endometrium with oestrogen. Genital TB responds well to treatment with a very high cure rate. Unfortunately, the conception rate following successful treatment is as low as 10–38% and the live birth rate 7–17%.9,19 Poor reproductive outcome also holds true for patients who undergo in vitro fertilization (IVF) treatment.20 Factors consistently associated with poor reproductive outcome are elderly age group, long duration of infertility, tubal occlusion, and absent or caseating endometrium.19,20 Some authors are of the opinion that endometrial involvement precludes IVF treatment and that these couples should rather consider other options like surrogacy or adoption.20 For those in whom conception does take place, the risk for ectopic pregnancy and miscarriage is increased.19
PERITONEAL TUBERCULOSIS This presentation of genital TB is often called ‘the great pretender’ because it closely resembles the presentation of advanced ovarian carcinoma. The clinical importance of peritoneal TB is emphasized by the numerous case reports and case series published over the past decade. The most common symptoms patients present with are abdominal distension due to ascites and abdominal pain. Other symptoms include anorexia and weight loss, night sweats, low-grade fever, malaise, and dyspnoea in the presence of a pleural effusion or massive ascites splinting the diaphragm.22–27 On clinical examination ascites can be demonstrated with or without an abdominopelvic mass and a possible pleural effusion.22–27 Because it is very difficult to make a firm diagnosis on this nonspecific clinical picture, certain special investigations may assist in an effort to do so. Paracentesis should be done when ascites is present and should be sent for biochemistry and cytology, microscopy for AFB, TB culture, and serology. The laboratory findings consistent with tuberculous ascites are:
43
lymphocytic exudate; absence of malignant cells; high total protein content (> 25 g/L); small serum–ascites albumin gradient (< 11 g/L); lactate dehydrogenase (LDH) above 90 U/L; and adenosine deaminase (ADA) above 30 IU/mL.22,24,25
Unfortunately microscopy for AFB and TB culture is often negative.25,28 Imaging by abdominal ultrasound or abdominal CT scan more often is also very non-specific. Findings on imaging include
Fig. 43.5 Tubercles on small bowel loops in a patient with ascites and a pelvic mass on preoperative ultrasound examination.
a pelvic mass, ascites, omental involvement, thickening of the small bowel mesentery and parietal peritoneum, and retroperitoneal lymphadenopathy.27–30 Serum CA125 measurement is markedly raised in many cases of peritoneal TB and may further mislead the clinician because it is a marker of non-mucinous epithelial ovarian cancer and can be elevated in a number of other benign intra-abdominal conditions.22–25,28 Serial measurement of CA125 after initiation of treatment can be helpful in monitoring response to treatment since it has been shown to normalize in response to treatment.31 Biopsies should be obtained by either laparoscopy or laparotomy when examination of ascitic fluid could not confirm the diagnosis.22,24–26,32 There is some controversy about the safety of laparoscopy in these patients but laparoscopy with the openentry technique should be safe and sufficient in most patients.23,26,28 Laparotomy can be done when the risk of bowel injury is regarded as being too high to safely perform laparoscopy. Peritoneal TB causes miliary nodules covering almost every surface in the abdomen, peritoneal thickening, an omental cake, adhesions, and adnexal pseudo-abscesses and can easily be mistaken for ovarian carcinoma (Fig. 43.5).23–25,27,32 Biopsy of lesions with intraoperative frozen section is mandatory to confirm the diagnosis because the extensive surgical treatment for ovarian carcinoma is very different from medical treatment for peritoneal TB.23–26 Confirmation of the diagnosis of peritoneal TB at this stage saves the patient from having unnecessary major surgery. Samples should also be sent for bacteriology, PCR, and histopathology.
TREATMENT Standard anti-TB drugs are used to treat genital TB. Most authors recommend initiating therapy with a four-drug regimen consisting of isoniazid, ethambutol, rifampicin, and pyrazinamide for the first 2 months followed by triple or dual therapy. Total duration of treatment should be 6 months to a year.26,28,29 Excellent cure rates are reported for all of the standard treatment regimens.
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REFERENCES 1. Angus BJ, Yates M, Conlon C, et al. Cutaneous tuberculosis of the penis and sexual transmission of tuberculosis confirmed by molecular typing. Clin Infect Dis 2001;33:e132–134. 2. Hassoun A, Jacquette G, Huang A, et al. Female genital tuberculosis: Uncommon presentation of tuberculosis in the United States. Am J Med 2005; 118(11):1295–1299. 3. Margolis K, Wranz PAB, Kruger TF, et al. Genital tuberculosis at Tygerberg Hospital—prevalence, clinical presentation and diagnosis. S Afr Med J 1992;81:12–15. 4. Marcus SF, Rizk B, Fountain S, et al. Tuberculous infertility and in vitro fertilization. Am J Obstet Gynecol 1994;171(6):1593–1596. 5. Nogales-Ortiz F, Tarancon I, Nogales FF Jr. The pathology of female genital tuberculosis. A 31-year study of 1436 cases. Obstet Gynecol 1979;53(4): 422–428. 6. Sutherland AM. Surgical treatment of tuberculosis of the female genital tract. Br J Obstet Gynaecol 1980; 87(7):610–612. 7. Saracoglu OF, Mungan T, Tanzer F. Pelvic tuberculosis. Int J Gynaecol Obstet 1992;37(2):115–120. 8. Raut VS, Mahashur AA, Sheth SS. The Mantoux test in the diagnosis of genital tuberculosis in women. Int J Gynecol Obstet 2001;72:165–169. 9. De Vynck WE, Kruger TF, Joubert JJ, et al. Genital tuberculosis associated with female infertility in the western Cape. S Afr Med J 1990;77:630–631. 10. Bhanu NV, Singh UB, Chakraborty M, et al. Improved diagnostic value of PCR in the diagnosis of female genital tuberculosis leading to infertility. J Med Microbiol 2005;54:927–931.
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11. Tripathy SN, Tripathy SN. Laparoscopic observations of pelvic organs in pulmonary tuberculosis. Int J Gynaecol Obstet 1990;32(2):129–131. 12. Koller AB. Granulomatous lesions of the cervix uteri in Black patients. S Afr Med J 1975;49(30):1228–1232. 13. Gatongi DK, Kay V. Endometrial tuberculosis presenting with postmenopausal pyometra. J Obstet Gynaecol 2005;25(5):518–520. 14. Martinez Maestre MA, Daza Manzano C, Martinez Lopez R. Postmenopausal endometrial tuberculosis. Int J Gynaecol Obstet 2004;86:405–406. 15. Chavhan GB, Hira P, Rathod K, et al. Female genital tuberculosis: hysterosalpingographic appearances. Br J Radiol 2004;77:164–169. 16. Kuohung W, Borgatta L, Larrieux JR, et al. Pelvic tuberculosis diagnosed by hysteroscopy during infertility evaluation. J Assist Reprod Genet 2000;17(8): 459–460. 17. Oosthuizen AP, Wessels PH, Hefer JN. Tuberculosis of the female genital tract in patients attending an infertility clinic. S Afr Med J 1990;77(11):562–564. 18. Namavar Jahromi B, Parsanezhada ME, GhaneShirazi R. Female genital tuberculosis and infertility. Int J Gynaecol Obstet 2001;75:269–272. 19. Tripathy SN, Tripathy SN. Infertility and pregnancy outcome in female genital tuberculosis. Int J Gynaecol Obstet 2002;76:159–163. 20. Parikh FR, Nadkarni SG, Kamat SA, et al. Genital tuberculosis: a major pelvic factor causing infertility in Indian women. Fertil Steril 1997;67:497–500. 21. Kumar A, Bhargava SK, Mehrotra G, et al. Enterotubal fistulae secondary to tuberculosis: report of three cases and review of literature. Clin Radiol 2001;56(10):858–860. 22. Piura B, Rabinovich A, Leron E, et al. Peritoneal tuberculosis: an uncommon disease that may deceive the gynecologist. Eur J Obstet Gynecol Reprod Biol 2003;110(2):230–234. 23. Koc S, Beydilli G, Tulunay G, et al. Peritoneal tuberculosis mimicking advanced ovarian cancer:
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a retrospective review of 22 cases. Gynecol Oncol 2006;103(2):565–569. Gurbuz A, Karateke A, Kabaca C, et al. Peritoneal tuberculosis simulating advanced ovarian carcinoma: is clinical impression sufficient to administer neoadjuvant chemotherapy for advanced ovarian cancer? Int J Gynecol Cancer 2006;16(Suppl 1):307–312. Protopapas A, Milingos S, Diakomanolis E, et al. Miliary tuberculous peritonitis mimicking advanced ovarian cancer. Gynecol Obstet Invest 2003;56(2):89–92. Chong VH, Rajendran N. Tuberculosis peritonitis in Negara Brunei Darussalam. Ann Acad Med Singapore 2005;34(9):548–552. Uzunkoy A, Harma M, Harma M. Diagnosis of abdominal tuberculosis: Experience from 11 cases and review of the literature World J Gastroenterol 2004; 10(24):3647–3649. Bilgin T, Karabay A, Dolar E, et al. Peritoneal tuberculosis with pelvic abdominal mass, ascites and elevated CA 125 mimicking advanced ovarian carcinoma: a series of 10 cases. Int J Gynecol Cancer 2001;11(4):290–294. Mahdavi A, Malviya VK, Herschman BR. Peritoneal tuberculosis disguised as ovarian cancer: an emerging clinical challenge. Gynecol Oncol 2002;84(1):167–170. Vazquez Munoz E, Gomez-Cerezo J, Atienza Saura M, et al. Computed tomography findings of peritoneal tuberculosis: systematic review of seven patients diagnosed in 6 years (1996–2001). Clin Imaging 2004;28(5):340–343. Simsek H, Savas MC, Kadayifci A, et al. Elevated serum CA 125 concentration in patients with tuberculous peritonitis: a case-control study. Am J Gastroenterol 1997;92(7):1174–1176. Hsieh LC, Chiang YC, Wei LH, et al. Images in surgery. Tuberculosis peritonitis. Surgery 2006;139(5):707–708.
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44
Ear, nose, and throat tuberculosis in adults and children Nico E Jonas and Chris AJ Prescott
INTRODUCTION Tuberculosis is the oldest documented infectious disease. The advent of human immunodeficiency virus (HIV), increase in poverty, and the rise in resistance to chemotherapeutic agents are the major factors responsible for the recent increase in cases of TB.1 Up to 30% of patients with TB of the head and neck region have associated lung or other organ involvement.2 Extrapulmonary TB is also more common in HIV-infected patients. Otolaryngologists are therefore likely to encounter TB affecting the nose, nasopharynx, oropharynx, middle ear, mastoid bone, larynx, deep neck spaces, or salivary glands.
TUBERCULOSIS OF THE EAR Tuberculous involvement of the temporal bone was described early in the eighteenth century, more than a century before Koch’s isolation of the tubercle bacillus in 1882.3 Primary TB infection of the middle ear cleft is rare in the absence of pulmonary TB. In some communities TB accounts for up to 4% of all otitis media.4 Tuberculous otitis media has been shown to be more common in HIVinfected than in HIV-uninfected children.5 The middle ear can be infected via direct transmission from the lungs, larynx, pharynx, and nose via the eustachian tube, or by haematogenous spread from other primary sites. Although it usually presents as chronic suppurative otitis media or mastoiditis, it may present as acute otitis media or mastoiditis.6 The historical picture of multiple tympanic membrane perforations and pale granulation tissue in the middle ear has changed possibly because of the common use of ear drops containing neomycin and gentamicin, which have a weak anti-TB effect.7 Nowadays the clinical features of tuberculous ear disease are commonly similar to the features of chronic otitis media, i.e. chronic tympanic membrane perforation, discharge, and hearing loss.8 Middle ear TB behind an intact tympanic membrane has been described in the literature.9 Tuberculous mastoiditis is usually a complication of unrecognized and therefore untreated TB otitis media. Patients can present with pain with or without swelling of the postauricular area. Tuberculous otitis media should be considered if there is: 1. a facial paralysis associated with chronic otitis media, in the absence of cholesteatoma (Fig. 44.1); 2. a history of pulmonary TB (present in at least 50% of cases);
3. a discharging ear with known TB affecting another anatomical site, especially in HIV-infected patients; 4. pale granulation tissue in the middle ear or in a previously created mastoid cavity; and 5. a postauricular abscess.8,10–12 Diagnosis of tuberculous ear disease by isolating acid-fast bacilli (AFB) from the ear discharge can be very difficult, especially if aminoglycoside-containing ear drops have been used. Furthermore the presence of other bacteria in the microbiology specimen will interfere with the isolation of the bacillus. As the isolation of AFB by smear microscopy or Mycobacterium tuberculosis by culture in the middle ear is often difficult, anti-TB treatment should be started if there is strong suspicion of TB and conventional treatment for chronic otitis media has failed. Treatment consists of systemic anti-TB chemotherapy. The role of surgery is limited to biopsy for diagnostic purposes, incision and drainage of a postauricular abscess, the management of intracranial complications, and removal of bony sequestra.13–15 There may be a role for surgery in the treatment of facial nerve palsy, although authors still disagree on this subject.15 Complications associated with middle ear and mastoid TB include hearing loss, facial palsy (especially in children), subperiosteal abscess, postaural fistula formation, and labyrinthitis. Intracranial complications such as meningitis, sigmoid sinus thrombosis, tuberculoma, and abscesses are rare.12,15,16
LARYNGEAL TUBERCULOSIS Laryngeal TB was very common in the early twentieth century and was described as the most common disease affecting the larynx.17 Currently it accounts for less than 1% of all TB cases.18 The most common symptom is hoarseness of the voice, which is present in 75–100% of cases. Other symptoms include dysphagia (difficulty swallowing), odynophagia (pain with swallowing), paralgesia (foreign body sensation), referred otalgia, and stridor. The majority of patients with laryngeal TB have underlying pulmonary TB and therefore symptoms such as coughing, haemoptysis, weight loss, night sweats, and fever can also be present.19 An interesting observation in a study done by Kulkarni et al.20 was that all patients with pulmonary TB and laryngeal manifestations were either defaulters or relapse cases. The signs associated with laryngeal TB range from minimal oedema and pallor of the laryngeal mucosa to florid with extensive
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Fig. 44.1 Patient with left facial nerve palsy (A) and a discharging ear (B) caused by tuberculous otitis media.
neoplasms, fungal infections, chronic granulomatous conditions, and laryngopharyngeal reflux. As the majority of patients will have underlying pulmonary TB the diagnosis can usually be made by chest radiography or sputum microscopy and/or culture of M. tuberculosis. Sputum microscopy has been reported to be positive in the majority (70–80%) of patients, which makes these patients an infection risk. Patients with ulcerative or exophytic lesions require histological confirmation, although Vidal et al.23 postulated that the coexistence of laryngeal TB and carcinoma is exceptionally rare. They suggested that patients with active pulmonary TB and laryngeal symptoms should undergo laryngeal biopsy if there is associated lymph node enlargement, if there are carcinoma risk factors, or when symptoms persist after a correct therapeutic regimen. Specimens can be obtained by either rigid or flexible endoscopy. Flexible fibreoptic bronchoscopy has the advantage of collecting uncontaminated specimens in the form of secretions, washings, lavage, cytology brushing, or biopsy.24 Treatment of laryngeal TB is with anti-TB drugs. In severe exophytic lesions where the airway is compromised patients might require debulking of the lesion or tracheostomy to relieve the airway obstruction. Because the majority of patients with laryngeal TB will have underlying pulmonary TB, strict infection control measures should be taken especially in patients with tracheostomies.
Fig. 44.2 Tuberculosis laryngitis.
ulceration of the endolaryngeal mucosal surfaces or exophytic granulomatous lesions, the latter being the more common (Fig. 44.2).21,22 The vocal folds are the most common site to be affected.1 The differential diagnosis includes benign and malignant
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TUBERCULOUS CERVICAL LYMPHADENOPATHY Lymphadenitis is the commonest extrapulmonary manifestation of TB and the cervical lymph nodes are the most common lymph node group involved.25,26
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Ear, nose, and throat tuberculosis in adults and children
44
Cervical TB lymphadenopathy, also known as scrofula, is the most common manifestation of TB of the head and neck region and is present in over 90% of patients with head and neck TB.2 Unilateral lymph node involvement is four times more common than bilateral involvement and two-thirds of patients will have involvement of a single lymph node group.27,28 Tubercle bacilli can reach lymph nodes via the lymphatic or haematogenous route. Tuberculous lymph node infection is staged as the following: 1. hyperplasia – the lymph node is enlarged, firm, and mobile; 2. periadenitis – lymph nodes are enlarged and become adherent to each other, but clinically are discrete (Fig. 44.3); 3. caseated lymph nodes – lymph nodes are completely adherent to each other and are clinically matted; 4. abscess formation – lymph node(s) break down to cause a fluctuant swelling or ‘cold abscess’ (Fig. 44.4); 5. collar stud abscess – pus penetrates the deep cervical fascia together with a fluctuant superficial swelling; 6. sinus formation – spontaneous if the above conditions are untreated or following incision and drainage of an abscess; and 7. calcification – remnants of TB infection progress eventually to calcification. The diagnosis can usually be made by fine needle aspiration (FNA).29 If FNA is negative and TB suspected it should be followed by an excision biopsy. Even in cases where the histopathology is negative, a positive culture result will still be obtained from 20% of patients.1 Treatment is primarily medical. Surgery should be reserved for obtaining tissue for histological diagnosis or to drain large abscesses. If possible surgery should be avoided because of the risk of creating a chronic fistula.
Fig. 44.4 Axial computed tomography scan of the neck showing a tuberculous neck abscess.
TUBERCULOSIS OF THE NOSE AND PARANASAL SINUSES Tuberculosis infection of the nose and paranasal sinuses is infrequent and if it occurs is usually secondary to pulmonary TB.30 Patients usually present with nasal discharge, nasal obstruction, nasolacrimal duct obstruction and epiphora (overflow of tears), mucosal ulcers, or midline granulomas. The diagnosis is usually made from histopathological examination of biopsy specimens of nasal tissue showing tuberculous granulomas. Treatment is with anti-TB drugs.
NASOPHARYNGEAL TUBERCULOSIS
Fig. 44.3 Tuberculous cervical lymphadenopathy.
Before the advent of anti-TB therapy, TB of the nasopharynx was not uncommon.32 Since the widespread use of anti-TB therapy, nasopharyngeal TB has become rare. A study by Rohwedder33 found involvement of the nasopharynx in only 0.1% of patients with active pulmonary TB. Primary nasopharyngeal TB is thought to be even rarer,34 and most of the literature is limited to singlecase reports. Nasopharyngeal TB usually occurs in the presence of active pulmonary infection and the route of infection is either via haematogenous or lymphatic spread. Primary nasopharyngeal TB is thought to result from direct infection of the upper respiratory tract. Presenting symptoms include nasal obstruction and cervical lymphadenopathy, which is present in over 50% of cases.35 Involvement of the eustachian tube will cause a middle ear effusion, with secondary symptoms such as otalgia, tinnitus, and hearing loss. Endoscopic examination usually reveals irregular nasal mucosa, ulceration, or a nasopharyngeal mass. The differential diagnosis of a nasopharyngeal mass with enlarged cervical lymph nodes includes nasopharyngeal carcinoma, lymphoma, and sarcoidosis, which makes histopathological evaluation mandatory.36 Response to anti-TB treatment is usually excellent.
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ORAL CAVITY AND OROPHARYNX TUBERCULOSIS The combination of mucosa in the oral cavity and oropharynx that is resistant to invasion and the inhibitory action of saliva on the tubercle bacilli means that infection is usually secondary to breaches in the mucosa in patients with underlying pulmonary TB. Other predisposing factors are poor dental hygiene, dental extraction, and leucoplakia. The tongue is the most common part of the oral cavity infected, but the floor of the mouth, soft palate, gingiva, lips, and hard palate can also be affected. Patients usually present with non-healing mucosal ulcers, but can also present with nodules, fissures, plaques, and vesicles (Figs 44.5 and 44.6).1 Ulcers are usually painless, but a case of oropharyngeal TB associated with severe dysphagia and odynophagia has been described.37
The differential diagnosis includes stomatitis, syphilis, sarcoidosis, mycotic infections, and malignancy. The diagnosis is made by histopathological examination and caseation is pathognomonic. The absence of caseation can make it difficult to distinguish the tubercles from other granulomatous lesions like sarcoidosis, leprosy, syphilis, and foreign body granulomas. Treatment is with anti-TB medication.
SALIVARY GLAND TUBERCULOSIS Involvement of the major salivary glands (submandibular, sublingual, and parotid) is uncommon and secondary to pulmonary TB in 25% of patients. In the absence of pulmonary TB the primary source of infection is usually the oral cavity or tonsil. Patients usually present with non-tender salivary gland swelling. Involvement is mostly confined to lymph nodes within the parotid, but the gland itself can become diffusely involved. In addition patients may present with systemic symptoms such as weight loss, irregular low-grade pyrexia, and night sweats. Investigation of suspected cases includes FNA, culture of salivary fluids, and sialography. Similar to other TB abscesses it is difficult to culture the organisms from pus obtained from the salivary gland. Often the diagnosis can only be made via open biopsy, which has a high risk of causing a chronic fistula.35 Treatment is with anti-TB drugs. Non- or poor responders should be screened for drug-resistant TB.
TUBERCULOSIS OF THE DEEP NECK SPACES
Fig. 44.5 Tuberculosis ulceration of oropharynx.
Tuberculous deep neck space infections are usually secondary to infection of the tonsil or pharynx. Retropharyngeal abscesses may be due to involvement of the retropharyngeal lymph nodes or secondary to Pott’s disease of the cervical spine. Diagnosis is usually suspected from history and clinical findings and is confirmed from microbiological or histological investigation. Most patients with a retropharyngeal abscess will present with a sore throat and odynophagia. Systemic symptoms such as fever and malaise are uncommon. Isolation of tubercle bacilli from pus is often very difficult. The diagnosis can often only be made from biopsy of the wall of the abscess cavity. A computed tomography (CT) scan is useful in determining the size and extent of the abscess. Treatment is with anti-TB drugs. In the case of a pointing abscess or if tissue is required for diagnostic purposes, incision, drainage, and biopsy is done. In the case of a retropharyngeal abscess, incision and drainage should be done transorally. It must be stressed that a high index of suspicion should be present in treating chronic deep neck space infections and, if incision and drainage is done, biopsy material should always be sent for histological analysis and TB culture.36
SKELETAL TUBERCULOSIS
Fig. 44.6 Tuberculosis ulceration of the tongue.
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From an ENT perspective skeletal TB can involve the skull, cervical spine, and facial bones. Cervical spine TB makes up less than 20% of spinal TB disease. These patients may present with a retropharyngeal or parapharyngeal abscess. The incidence of TB of the skull varies in reports from 0.1% to 3.7% of all cases of skeletal TB. It is mainly a disease of children with 50% of patients below 10 years and 90% below 20 years of age.
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Ear, nose, and throat tuberculosis in adults and children
The disease usually involves the frontal and parietal bones. The tuberculous lesions begin in the diploe and can destroy both outer and inner tables of the skull. The periosteum is usually spared. The lesions may be single or multiple. The first symptom is usually that of a swelling with a soft fluctuant centre. Skin attachment, discoloration, and sinus formation are late features.38–40 Diagnosis is usually made by histopathological investigations. CT scans are helpful in showing the extent of bony erosion and extent of an associated abscess (Figs 44.7 and 44.8).36 Treatment is with anti-TB drugs, but in case of spinal TB, longer duration of treatment is often recommended (see Chapter 48).
44
Surgery is indicated for obtaining tissue for histological analysis or for removal of a bony sequestrum. Any tissue removed during surgery should be sent for histology and culture.
TUBERCULOSIS OF THE THYROID GLAND Tuberculosis of the thyroid gland is exceedingly rare. Patients can present with a thyroid nodule or abscess and usually have associated cervical lymphadenopathy and pulmonary TB.41,42 Suspected cases should be investigated as for any other thyroid nodule with FNA, ultrasound, chest radiograph, and thyroid scan. Treatment of TB thyroid enlargement is thyroid surgery and anti-TB chemotherapy.43 Several cases of rifampicin-induced thyroiditis and hypothyroidism have been described in the literature.44–46
AMINOGLYCOSIDES IN MANAGEMENT OF DRUG-RESISTANT TUBERCULOSIS
Fig. 44.7 Axial CT scan of the head showing a destructive TB lesion of the posterior fossa skull and abscess in and around the sigmoid sinus.
Patients with previous or subsequent TB infection should be screened for multidrug-resistant (MDR) TB. When treating MDR TB, aminoglycosides form an important part of the treatment regimen. The use of aminoglycosides is limited by ototoxicity, vestibular toxicity, and nephrotoxicity. Ototoxicity is defined as 20 db hearing loss in one frequency or 15 db hearing loss at two adjacent tested frequencies. Up to 37% of patients receiving aminoglycosides are at risk of developing ototoxicity, while 9% of patients will develop vestibular toxicity. Ototoxicity is associated with older age, longer duration of treatment, and greater total dose received.47 Hearing loss associated with ototoxicity is diagnosed by audiogram and vestibular toxicity is diagnosed by history and physical examination. Subjective changes in hearing or balance correlate poorly with objective findings. Vestibular toxicity is mostly mild and reversible. It seems to be temporarily related to infusion of aminoglycosides rather than being a persistent finding.
CONCLUSIONS
Fig. 44.8 Axial CT scan of the head showing extensive bony destruction of posterior cranial fossa.
Tuberculosis in the head and neck region can mimic malignancy and chronic granulomatous conditions. Because of the variable nature of manifestations of TB, its ability to target almost every organ in the body individually or together makes it essential to have a high degree of suspicion to enable early diagnosis. Tuberculosis of cervical lymph nodes is the commonest presentation followed by laryngeal TB. If FNA fails to confirm the diagnosis of cervical TB lymphadenitis, tissue biopsy should be performed. Persistent otorrhoea that does not respond to conventional treatment, or facial paralysis in a patient with a discharging ear, should alert the physician to a diagnosis of TB. Up to 30% of patients with TB of the head and neck have associated TB elsewhere, and therefore must be investigated for pulmonary or systemic TB. Early diagnosis and prompt anti-TB treatment will successfully treat the majority of TB infections. Aminoglycosides are important drugs in the management of MDR TB. These patients should be screened for ototoxicity (hearing loss) and vestibular toxicity.
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REFERENCES 1. Williams RG, Douglas-Jones T. Mycobacterium marches back. J Laryngol Otol 1995;109:5–13. 2. Nalini B, Vinayak S. Tuberculosis in ear, nose, and throat practice: its presentation and diagnosis. Am J Otolaryngol 2006;27:39–45. 3. Singh B. Role of surgery in tuberculous mastoiditis. J Laryngol Otol 1991;105:907–915. 4. Awan MS, Salahuddin I. Tuberculous otitis media: two case reports and literature review. Ear Nose Throat J 2002;81:792–794. 5. Schaaf HS, Geldenhuys A, Gie RP, et al. Culturepositive tuberculosis in human immunodeficiency virus type 1-infected children. Pediatr Infect Dis J 1998;17:599–604. 6. Mustafa A, Debry CH, Wiorowski M, et al. Treatment of acute mastoiditis: report of 31 cases over a ten year period. Rev Laryngol Otol Rhinol (Bord) 2004;125:165–169. 7. Cho YS, Lee HS, Kim SW, et al. Tuberculous otitis media: a clinical and radiologic analysis of 52 patients. Laryngoscope 2006;116:921–927. 8. Odetoyinbo O. Early diagnosis of tuberculous otitis media. J Laryngol Otol 1988;102;133–135. 9. Gierek T, Klimczak-Golab L, Jura-Szoltys E. Middle ear tuberculosis behind an intact tympanic membrane - a case report. Otolaryngol Pol 2002;56:629–631. 10. Varty S, Vaidya D, Parasram K, et al Tuberculous otitis media—are we missing it? Indian J Otolaryngol Head Neck Surg 2000;52;143–146. 11. Hoshino T, Miyashita H, Asai Y. Computed tomography of the temporal bone in tuberculous otitis media. J Laryngol Otol 1994;108:702–705. 12. Windle-Taylor PC, Bailey CM. Tuberculous otitis media: a series of 22 patients. Laryngoscope 1980;90:1039–1044. 13. Weiner GM, O’Connell JE, Pahor AL. The role of surgery in tuberculous mastoiditis: appropriate chemotherapy is not always enough. J Laryngol Otol 1997;111:752–753. 14. Thandar MA, Fagan JJ, Garb M. Extensive calvarial tuberculosis: a rare complication of tuberculous mastoiditis. J Laryngol Otol 2004;118:65–68. 15. Saunders NC, Albert DM. Tuberculous mastoiditis: when is surgery indicated? Int J Pediatr Otolaryngol 2002;65:59–63.
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16. Mongkolrattanothai K, Oram R, Redleaf M, et al. Tuberculous otitis media with mastoiditis and central nervous system involvement. Pediatr Infect Dis J 2003;22:453–456. 17. Thomson St. The Mitchell lecture on tuberculosis of the larynx: its significance to the physician. BMJ 1924;2:841–844. 18. Gallietti F, Georgis GE, Oliaro A, et al. Tuberculosis of the larynx. Panminerva Med 1989;31:134–136. 19. Levenson MJ, Ingerman M, Grimes C, et al. Laryngeal tuberculosis: review of twenty cases. Laryngoscope 1984;94:1094–1097. 20. Kulkarni NS, Gopal GS, Ghaisas SG, et al. Epidemiological considerations and clinical features of ENT tuberculosis. J Laryngol Otol 2001; 115:555–558. 21. Soda A, Rubio H, Salazar M, et al. Tuberculosis of the larynx. Clinical aspects of 19 patients. Laryngoscope 1989;99:1147–1150. 22. Ramadan HH, Tarazi AE, Baroudy FM. Laryngeal tuberculosis: presentation of 16 cases and review of the literature. J Otolaryngol 1993;22:39–41. 23. Vidal R, Mayordomo C, Miravitlles M, et al. Pulmonary and laryngeal tuberculosis: a study of 26 patients. Rev Clin Esp 1996;196:378–380. 24. Khoo KK, Meadway J. Fibreoptic bronchoscopy in rapid diagnosis of sputum smear negative pulmonary tuberculosis. Respir Med 1989;83:335–338. 25. Raviglione MC, O’Brien RJ. Tuberculosis. In: Harrison’s Principles of Internal Medicine, 15th edn. New York: McGraw-Hill, 2001: 1024–1035. 26. Kheiry J, Ahmed ME. Cervical lymphadenopathy in Khartoum. J Trop Med Hyg 1992;95:416–419. 27. Baskota DK, Prasad R, Kumar Sinha B, et al. Distribution of lymph nodes in the neck in cases of tuberculous cervical lymphadenitis. Acta Otolaryngol 2004;124:1095–1098. 28. Ibekwe AO, Al Shareef Z, Al Kindy S. Diagnostic problems of tuberculous cervical adenitis (scrofula). Am J Otolaryngol 1997;18:202–205. 29. Weiler Z, Nelly P, Baruchin AM, et al. Diagnosis and treatment of cervical tuberculous lymphadenitis. J Oral Maxillofac Surg 2000;58:477–481. 30. Hup AK, Haitjema T, De Kuijper G. Primary nasal tuberculosis. Rhinology 2001;39:47–48. 31. Blanco Aparicio M, Verea-Hernando H, Pombo F. Tuberculosis of the nasal fossa manifested
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by a polypoid mass. J Laryngol Otol 1995;24: 317–318. Belal A. Latent tuberculosis in tonsils and adenoids; a study of 127 cases. J Laryngol Otol 1951;65:414–425. Rohwedder JJ. Upper respiratory tract tuberculosis. Sixteen cases in a general hospital. Ann Intern Med 1974;80:708–713. Waldron J, van Hasselt CA, Skinner DW, et al. Tuberculosis of the nasopharynx: clinicopathological features. Clin Otolaryngol Allied Sci 1992;17:57–59. Suoglu Y, Erdamar B, Colhan I, et al. Tuberculosis of parotid gland. J Laryngol Otol 1998;112:588–591. Buchwald C, Nissen F, Thomsen J. Parapharyngeal abscess and torticollis. J Laryngol Otol 1990;104: 829–830. Caylan R, Aydin K, Caylan R. Oropharyngeal tuberculosis causing severe odynophagia and dysphagia. Eur Arch Otorhinolaryngol 2002;259:229–230. Pelteret RM. Tuberculous osteitis of the skull. Ann Trop Paediatr 1989;9:40–42. Unuvar E, Oguz F, Sadikoglu B, et al. Calvarial tuberculosis. J Paediatr Child Health 1999;35:221–222. Malhotra R, Dinda AK, Bhan S. Tubercular osteitis of skull. Indian Paediatr 1993;30:1119–1123. Jaffe RH. Tubercle-like structures in human goitres. Arch Surg 1930;21:717–728. Johnson AG, Philips ME, Thomas RJ. Acute tuberculous abscess of thyroid. Br J Surg 1973;60:668–669. Zivaljevic V, Paunovic I, Diklic A. Tuberculosis of the thyroid gland: a case report. Acta Chir Belg 2007;107:70–72. Takasu N, Kinjou Y, Kouki T, et al. Rifampicininduced hypothyroidism. J Endocrinol Invest 2006;29:645–649. Khokhar O, Gange C, Clement S, et al. Autoimmune hepatitis and thyroiditis associated with rifampicin and pyrazinamide prophylaxis: an unusual reaction. Dig Dis Sci 2005;50:207–211. Takasu N, Takara M, Komiya I. Rifampicin-induced hypothyroidism in patients with Hashimoto’s thyroiditis. N Engl J Med 2005;352:518–519. Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis 2004;38:1538–1544.
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Tuberculosis of the breast Mallika Tewari and Hari S Shukla
DEFINITION Breast TB is defined as infection by Mycobacterium tuberculosis leading to disease of the breast parenchyma. It is a rare form of extrapulmonary TB.1,2
HISTORY OF BREAST TUBERCULOSIS History of breast TB dates back to 1829 when Sir Astley Cooper reported the first case of mammary TB. He called it ‘the scrofulous swelling of the bosom’.3 A literature review by Morgan in 1931 revealed 439 cases of tuberculous mastitis with the incidence between 0.5% and 1.04%.4 In 1944, Klossner5 reported 50 cases of breast TB in women out of 75,000 with lung involvement. Of approximately 8,000 breast specimens studied between 1938 and 1967, Haagensen6 reported only five cases of breast TB. Only 500 cases were documented from the world literature by Hamit and Ragsdale in 1982.7 Since then, case records and reviews have been published at infrequent intervals mostly in western literature. Publications often report findings of clinics serving an ethnically diverse population.8 Breast TB is rare in western countries, with the incidence being < 0.1% of breast lesions examined histologically.1,9,10
INDIAN LITERATURE ON BREAST TUBERCULOSIS The incidence of breast TB, in general, mirrors that of TB in the community. The disease is often overlooked and misdiagnosed as breast carcinoma or pyogenic breast abscess.11 Reports from India of breast TB have been few. Up until 1987 fewer than 100 cases were reported.12 The first 13 cases were reported by Chaudhuri from 433 breast lesions she had studied.13 This report was followed by several others.12,14–18 Several Indian series report the incidence of breast TB amongst the total number of mammary conditions to vary between 0.64% and 3.59%.15,17 In our own series, we have found 30 patients with breast TB out of 1,180 breast lesions examined over the past 20 years (January 1983 to December 2003) in the department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India, with an overall incidence of 2.5%.19
CLASSIFICATION OF BREAST TUBERCULOSIS PRIMARY AND SECONDARY BREAST TUBERCULOSIS Breast TB may be broadly categorized as primary when the breast lesion is the only manifestation of TB, and secondary when a demonstrable focus of TB exists elsewhere in the body.20 The theory of secondary involvement of the breast from a tuberculous lesion at another site was supported by Raw21 and Morgan,4 and seconded by Dubey and Agarwal from India.16 However, Vassilakos22 stated that primary breast TB is probably quite rare and is diagnosed because the clinician is unable to detect the true nidus of the disease. Similarly Mukerjee et al.17 did not favour the classification. It is now increasingly accepted that breast TB is almost invariably secondary to a lesion elsewhere in the body.12,15 The primary form may rarely result from infection of the breast through abrasions or through openings of the ducts in the nipple.
HISTORICAL CLASSIFICATION OF BREAST TUBERCULOSIS Breast TB was first classified into five different types by McKeown and Wilkinson:20 1. nodular tuberculous mastitis; 2. disseminated or confluent tuberculous mastitis; 3. sclerosing tuberculous mastitis; 4. tuberculous mastitis obliterans; and 5. acute miliary tuberculous mastitis. This classification has always been followed even though the clinical scenario of breast TB has gradually changed over the years (Table 45.1).
Nodular tuberculous mastitis The nodulocaseous form of breast TB presents as a well-circumscribed, slowly growing painless mass(es) that progresses to involve the overlying skin, possibly ulcerate, form sinuses and possibly become painful. In the early stage it is difficult to differentiate from a fibroadenoma, while in later stages it mimics a carcinoma.23,24 Sixteen out of 20 patients investigated by Dubey and Agarwal16 were found to have nodular tuberculous mastitis and only two had sclerosing tuberculous mastitis. All four cases reported by Dharkar et al.15 had nodular variety. Similarly, Mukerjee et al.17 found nine
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Table 45.1 Classification of breast tuberculosis Historical classification 20 (McKeown & Wilkinson )
New classification 19 (Tewari & Shukla )
1. Nodular tuberculous mastitis 2. Disseminated/confluent tuberculous mastitis 3. Sclerosing tuberculous mastitis 4. Tuberculous mastitis obliterans 5. Acute miliary tuberculous mastitis
1. Nodulocaseous tuberculous mastitis 2. Disseminated/confluent tuberculous mastitis 3. Tuberculous breast abscess
of their 14 cases to have the nodulocaseous variety and three to have sclerosing tuberculous mastitis. Even Alagaratnam and Ong25 reported that 15 of their cases would be classified as nodular and only one as disseminated tuberculous mastitis. Recent reports also indicate that the nodulocaseous variety is still the commonest form of breast TB.26–28
Disseminated/confluent tuberculous mastitis Few reports from recent literature describe the disseminated form of breast TB.26,27 It is characterized by multiple foci throughout the breast that later caseate leading to sinus formation. The overlying skin is thickened and stretched with or without painful ulcers. The breast may be tense and tender. The draining axillary lymph nodes are enlarged and matted.27 Sclerosing tuberculous mastitis The sclerosing variety finds mention in old literature by usually affecting involuting breasts of older females. Excessive fibrosis rather than caseation is the dominating feature. There is a hard, painless, slow-growing lump with nipple retraction. Suppuration is rare. It may be misdiagnosed as a scirrhotic carcinoma.27 Often the entire breast becomes hard because of dense fibrous tissue. It is rare today. Tuberculous mastitis obliterans Tuberculous mastitis obliterans, as described by McKeown and Wilkinson,20 is characterized by duct infection producing proliferation of lining epithelium and marked epithelial and periductal fibrosis. The ducts are occluded and cystic spaces resembling ‘cystic mastitis’ are produced. Miliary tuberculous mastitis In acute miliary tuberculous mastitis breast disease is a part of a generalized miliary TB. NEW CLASSIFICATION OF BREAST TUBERCULOSIS With the changing paradigm of the presentation of TB, miliary TB is rare today. Moreover, there have been hardly enough reports during the past two decades to merit the sclerosing tuberculous
mastitis, tuberculous mastitis obliterans and acute miliary tuberculous mastitis in the classification of breast TB. Tuberculous breast abscess is often a common mode of presentation of breast TB especially in young women. In a review of benign breast disorders in India, Shukla and Kumar29 found tuberculous breast abscess to be a common presentation of breast TB. Nine cases were reported by Shinde et al.27 and we in our series found eight patients who presented with a fluctuant breast abscess. Hence breast TB may be reclassified as nodular, disseminated and abscess varieties. The sclerosing type, mastitis obliterans and miliary variety are of historical importance only (Table 45.1).
PRESENTATION (TABLE 45.2) AGE AND SEX The history of the presenting symptoms in breast TB is usually less than a year but varies from few months to several years.16,17 Breast TB commonly affects women in the reproductive age group,27 between 21 and 30 years, similar to the highest incidence of pulmonary TB in the same age group of females.29 This may be because the female breast undergoes frequent changes during the period of activity and is more liable to trauma and infection.17 In pregnant and lactating women the breast is vascular with dilated ducts, making it predisposed to trauma and more susceptible to tuberculous infection.12,27 Twenty-four out of 30 patients in our series were between 20 and 40 years.19 Two patients were under 20 years and only one was over 60 years of age. It is uncommon in prepubescent females and elderly women.7,30 Breast TB is rare in males and male sex is reported in about 4% of cases.4,31 Bilateral involvement is uncommon (3%).12
CLINICAL FEATURES Breast TB most commonly presents as a lump in the central or upper outer quadrant of the breast.18,23,29 It is probably due to frequent extension of TB from axillary nodes to the breast. Multiple lumps are less frequent.15 The lump is often indistinguishable from carcinoma of the breast, being irregular, hard and at times fixed to either skin or muscle or even the chest wall.27 However, the lump is usually painful. The breast remains mobile unless involvement is secondary to TB of the underlying chest wall.12 Tuberculous ulcer over the breast skin with or without discharging sinuses and tuberculous breast abscess are the other common forms of clinical presentation of breast TB (Figs 45.1–45.4).29 Peau d’orange is often seen in patients with extensive axillary nodal TB. Purulent nipple discharge or persistent discharging sinus may be the rare presenting feature.
Table 45.2 Common clinical features, diagnostic investigations and treatment options in breast tuberculosis Clinical features
Diagnostic investigations
Treatment options
Breast 1. Lump only 2. Tuberculous ulcer lump 3. Sinus(es) lump 4. Tuberculous breast abscess Axillary lymph node: Present/Absent
1. Fine needle aspiration cytology 2. Core biopsy 3. Open biopsy Incisional Excisional
1. 2. 3. 4. 5.
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Anti-TB treatment only Anti-TB treatment þ aspiration Primary excision biopsy þ anti-TB treatment Anti-TB treatment þ excision of residual lump Simple mastectomy
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3. spread from contiguous structures; 4. direct inoculation; and 5. ductal infection.
Fig. 45.1 Mammography shows a large, dense, well-defined lump measuring 10 8 cm just behind the involute mammary gland, accompanied by thickening of the overlying skin. No calcification is found. Courtesy of AN Chalazonitis, Athens, Greece.
PATHOGENESIS M. tuberculosis and non-tuberculous mycobacteria can cause breast TB with M. tuberculosis being the most frequently isolated organism. The breast is remarkably resistant to TB. This is due to the fact that, like skeletal muscles and spleen, it provides an infertile environment for the survival and multiplication of tubercle bacilli.17 The breast may become infected in a variety of ways:20 1. haematogenous; 2. lymphatic;
Of these the most accepted view for spread of infection is centripetal lymphatic spread.17 The path of spread of the disease from lungs to breast tissue was traced by McKeown and Wilkinson20 as via the tracheobronchial, paratracheal, mediastinal lymph trunk and internal mammary nodes. According to Cooper’s theory, communication between the axillary glands and the breast results in secondary involvement of the breast by retrograde lymphatic extension.32 Supporting this hypothesis is the fact that axillary node involvement occurs in 50–75% of cases of tuberculous mastitis.26 In our own series ipsilateral axillary nodal involvement was present in 18 cases (60%).19 Breast is resistant to tuberculous infection by blood stream, even in patients debilitated by TB.20 Occasionally direct extension from contiguous structures such as infected rib, costochondral cartilage, sternum, shoulder joint and even the chest wall from a tuberculous pleurisy or via abrasions in the skin can occur.33,34 An interesting hypothesis correlating the prevalence of TB in the faucial tonsils of suckling infants with the higher incidence of breast TB in lactating women in India, thereby suggesting the spread of infection orally from the suckling infant to the nipple, and, in turn, to the lactating breast via lacticiferous ducts, was proposed by Wilson and MacGregor.35 In all cases, bacilli infect the ducts and spare the lobules. This may be the sole example of primary breast TB relevant even today.
Fig. 45.2 Mammogram of a 38-year-old woman with a history of an enlarging erythematous right breast. Examination revealed peau d’orange in the overlying skin, nipple retraction and enlarged, hard axillary and supraclavicular lymph nodes. Mammography showed (A) extreme skin thickening over the entire right breast, diffusely increased density and an extensive reticular pattern compared with the left breast (B). Courtesy of AN Chalazonitis, Athens, Greece.
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BREAST TUBERCULOSIS IN PATIENTS WITH HIV INFECTION AND AIDS
Fig. 45.3 Same patient as in Fig. 45.1. Magnetic resonance scan of the thorax showing a large regularly bordered mass in the left breast, in close contact with the anterior thoracic wall posteriorly and subcutaneous fat anteriorly. A second smaller pleural mass is close to it. In the T2-weighted image both masses are characterized by extremely high and homogeneous signal intensity. Courtesy of AN Chalazonitis, Athens, Greece.
The epidemic of acquired immunodeficiency syndrome (AIDS) has been accompanied by a resurgence of TB. The incidence of extrapulmonary TB is about 50% in patients with AIDS, whereas it is 10–15% in patients without human immunodeficiency virus (HIV) infection.36 In view of the recent increase in the incidence of TB in certain developed countries and the growth in the proportion of cases of extrapulmonary TB especially in HIV-infected individuals mammary TB may no longer be uncommon in the developed world.37 Authors describe it as an AIDS-defining illness.2,10,38,39 There are scattered case reports of breast TB in HIV-infected individuals in indexed medical literature. The presentation is no different from that in HIV-uninfected individuals. Breast TB may manifest as a breast lump or as a breast abscess.38–40 It is important to anticipate such a possibility when patients are at risk for HIV infection and highlights the necessity for performing mycobacterial smears and cultures in such cases.39 Mycobacterium avium–intracellulare (MAI) attacks mainly immunocompromised patients with long-standing pulmonary disease, the symptoms being similar to those of pulmonary TB, and causes disseminated disease in patients with AIDS. Extrapulmonary infection by MAI commonly presents as cervicofacial lymphadenitis in children. Breast and other extrapulmonary sites (musculoskeletal, maxillary sinus, mastoid, small bowel, genitourinary tract and cornea) are less common.41 Breast lesion caused by an atypical mycobacterium has recently been reported by Verfaillie et al.42
DIAGNOSIS OF BREAST TUBERCULOSIS Because of the infrequency of breast TB, it is often misdiagnosed and the patient is often subjected to numerous investigations before a definitive diagnosis is reached. It warrants a high index of suspicion on clinical examination and pathological or microbiological confirmation of all suspected lesions. A biopsy of any chronic breast lesion is mandatory.
MANTOUX TEST This test is usually positive in adults in TB-endemic areas. It simply demonstrates that at some point the patient was exposed to TB. It is, therefore, of no diagnostic value for breast TB and today stands obsolete.
RADIOLOGICAL INVESTIGATIONS Modern radiological investigations help to define the extent of the lesion rather than confirm diagnosis. Sophisticated radiological tools such as mammography, computed tomography (CT) and magnetic resonance imaging (MRI) of the breast have been extensively explored for the diagnosis of breast TB but to no avail (Figs 45.1–45.3).
Fig. 45.4 Typical granulomatous inflammatory lesion with Langerhanstype giant cells (A) and focal caseous necrosis (B) on histopathology of suspected breast TB.
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Chest radiograph The chest radiograph may show evidence of active or healed tuberculous lesions in the lungs in a few cases,17 and may also reveal clustered calcifications in the axilla, suggesting the possibility of lymph node TB in suspected patients.29
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Mammography The mammogram in breast TB is of limited value as the findings are often indistinguishable from those of carcinoma of the breast.27,28 The mammographic picture of nodular TB is usually of a dense round area with indistinct margins without the classic halo sign found in fibroadenoma.28 It is very similar to carcinoma except the size of the lesion, which correlates with the clinical size.27 The disseminated variety mimics inflammatory carcinoma and the radiographs show dense breast with thickened skin.34 Sclerosing tuberculous mastitis reveals a homogeneous dense mass with fibrous septa and nipple retraction.12,27,43,44 A careful evaluation of the degree of density and trabecular thickening of the mass in relation to its size might help in differentiating breast TB from carcinoma of the breast.45 However, the finding of breast TB in young women 20–40 years of age with dense breasts makes interpretation of mammograms difficult. Moreover, this facility might not be available to and economical for many patients from less developed nations where the disease is commonly found. Ultrasound of the breast Ultrasonography of the breast is cheap, is easily accessible and helps in characterizing the lesion better (especially cystic from solid lesions) without exposing the patient to radiation.28 In the nodular form of the disease lesions are either hypoechoic with ill-defined margins or complex cystic masses. In diffuse breast TB, ill-defined hypoechoic masses are seen, whereas in patients with sclerosing breast TB, increased echogenicity of the breast parenchyma often with no definite mass is seen.28,46 At times a beak-like fistulous connection between a retromammary abscess and the thoracic wall is seen on the sonogram.44 Ultrasound-guided fine needle aspiration decreases the failure rate and obviates the need for multiple punctures.28,43 The mammographic and sonographic features of tuberculous mastitis as stated by a recent study include a mass lesion mimicking malignant tumors (30%), smooth-bordered masses (40%), axillary or intramammary adenopathy (40%), asymmetric density and duct ectasia (30%), skin thickening and nipple retraction, macrocalcification (20% each) and skin sinus (10%). On ultrasound 60% had hypoechoic masses, 40% focal or sectorial duct ectasia and 50% axillary adenopathy.47 Computed tomography of the breast CT scan seldom adds to the diagnostic yield other than in defining the involvement of the thoracic wall in patients presenting with a deeply adhered breast lump.48 Tuberculous breast abscess may be seen on contrast CT as a smoothly marginated, inhomogeneous, hypodense lesion with surrounding rim. A direct fistulous tract with the pleura or a destroyed rib fragment in the abscess can also be seen.49 Percutaneous drainage of a tuberculous breast abscess under CT guidance is feasible.48 CT can show area(s) of lung destruction beneath the pleural disease,48,50 and is a valuable tool in demonstrating the extent of disease, in the planning of surgery and in the assessment of response to treatment. Magnetic resonance imaging of the breast MRI of the breast may reveal a smooth or irregular bright signal intensity lesion on T2-weighted images, suggesting a breast abscess. Again the findings are non-specific and reports on MRI of the breast suggest its usefulness only in demonstrating the extramammary extent of the lesion.46,49,50 MRI may also help in assessing the efficiency of treatment of breast TB.51
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Positron emission tomography scan Tuberculous lymph nodes and lung show intense focal uptake of fluorine-18 fluorodeoxyglucose (F-18 FDG) on positron emission tomography scan. This fact should be well remembered while interpreting results of cancer patients in a region endemic for TB.52 FINE NEEDLE ASPIRATION CYTOLOGY Fine needle aspiration cytology (FNAC) from the breast lesion continues to remain an important diagnostic tool of breast TB.2,53 Approximately 73% of breast TB can be diagnosed on FNAC when both epithelioid cell granulomas and necrosis are present.2 Failure to demonstrate necrosis on FNAC does not exclude TB in view of the small quantity of sample harvested and examined. The determination of acid-fast bacilli (AFB) on FNAC is not mandatory, since, for AFB to be seen microscopically, their number must be 10,000–100,000/mL of material.54 In tuberculous breast abscess FNAC may be inconclusive and the FNA picture may be dominated by acute inflammatory exudates. AFB-negative breast abscesses that fail to heal despite adequate drainage and antibiotic therapy and those with persistent discharging sinuses should raise suspicion of underlying TB. Biopsy of the abscess wall and demonstration of characteristic histological features or culture is essential for confirming the diagnosis of breast TB.2,26
CULTURE Though mycobacterial culture remains the gold standard for diagnosis of TB, the time required and frequent negative results in paucibacillary specimens are important limitations.1 During the past two decades several rapid techniques for detection of early mycobacterial growth (5–14 days as compared with 2–8 weeks with conventional methods), which can help in obtaining the culture and sensitivity reports relatively early, have been described. Prominent among such methods are BACTEC, mycobacterial growth indicator tube (MGIT), Septi-chek and MB/BacT systems.55 However, even culture is not always helpful in diagnosing breast TB. Only 25–30% of the cases of tuberculous mastitis reported by Morgan4 and four of the 12 patients with a breast abscess cavity reported by Alagaratnam and Ong25 were culture positive.
POLYMERASE CHAIN REACTION (PCR) Gene amplification methods (PCR as well as isothermal) developed for diagnosis of TB are demonstrably highly sensitive, especially in culture-negative specimens from different paucibacillary forms of disease. A variety of PCR techniques for detection of specific sequences of M. tuberculosis and other mycobacteria have been developed. PCR has positivity rates ranging from 40% to 90% in diagnosing tuberculous lymphadenitis.55 PCR in the diagnosis of breast TB is less often reported, mostly as a tool to distinguish tuberculous mastitis from other forms of granulomatous mastitis in selected reports.44 However, PCR is by no means absolute in diagnosing tuberculous infection and false-negative reports are still a possibility.55 Most of these new techniques are too expensive and sophisticated to be of any practical benefit to the vast majority of TB patients living in underdeveloped countries such as India for whom an early and inexpensive diagnosis remains as elusive as ever.
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HISTOPATHOLOGY OF THE SPECIMEN Tuberculous mastitis is a form of granulomatous inflammation. Histological findings include epithelioid cell granulomas with caseous necrosis in the specimen (Fig. 45.4). Core needle biopsy provides a good sample often yielding a positive diagnosis. However, open biopsy (incision or excision) of breast lump, ulcer or sinus or from the wall of a suspected tuberculous breast abscess cavity almost always confirms breast TB.2,27
Granulomatous mastitis Granulomatous mastitis is a heterogeneous group of diseases of unknown aetiology.56 The characteristic feature is a predominant lobular inflammatory process.57 Most cases are not associated with bacterial pathogens (TB being excluded). Clinical presentation varies from localized breast lumps, to abscess to extensive inoperable lesions often mimicking a carcinoma. Theories regarding the aetiology suggest a possible role of autoimmune or hypersensitivity process. Scattered reports in literature have revealed isolation of Staphylococcus aureus, Propionibacterium acne and Corynebacterium species from a few cases.58 Treatment includes excision, drainage for abscess and antibiotics. There are a considerable number of other conditions characterized histologically by a tuberculoid type of tissue reaction. These conditions include sarcoidosis, various fungal infections and granulomatous reactions to altered fatty material. Sometimes the microscopic picture is indistinguishable from that of TB.33 Breast tuberculosis versus carcinoma of the breast Clinical examination often fails to differentiate carcinoma from TB and a high index of suspicion is necessary. Factors predictive but not diagnostic of breast TB include constitutional symptoms, mobile breast lump, multiple sinuses and an intact nipple and areola in a young, multiparous or lactating female.12,27 Nipple retraction, peau d’orange and involvement of axillary lymph nodes are more common in malignancy than in TB. Mammography is not of much help as the findings in carcinoma in advanced stage are similar to those of a tuberculous lesion.27,44 Carcinoma and TB of the breast occasionally coexist. Similar finding in the axillary lymph nodes may also be seen.6,59 In assessing diagnosis it is important to remember that recognition of TB does not exclude concomitant breast cancer.
isoniazid (H) and pyrazinamide (Z). The Revised National Tuberculosis Control Programme of India recommends a category III regimen (2HRZ/4HR) for less serious forms of extrapulmonary TB, namely lymph node TB, cutaneous TB and unilateral pleural effusion, and a category I regimen (2EHRZ/4HR) for more severe forms of extrapulmonary TB. Drugs are administered three times weekly.61 The World Health Organization has recommended a four-drug intensive phase (2EHRZ) in the category III regimen as well. Multidrug-resistant breast TB has been mentioned albeit rarely in literature. Such patients require second-line anti-TB drugs.62 Local streptomycin has been claimed to be useful.15 The overall prognosis is good with adequate medical treatment.12 Mutilating surgery such as simple mastectomy for breast TB was in vogue in the past with the belief that the lesion tends to persist and reappear with conservative treatment even with chemotherapy.35 However, today minimal surgical intervention is required for drainage of breast abscess or biopsy from the abscess wall, scraping of sinuses in the breast, or incisional or excisional biopsy.12,18,27 Small lesions are eminently treatable by an excision biopsy followed by a full course of anti-TB treatment.27 A residual lump following anti-TB treatment may require surgical removal. Simple mastectomy with or without axillary clearance is rarely required for extensive disease comprising a large, painful ulcerated mass involving the entire breast and draining axillary lymph nodes rendering organ preservation impossible.27 For concomitant breast cancer the form of surgery is dependent upon the stage of breast cancer. In our series, FNAC was positive in 11, core needle biopsy was positive in two and an open biopsy was required in 17 patients. All eight patients with tuberculous breast abscess responded to repeat aspiration in conjunction with anti-TB treatment. All patients were treated with anti-TB treatment (2EHRZ/ 7HR) for a total of 9 months and were recurrence free in 12–200 months of followup. Simple mastectomy was performed in one patient who defaulted after initial diagnosis and returned with a large ulcerated breast lesion and matted axillary nodes.19
CONCLUSION TREATMENT The treatment of breast TB consists of anti-TB treatment and surgery with specific indications. Antituberculosis treatment is the backbone of treatment of breast TB.60 No specific guidelines for the chemotherapy of breast TB are available per se. The regimen generally followed in the treatment of breast TB is similar to that used in pulmonary TB.1,35 Extrapulmonary TB except for tuberculous meningitis can be treated with a 6-month regimen comprising 2 months of intensive phase treatment (with a four-drug combination) followed by a 4-month continuation phase (with a two-drug combination). The chief first-line drugs are ethambutol (E); streptomycin (S), rifampicin (R),
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Extrapulmonary TB occurring in the breast is rare. Breast TB is uncommon even in countries where the incidence of pulmonary and extrapulmonary TB is high. With the advent of the HIV/AIDS epidemic and the consequential rise in the number of TB cases it is pertinent that lesions of the breast are screened to exclude breast TB. Not having well-defined clinical features, the true nature of the disease remains obscure and it is often mistaken for carcinoma or pyogenic breast abscess. It also presents a diagnostic problem on radiological and microbiological investigations and thus a high index of suspicion is important. Caseating epithelioid cell granulomas in the tissue samples are diagnostic of TB. The disease is eminently curable with modern anti-TB chemotherapeutic drugs with surgery playing only a background role.
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A study of 100 patients. World J Surg 1995; 19:379–381. Popli MB. Pictorial essay: tuberculosis of the breast. Ind J Radiol Imag 1999;9:127–132. Shukla HS, Kumar S. Benign breast disorders in Nonwestern populations: Part II—Benign breast disorders in India. World J Surg 1989;13:798–800. Indumathi CK, Alladi A, Dinakar C, et al. Tuberculosis of the breast in an adolescent girl: a rare presentation. J Trop Pediatr 2007;53:133–134. Jaideep C, Kumar M, Khanna AK. Male breast tuberculosis. Postgrad Med J 1997;73:428–429. Domingo C, Ruiz J, Roig J, et al. Tuberculosis of the breast: a rare modern disease. Tubercle 1990;71:221–223. Symmers WStC. The breasts. In: Symmers WStC (ed.). Systemic Pathology, vol. 4, 2nd edn. New York: Churchill Livingstone, 1978: 1759–1861. Hale JA, Peters GN, Cheek JH. Tuberculosis of the breast: rare but still exists. Review of literature and report of additional case. Am J Surg 1985;150:620–624. Wilson TS, MacGregor JW. The diagnosis and treatment of tuberculosis of the breast. Can Med Assoc J 1963;89:1118–1124. Aguado JM. Pons F, Casafont F, et al. Tuberculous peritonitis: a study comparing cirrhotic and noncirrhotic patients. J Clin Gastroenterol 1990;550–554. Leleu O, Aubry P, Verhoest P, et al. Tuberculosis of the breast. Rev Mal Respir 1997;14(5):401–403. Mendes Wda S, Levi M, Levi GC. Breast tuberculosis: case report and literature review. Rev Hosp Clin Fac Med Sao Paulo 1996;51(4): 136–137. Hartstein M, Leaf HL. Tuberculosis of the breast as a presenting manifestation of AIDS. Clin Infect Dis 1992;15(4):692–693. Fred HL. An enlarging breast mass in an HIVseropositive woman. Hosp Pract (Minneap) 1995;30(5): 31–32. Alagarswamy RK, Halfpenny W, Thiruchelvam JK, et al. Rare presentation of Mycobacterium aviumintracellulare infection. Br J Oral Maxillofac Surg 2007;45(8):670–672. Verfaillie G, Goossens A, Lamote J. Atypical mycobacterial breast infection. Breast J 2004;10:60. Schnarkowski P, Schmidt D, Kessler M, et al. Tuberculosis of the Breast: US, mammographic, and CT Findings. J Comput Assist Tomogr 1994; 18:970–971. Makanjuola D, Murshid K, Al Sulaimani S, et al. Mammographic features of breast tuberculosis: the skin bulge and sinus tract sign. Clin Radiol 1996;51:354–358.
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45. Al-Marri MR, Aref E, Omar AJ. Mammographic features of isolated tuberculous mastitis. Saudi Med J 2005;26:646–650. 46. Oh KK, Kim JH, Kook SH. Imaging of tuberculous disease involving breast. Eur Radiol 1998; 8:1475–1480. 47. Sakr AA, Fawzy RK, Fadaly G, et al. Mammographic and sonographic features of tuberculous mastitis. Eur J Radiol 2004;51:54–60. 48. Romero C, Carrerira C, Cereceda C, et al. Mammary tuberculosis: percutaneous treatment of mammary tuberculous abscess. Eur Radiol 2000;10:531–533. 49. Bhatt GM, Austin HM. CT demonstration of empyema necessitates. J Comput Assist Tomogr 1985;9:1108–1109. 50. Chung SY, Yang I, Bae SH, et al. Tuberculous abscess in retromammary region: CT findings. J Comput Assist Tomogr 1996;20:766–769. 51. Fellah L, Leconte I, Weynand B, et al. Breast tuberculosis imaging. Fertil Steril 2006;86:460–461. 52. Bakheet SM, Powe J, Ezzat A, et al. F-18-FDG uptake in tuberculosis. Clin Nucl Med 1998; 23(11):739–742. 53. Mehrotra R. Fine needle aspiration diagnosis of tuberculous mastitis. Indian J Pathol Microbiol 2004;47:377–380. 54. Pagel W, Simmonds FAH, Macdonald J, et al. Pulmonary Tuberculosis, 4th edn. London: Oxford University Press, 1964: 245. 55. Katoch VM. Newer diagnostic techniques for tuberculosis. Indian J Med Res 2004;120:418–428. 56. Tse GM, Poon CS, Ramachandram K, et al. Granulomatous mastitis: a clinicopathological review of 26 cases. Pathology 2004;36:254–257. 57. Yip CH, Javaram G, Swain M. The value of cytology in granulomatous mastitis: a report of 16 cases from Malaysia. Aust N Z J Surg 2000;70(2): 103–105. 58. Taylor GB, Paviour SD, Musaad S, et al. A clinicopathological review of 34 cases of inflammatory breast disease showing an association between corynebacteria infection and granulomatous mastitis. Pathology 2003;35(2):109–119. 59. Fujii T, Kimura M, Yanagita Y, et al. Tuberculosis of axillary lymph nodes with primary breast cancer. Breast Cancer 2003;10:175–178. 60. Elmrabet F, Ferhati D, Amenssag L, et al. Breast tuberculosis. Med Trop (Mars) 2002;62:77–80. 61. Jawahar MS. Current trends in chemotherapy of tuberculosis. Indian J Med Res 2004;120:398–417. 62. Kumar P, Sharma N. Primary MDR-TB of the breast. Indian J Chest Dis Allied Sci 2003; 45:63–65.
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46
Ocular tuberculosis in adults and children Salil Mehta and Ishwarprasad Gilada
BACKGROUND Choroidal tubercles were first recognized in 1830 by Gueneau de Mussy and were first anatomically demonstrated in 1855 by Jaeger. Among the first complete histopathological reports was one by Manz in 1858 who described the ocular findings of a 15-year-old girl who had died of miliary TB. Fraenkel (1867) was the first to describe the ophthalmoscopic appearance of tubercles, and the diagnostic value of the ophthalmoscopic detection of tubercles was subsequently expanded on by Bouchut, Fraenkel and Weiss. The work of Hoeve (1925), Bollack (1927) and Baldenweck (1938) firmly established the role of ophthalmoscopy in the diagnosis of miliary TB. By the mid-twentieth century ocular TB was a common diagnosis world-wide. In the developed world, it was commonly seen in institutions and hospitals that had large numbers of TB patients. In a large study of 10,524 patients in a US sanatorium (1940–1966) Donoghue1 found that 1.4% of patients needed treatment for ocular TB. Illingworth and Wright2 reviewed publications from 1913 to 1947 and found 206 cases of choroidal tubercles in 737 patients (28%). Simultaneously TB was also a common cause of intraocular inflammation in patients and a frequent finding in ophthalmology clinics. In 1960 Woods estimated that 21.8% of patients with predominantly posterior uveitis had a tuberculous aetiology.
EPIDEMIOLOGY In the modern era, with better public health measures and effective antituberculous therapy there has been a marked decrease in ocular TB that parallels the decline in the prevalence of systemic TB. This is borne out by studies that have examined the ocular lesions in patients with systemic TB. In a study in Madrid 100 patients with culture-positive TB underwent ophthalmological evaluation and lesions attributable to TB (commonly choroiditis but also including papillitis, retinitis, vitritis and vasculitis) were seen in 18 patients (18%), of whom 11 had human immunodeficiency virus (HIV) infection.3 In a study of 1,005 patients in Madras 1.39% had ocular lesions, usually healed focal choroiditis (seen in 50%).4 The prevalence of ocular TB increases in the presence of dissemination with as many as 60% of such patients showing evidence of ocular TB.5 Tuberculosis is also less prevalent as an aetiological agent in patients with intraocular inflammation in developed countries. This
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may result from a reduced prevalence of TB but is also due in part to awareness of other aetiologies and better diagnostic techniques. Tuberculosis was found to be responsible for 0.2% of cases of posterior uveitis and in no cases of anterior uveitis in Southern California.6 Schlaegel and O’Connor7 reported that TB was responsible for 0.28% of uveitis cases in the 1970s, which had fallen from an incidence of 8.6% in the 1950s. In developing countries with a still high prevalence of TB, it remains a relatively common aetiological agent. Studies from north India have estimated that it is the aetiological agent in 7.9% of cases of anterior uveitis, 4% of cases of intermediate uveitis, 8.95% of cases of posterior uveitis and 26% of cases of panuveitis. Overall, 125 out of 1,233 (10.1%) cases had a tuberculous aetiology.8 Interestingly, a study from Italy revealed TB as the aetiological agent in 3.6% of cases of anterior uveitis, 2.5% of cases of posterior uveitis and 0.7% of cases of panuveitis.9 The advent of the HIV epidemic has led to an increase in the prevalence of ocular TB in patients with systemic HIV/TB coinfection but large studies are few. In a study of 307 patients in Malawi, choroidal granulomas were seen in 2.8% of patients with mycobacteraemia and acquired immunodeficiency syndrome (AIDS).10 However, another study showed no lesions suggestive of ocular TB in 154 patients with AIDS in Burundi.11 In a prospective study from Mumbai, India, 23.5% of AIDS patients with systemic TB had ocular lesions (Box 46.1).12
AETIOPATHOGENESIS OF OCULAR TUBERCULOSIS In humans, ocular TB, as is systemic TB, is caused by one of the members of the Mycobacterium tuberculosis complex: M. tuberculosis, Mycobacterium bovis or Mycobacterium africanum; most commonly by M. tuberculosis. Mycobacterium tuberculosis bacilli are spread by airborne droplets released into the atmosphere by individuals with pulmonary, usually cavitatory, TB on coughing and speaking. These particles are inhaled and pass into the lungs. The site of primary infection for M. bovis is the alimentary canal. The bacilli multiply locally and spread into the blood stream via the lymphatic system. This results in a haematogenous spread to several organs, usually the lung apices, skeletal system and the choroid. There is an immune response that prevents clinical disease in most individuals while a small proportion develop clinical disease at this stage: 5–10% of patients develop clinical disease at some later stage in life (reactivation TB), usually in response to HIV infection, cancer or any other immune deficiency state.
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Box 46.1 Prevalence of ocular tuberculosis
The prevalence of ocular TB has mirrored the decline in systemic TB in the developed world but is still common in the developing world. Currently, ocular TB may be seen in 1.4–60% of patients with systemic TB. Ocular TB may be diagnosed in 0.2–7.9% of patients with intraocular inflammation. The advent of the HIV epidemic has led to an increase in ocular TB with between 2.8% and 23.5% of HIV/TB coinfections demonstrating ocular TB.
Ocular TB may occur at any stage, i.e. primary infection or reactivation of latent disease; thus patients may range in age from children to the very elderly. Patients may be immunocompetent or may have varying degrees of immunosuppression with disease being reported in patients following renal and other solid organ transplants or in those on long-term immunosuppressive agents. The majority of reports describe M. tuberculosis as the causative agent. M. bovis has been implicated in isolated cases of ocular TB. Kurup and Chan13 have described a 33-year-old woman with nodular scleritis and a choroidal mass who had partially treated abdominal TB 6 years earlier. This was thought to be M. bovis and acquired due to the consumption of unpasteurized milk. Atypical mycobacteria have also been implicated in the aetiology of ocular TB. Typically these include lid and corneal infections.
SIGNS AND SYMPTOMS Very few data exist regarding the epidemiology or clinical features of ocular disease associated with drug-resistant TB. Ocular TB can affect virtually any ocular tissue. The specific manifestations and aetiopathogenesis of each are summarized in Table 46.1.
EYELID TUBERCULOSIS This is commonly a childhood disease and may be a variant of lupus vulgaris (cutaneous TB) (Fig. 46.1). These include reddishbrown nodules that turn to an apple-jelly colour on direct compression or erosive skin lesions. Tuberculosis can also resemble chalazia and the scrapings of unusual or atypical chalazia should be subject to histopathological examination. Extensions into the globe or into the orbit are possible and should be looked for.14
Fig. 46.1 Lupus vulgaris affecting upper and lower lids. Note the scleral thinning due to previous TB nodular scleritis. Courtesy of Professor Miles Stanford, King’s College, London.
Tuberculosis presenting as infective lesions including abscesses and cellulitis of the eyelid are also well-reported manifestations. Raina et al.15 have described the features of seven children with preseptal cellulitis with clinical and radiological evidence of TB elsewhere in the body, commonly pulmonary. Spontaneous fistulization was common in these patients and acid-fast bacilli (AFB) were seen in one of these seven. Chang and associates16 identified six patients who presented with periocular infections due to atypical mycobacteria including four with Mycobacterium chelonae and two with Mycobacterium fortuitum. Four factors including immunosuppression, nasolacrimal duct obstruction, the presence of a foreign body and a history of recent surgery were identified for the occurrence of these infections. Rarely, disease from the contiguous sinuses can spread to the eyelid and manifest as an abscess.
CONJUNCTIVAL TUBERCULOSIS This manifestation was first described in 1864 by Arlt. A large comprehensive review was published by Eyre in 1912, who identified 177 cases in the literature and 29 of his own with a confirmed diagnosis of TB based on histology or animal inoculation. The majority of the patients were less than 20 years old and had unilateral disease with the upper palpebral conjunctiva being most commonly affected.
Table 46.1 Specific manifestations and aetiopathogenesis of ocular tuberculosis Ocular tissue
Manifestation
Aetiopathogenesis
Eyelids Conjunctiva Cornea Sclera Uvea Retina Orbit Meninges/brain
Lupus vulgaris, lid abscess Conjunctivitis Phlyctenulosis, ulcers, interstitial keratitis Scleritis Chronic granulomatous anterior uveitis, tubercles, disseminated choroiditis, panuveitis Vasculitis, retinitis Proptosis, orbital apex syndrome Optic atrophy, disc oedema, cranial nerve palsies
Direct Direct Direct Direct Direct Direct Direct Direct
infection infection infection/hypersensitivity infection infection infection/hypersensitivity infection infection
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He identified five different types: ulcerative, hypertrophic, miliary tubercle, lupus and pedunculated tumour. A total of 160 patients had been investigated for systemic TB and only seven had evidence of the same. In more recent literature, primary tuberculous conjunctivitis has been described as a mucopurulent conjunctivitis with lid oedema and marked lymphadenopathy, which may undergo either caseation or fistulization. The diagnosis is via AFB staining of conjunctival smears or conjunctival biopsy. An unusual variant was reported by Lamba and Srinivasan,17 who reported the ocular and systemic findings of a 30-year-old female patient with miliary TB. Two reddish yellow, soft, non-tender nodules were seen on the conjunctiva with a necrotic surface. There was an associated anterior and posterior uveitis. Scrapings revealed AFB on Ziehl–Neelsen stain with subsequent positive cultures.
SCLERAL TUBERCULOSIS As early as 1907, Verhoeff identified TB in patients with scleritis based on histopathological findings. Of these 13 patients, only three had systemic disease; yet Verhoeff concluded that the presence of systemic disease was necessary. In recent times, well-documented scleral TB was reported by Bloomfield et al.,18 who reported the ocular and systemic findings of an 82-year-old female patient. AFB were seen in tissue sections and M. tuberculosis was grown on culture. The patient was successfully treated with oral isoniazid and rifampicin, along with topical and subconjunctival streptomycin.18 Tuberculosis may present as a focal area of necrotizing scleritis that manifests as a dark-red area that reveals chronic granulomatous inflammation with caseating necrosis. In rare cases, scleral necrosis can occur. This diagnosis, though rare, is a differential diagnosis in patients unresponsive to traditional methods of treatment. In a single instance, Gupta et al.19 have reported a case of posterior scleritis in a 45-year-old female patient who presented with optic disc oedema and choroidal folds. A B-scan showed sclerochoroidal thickening with fluid in the subtenon space and investigations revealed a positive Mantoux test and right upper lobe infiltrates. There was a good response to systemic corticosteroids and anti-TB therapy.19
PHLYCTENULOSIS The presence of a foreign protein within the cornea/conjunctiva may produce a non-specific allergic reaction termed phlyctenular keratoconjunctivitis (see Chapter 47, Fig. 47.8). The association of TB and phlyctenulosis was made early on. The first large series was published by Gibson in 1918 with a series of 92 patients with phlyctenular keratoconjunctivitis. Of these, 90% had positive Mantoux tests with clinical disease being seen in 26% of these patients. Yet other large cohorts of patients with systemic TB have failed to show a high prevalence of phlyctenulosis. In one study of 1,073 patients and 105 contacts and another of 600 patients, phlyctenulosis was seen in only two patients in either series. However, several authors continue, based on epidemiological evidence, to suggest a strong link between phlyctenulosis and tuberculoprotein hypersensitivity, particularly in areas with a high prevalence of TB such as South Asia. Phlyctenulosis commonly presents with redness, watering and irritation. The typical patient is likely to be a malnourished child with single to multiple, 1- to 3-mm, grey to yellow-coloured limbal nodules. The epithelium over the nodule may become necrotic and lead to small ulcerations. These may then migrate
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centrally with a leash of superficial blood vessels with it. At this stage, more severe symptoms of photophobia and watering are common. Topical steroids are necessary to treat the phlyctenulosis and systemic anti-TB therapy may be needed if any clinical disease is present. Recurrences are common within the childhood years. Phlyctenulosis has also been reported in association with parasite infestations and staphylococcal blepharitis.
CORNEAL TUBERCULOSIS Reported findings include infiltrations, ulcerations and interstitial keratitis. Interstitial keratitis usually presents unilaterally as infiltrates in the peripheral stroma with accompanying vascularization. It is postulated that deposition of mycobacterial proteins in the corneal tissues may induce an immune reaction (hypersensitivity reaction) in these tissues. Topical steroids are necessary to treat the keratitis and systemic anti-TB therapy may be needed if any clinical disease is present. Atypical mycobacteria, chiefly M. chelonae, are an increasingly common source of corneal infections following laser-assisted intrastromal keratomileusis (LASIK). Typically these present as haziness at the flap–corneal interface or as corneal abscesses in severe cases. Treatment consists of frequent use of fourth-generation fluoroquinolones and flap excision in severe cases.
ANTERIOR UVEITIS Anterior uveitis is commonly a chronic granulomatous inflammation but may be acute or non-granulomatous. Frequently it may be recurrent in nature. The intensity may range from mild to severe with dense posterior synechiae. The keratic precipitates are classically described as large and greasy, appearing like ‘muttonfat’ or may be fine and white. Translucent nodules may occur at the pupillary margin (Koeppe nodules) or greyish nodules may be seen on the iris surface or in the superficial stroma (Busacca nodules). These Busacca nodules may represent a form of iris tubercle. Treatment is with topical or periocular steroids and systemic anti-TB drugs (if a focus of TB is present).
POSTERIOR UVEITIS (CHOROIDAL TUBERCULOSIS) Choroidal tubercles and similar larger sized lesions called tuberculomas are the most reported manifestation of ocular TB with a prevalence ranging from 1.4% in patients with pulmonary TB to 60% in patients with disseminated TB (Fig. 46.2). They are grey to yellow–white in colour and measure from 1/4 of the disc diameter (DD) to several DDs in size and are usually located in the posterior pole. They may number from one to 50 (usually about five) and may have an overlying serous detachment. Histopathologically they represent caseating granulomas characterized by stromal destruction, swelling of the adjacent choroid and infiltration with round, epithelioid and giant cells. Tubercle bacilli have been found within choroidal tubercles, suggesting that these tubercles represent direct tissue infection. Fundus fluorescein angiography of these tubercles shows an initial hypofluorescence or minimal hyperfluorescence within the tubercle, which increases in the later phases. There is also a consistent appearance of significant peritubercular fluorescence from the earliest phases that increases in intensity in the late phases.20 This picture suggests that the inflammatory activity extends well beyond the visible tubercle. Optical coherence tomography studies of tubercles reveal an attachment between
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ORBITAL TUBERCULOSIS
Fig. 46.2 Choroidal tubercles in an HIV-infected patient. Courtesy of Professor Miles Stanford, King’s College, London.
the retinal pigment epithelial–choriocapillaris layer and the neurosensory retina covering the granuloma which is associated with surrounding subretinal fluid and inflammatory infiltrates in the deeper retinal layers.21 The differential diagnosis includes granulomas of sarcoidosis, gummas of syphilis, candidal chorioretinitis and metastases from malignancies. A variant of serpiginous choroiditis has been described in patients with systemic (usually pulmonary) TB. A case series has presented the ocular and systemic findings of seven patients with this variant.22 Three presentations including multifocal progressive choroiditis with a wave-like progression to confluent diffuse lesions or diffuse plaque-like choroiditis with an amoeboid pattern have been described. The polymerase chain reaction (PCR) results from aqueous and vitreous humor were positive for M. tuberculosis. Treatment consisted of systemic/topical steroids and anti-TB therapy (Fig. 46.3).
This manifestation was first described by Abadie in 1881 but today is confined to areas where the prevalence of TB is high. Orbital TB may occur via haematogenous spread or directly spread from contiguous structures. This disease is usually seen in patients less than 20 years old and is usually unilateral, chronic and slowly progressive. Several presentations including proptosis, eyelid swelling, orbital pain and discomfort, decreased visual acuity and visual field abnormalities are possible. Unusual variants include cases when fistulization in an orbital abscess led to a diagnosis of orbital TB, fungating masses protruding out from the orbit and lesions surrounding the optic nerve.23–25 Tuberculosis can also present as a ‘cold abscess’, i.e. a soft fluctuating mass lesion but without the classical appearance (pain, redness, erythema) of an acute bacterial abscess. Radiological evidence of active or healed pulmonary TB is common. Computed tomography of the orbit is the preferred investigation in these cases and frequently reveals bony erosions. Diagnosis is via histopathological examination and culture of orbital tissue biopsy material or orbital fine needle studies. Treatment consists of standard anti-TB therapy along with appropriate surgery.
RETINAL TUBERCULOSIS The presentations of retinal TB include retinitis and retinal vascular disease.
Retinal vascular disease Two distinct forms appear to exist. These include (1) Eales’ disease and (2) tuberculous retinal vasculitis. Eales’ disease is an immune-mediated retinal periphlebitis mostly found in South Asia. In 1880, Henry Eales first described a syndrome in young men that consisted of recurrent retinal and vitreal haemorrhages in association with constipation and epistaxis. Peripheral retinal periphlebitis and the consequent peripheral retinal ischaemia is the hallmark of this condition that mostly affects young men in the age group 20–40 years. Positive Mantoux tests have consistently been reported in this group of patients, suggesting an association with systemic TB but clinical or radiological evidence of pulmonary TB is uncommon. Renie and associates26 reported that two of 32 patients in their series had active pulmonary TB, whereas positive Mantoux tests and normal chest radiographs were seen in eight of 19 of the remaining. However, one group has used PCR techniques to determine the presence of mycobacterial DNA within vitreal fluid and epiretinal tissue removed during vitreous surgery of these patients.27 Clinically, this disease is manifest in four stages: 1. mild periphlebitis; 2. widespread periphlebitis involving larger vessels and adjacent arterioles; 3. neovascularization with retinal and vitreal haemorrhages; and 4. fibrovascular proliferations with recurrent vitreous haemorrhages.
Fig. 46.3 Large tuberculoma affecting the temporal retinal periphery of the right eye. The patient also had an associated exudative retinal detachment. Courtesy of Professor Miles Stanford, King’s College, London.
The commonest mode of presentation is sudden unilateral visual loss due to vitreous haemorrhage. Clearing of this haemorrhage may show haemorrhages and exudates along the peripheral vessels. Detailed examination usually reveals peripheral retinal periphlebitis in the contralateral eye. Visual loss – but a reversible one – is common with vitreous haemorrhages, but permanent visual morbidity
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may occur as a result of macular lesions or tractional retinal detachments. A fundus fluorescein angiographic examination is mandatory for assessing the extent of ischaemia and neovascularization. Extensive peripheral ischaemia or the presence of retinal neovascularization should suggest the need for laser photocoagulation for preventing vitreous haemorrhage. Vitreal haemorrhages that do not clear may need vitrectomy with laser photocoagulation either intraoperatively or in the immediate postoperative period. Extensive fibrovascular proliferations and tractional retinal detachments may need appropriate surgery. Systemic and periocular corticosteroids may be used for the control of the vasculitis. Few data regarding the role of systemic anti-TB therapy in these patients are available. There is another group of patients in whom retinal vasculitis is consistently associated with active systemic TB. These may be a direct result of infection with M. tuberculosis or a combination of hypersensitivity and direct infection. Rosen et al.28 described nine patients with retinal vasculitis in a series of 12. In these patients, there was a florid retinal periphlebitis associated with a moderate vitreous infiltrate and a tendency to peripheral ischaemia and neovascularization. The Mantoux test was strongly positive in all these patients but active systemic disease was seen in only three patients. Gupta et al.29 were able to identify a tuberculous aetiology via PCR in 13 patients with retinal vasculitis and have suggested that the presence of active or healed choroiditis in patients with retinal vasculitis tends to suggest TB. A fundus fluorescein angiographic examination is recommended to assess the extent of ischaemia and neovascularization. Extensive peripheral ischaemia or the presence with retinal neovascularization should suggest the need for laser photocoagulation to prevent vitreous haemorrhage. Systemic/ periocular corticosteroids may be used for the control of the vasculitis and standard anti-TB therapy is mandatory. Tuberculous retinitis is rare and may result from spread from the choroid or via haematogenous dissemination. Tuberculous retinitis may present as a focal or diffuse retinitis with or without vitreous opacification.
TUBERCULOUS PANOPHTHALMITIS This disease begins with painless, progressive reduction of vision, reduced eye movements, corneal haze, granulomatous inflammation and hypotony. This disease is common in children or adults with malnutrition or evidence of drug use and in those with systemic TB. Chawla et al.30 described the findings in a 12-yearold girl who presented with a painless, progressive visual loss. She had a vascularized cornea, iris nodules and scleral necrosis. Histopathological examination of the enucleated globe showed a necrotizing granulomatous inflammation, epithelioid cell granulomas along with areas of caseous necrosis. The authors suggest that the absence of pain, nodules on the eyeball and a tendency to perforation may be indicators of a tuberculous aetiology. In the early stages, anti-TB therapy may be beneficial but, in the later stages, enucleation may be necessary in the case of blind eyes to establish the diagnosis.
NEURO-OPHTHALMOLOGICAL ASPECTS Neuro-ophthalmological findings are common and varied in patients with neurotuberculosis. In one series of 100 Indian patients with tuberculous meningoencephalitis, 67 (67%) had neuro-ophthalmic features. Common findings included 32 (32%) patients with optic
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neuritis (50% of whom progressed to optic atrophy), 20 patients with gaze palsy and others with third and sixth nerve palsy, conjugate deviation, primary optic atrophy and complete ophthalmoplegia. Raised intracranial tension was also commonly seen.31 In a large series of 1,430 patients with TB meningitis from Cairo, Egypt, 35% of patients had a sixth nerve palsy followed by 10% with a third nerve palsy. Fundal abnormalities were seen in 17% of patients and included 6% with temporal pallor, 4% with optic atrophy and 7% with papilloedema.32 The neuro-ophthalmic findings often depend on the clinicopathological manifestation of neurotuberculosis seen in the individual patient. The commonest manifestation is TB meningitis characterized by the formation of thick gelatinous basal exudates, which often extend to the basal cisterns and the Sylvian fissure. There is usually an inflammation of the adjacent small and medium-sized vessels (vasculitis) as well as that of the underlying brain parenchyma. This vasculitis induces cranial nerve lesions at the skull base and this includes optic nerve lesions and palsies of the oculomotor nerves. Involvement of the optic nerve is the most feared complication and produces a primary type of optic atrophy in varying degrees. Early involvement of the optic nerve may lead to patients presenting with visual loss and fever or may be a late feature with the diagnosis made on routine ophthalmoscopy. Concurrent administration of systemic corticosteroids along with anti-TB therapy has been suggested as a measure for reducing this complication. In one small trial, 27 patients with TB meningitis were treated with ethambutol, isonicotinic acid hydrazide, streptomycin and dexamethasone and 28 were treated with triple antituberculous drugs only. Ocular complications developed in two of the patients to whom steroids were given compared with seven of those not receiving dexamethasone. However, large-scale controlled double-blind studies are needed to confirm this hypothesis. Girgis et al.33 have suggested that dexamethasone reduces the ocular complications in patients with TB meningitis but does not reverse established damage. The propensity of optic atrophy to occur in TB meningitis have led Kumar et al.34 to develop a diagnostic rule that includes five variables (optic atrophy, focal neurological deficit, symptoms lasting longer than 6 days, abnormal movements and neutrophils constituting less than 50% of CSF neutrophils) and found that it had a diagnostic sensitivity of 98% and a specificity of 44% when one feature was present and a diagnostic sensitivity of 55% and specificity of 98% if three or more features were present. The long-term sequelae of optic nerve involvement are associated with significant visual morbidity, often leading to optic atrophy and blindness. In the Cairo study, 13% of patients had permanent neurological sequelae, of which 27% was optic atrophy.32 Oculomotor palsies are also common with all the oculomotor nerves (III, IV and VI cranial nerves). The sixth is the most commonly involved, followed by the third and the fourth.35 In a review of TB meningitis, Thwaites and Hien36 noted that 30–40% of patients had a sixth nerve palsy as compared with 5– 15% who had a third nerve palsy. These nerve palsies may recover fully or may be a permanent neurological sequela. Less common forms of neurotuberculosis include intracranial tuberculomas that are avascular spherical granulomatous lesions. Tuberculomas may compress the optic nerve or any of the oculomotor nerves at any point in the neuroparenchyma, producing visual loss or oculomotor palsies. Both forms of neurotuberculosis may cause papilloedema and unilateral or bilateral sixth nerve palsy due to a raised intracranial
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Ocular tuberculosis in adults and children
pressure. This may be due to a block in the drainage of cerebrospinal fluid at the foramen of Lushka and Magendie (in cases of TB meningitis) or to the space-occupying lesion effects of large tuberculomas. The end result is a secondary optic atrophy if left untreated. Intraocular findings, apart from cranial nerve involvement, are also common in patients with neurotuberculosis. These include intraocular infections (chorioretinitis and tubercles) and hypersensitivity reactions such as retinal vasculitis. Choroidal tubercles represent direct choroidal infection and as such result from concurrent haematogenous dissemination. Kennedy and Fallon37 found choroidal tubercles in one out of 52 patients (2%) in a series of patients of TB meningitis. Tubercles are commoner in patients with meningitis associated with miliary TB and their appearance has been suggested as a guideline for its diagnosis: Illingworth38 found choroidal tubercles in 10% of patients with neurotuberculosis following miliary disease. Recently Mehta et al.39 have suggested that the presence of choroidal tubercles in patients with neurotuberculosis indicated the presence of another focus of tuberculous infection, usually pulmonary.
OCULAR TUBERCULOSIS IN HIV-INFECTED PATIENTS HIV infection has led to a marked resurgence of systemic TB. In countries with an already high prevalence of systemic TB, TB has become the commonest superinfection in HIV-infected patients. In these individuals, the risk of developing active TB, due to both reactivation of latent TB and new infections, has shown a 20-fold increase to 8%, from the 0.4% seen in immunocompetent individuals.40 This has led to the term ‘the cursed duet’ being applied to HIV/TB coinfection. The development of systemic TB is seen in AIDS-defining lesions and is more common at CD4 counts < 500 cells/mm3. This TB may be pulmonary or extrapulmonary but the diagnosis remains difficult due to the problems in interpreting commonly performed tests such as the Mantoux test or conventional radiography. Several initial case reports described ocular TB due to HIV/TB coinfection and these occurrences were mostly in the form of choroidal tubercles. In a prospective series of 46 AIDS patients, 17 had evidence of systemic TB and of these four (23.5%) had lesions attributable to ocular TB. These included choroidal tubercles seen in three patients and chorioretinitis in one patient. The mean CD4 counts were 250 cells/mm3 and all patients had evidence of disseminated TB (pulmonary and abdominal).12 In another large series of 766 patients, ocular TB was detected in 19 eyes in 15 patients (1.95%). The spectrum included choroidal granulomas in 10 eyes, subretinal abscess/panophthalmitis in seven eyes and conjunctival abscess/panophthalmitis in one eye each. The mean CD4 count was 160.85 cells/mm3 and all cases had evidence of pulmonary TB.41 Ocular TB is usually a posterior uveitis and appears to be a part of a widespread process of disseminated TB at CD4 counts lower than 250 cells/mm3. The methods of diagnosis and principles of treatment are similar to those for immunocompetent patients but include the use of antiretroviral agents in addition to anti-TB therapy. Due care needs to be given to rifampicin–protease inhibitor interactions to avoid therapeutic failures and some authorities have suggested rifabutin in place of rifampicin.
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RARE PRESENTATIONS Case reports have described the following manifestations of ocular TB.
ISOLATED MACULAR OEDEMA Torres et al.42 described the clinical and angiographic findings of a 61-year-old woman with cystoid macular oedema and no other ocular findings. Her Mantoux test was positive and M. tuberculosis was detected from her sputum. Following systemic anti-TB treatment the oedema disappeared and her vision returned to normal.
OCULAR TUBERCULOSIS IN THE ABSENCE OF DETECTABLE SYSTEMIC TUBERCULOSIS While the presence of systemic TB is usually the norm when ocular TB is present, at least five patients with isolated ocular TB have been described in the literature. Of these, four had choroidal tuberculomas and one had a vitritis/retinitis. In the presence of normal chest radiography, the diagnosis was made on Mantoux testing, PCR of the aqueous humour or histopathology of the enucleated globe.43
INTRAOCULAR INFECTION WITH PIGMENTED HYPOPYON A 38-year-old female patient on pulsed cyclophosphamide treatment for membranous glomerulonephropathy developed hypopyon uveitis and severe visual loss. The hypopyon was pigmented and when aspirated revealed AFB on culture and staining. Eventually the patient developed multiple scleral abscesses and the eye was enucleated despite anti-TB therapy.44
OCULAR TUBERCULOSIS FOLLOWING SYSTEMIC CORTICOSTEROID THERAPY Rosen et al.28 described a 35-year-old male patient with unilateral anterior uveitis and bilateral vitritis and periphlebitis. There was a significant improvement in his ocular status following systemic corticosteroid therapy but he developed miliary TB with choroidal tubercles after 8 months. The authors suggest that the earlier retinal vasculitis was a hypersensitivity phenomenon that responded to corticosteroid therapy. Following the reactivation of the TB after steroid therapy, he then developed miliary dissemination and choroidal tubercles.
INVESTIGATIONS AND DIAGNOSIS OF OCULAR TUBERCULOSIS (BOX 46.2) OCULAR INVESTIGATIONS Following a detailed clinical examination, the isolation of M. tuberculosis from ocular tissues is necessary to establish a diagnosis of ocular TB. Samples may be obtained from the aqueous humour, vitreous humour, subretinal fluid,45 specific tissue biopsies (eyelid tissue, conjunctiva, cornea, sclera, retina or uvea) or the enucleated globe. However, these are often of small volume and pose a risk of ocular morbidity, especially the risks of endophthalmitis and retinal
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Box 46.2 The diagnosis of ocular tuberculosis
The diagnosis of ocular TB is frequently difficult as any ocular tissue can be affected, specimens are limited and the disease may mimic other disease patterns. Ocular evaluation includes clinical examination and collection of specimens from aqueous humour, vitreous humour, uveal or retinal tissue or subretinal fluid. Processing includes microscopy, culture or PCR techniques for definitive proof. Systemic evaluation includes chest radiography (computed tomography preferred), abdominal radiography, Mantoux testing and collection/processing of sputum, lymph nodes, bone marrow etc. as necessary.
detachment. These samples, once obtained, may undergo the following: 1. Microscopy: this is the easiest test but needs densities of 5,000–10,000 bacilli per millilitre for a positive result. The success rate may be increased by centrifugation of samples. Tissue sections may be stained after formalin fixation. Stains in use include conventional acid-fast stains, e.g. Ziehl– Neelsen or fluorescent acid-fast stains. 2. Culture: culturing is more sensitive and is reported to be capable of detecting densities of 10–100 bacilli per millilitre. Drawbacks include prolonged incubation of up to 8 weeks. Commonly used culture media include Lo¨wenstein–Jensen. 3. PCR techniques: these are becoming the technique of choice in the diagnosis of ocular TB. They are capable of detecting mycobacterial DNA from all samples and are ideally suited for ocular diagnostic work as they require small volumes and are extremely specific. In one case series of 53 patients, the specificity was 100% and the sensitivity was 37%.46
SYSTEMIC INVESTIGATIONS As the majority of cases of ocular TB are associated with systemic disease, these investigations are of importance in all patients with ocular inflammatory disease. Evidence of systemic TB in the presence of ocular inflammation suggests ocular TB but does not confirm it.
Radiography Chest radiographs may reveal active pulmonary TB in the form of infiltrates and cavitation in apical or posterior segments of the upper lobe or occasionally lower lobe infiltrates. At times, pleural effusions may be seen. Hilar lymphadenopathy as the only feature of pulmonary TB is common in patients of South Asian origin and computed tomography may be a better chest imaging modality in these patients.47 Hilar lymphadenopathy is also a common feature of patients with coexistent HIV. Abdominal CT scan or ultrasonography may reveal mesenteric, periportal or retroperitoneal lymphadenopathy suggestive of isolated abdominal TB or as a component of disseminated TB. Mantoux testing The Mantoux test assesses the patient’s response to a stimulus of purified protein derivative (PPD). Three available strengths are 1, 5 and 250 tuberculin units and 0.1 mL is injected intradermally into the volar forearm to produce a wheal of 6–10 mm diameter. After
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48–72 hours the induration is measured in millimetres at the point of injection and interpreted according to current guidelines. The Mantoux test is a delayed-type hypersensitivity reaction and merely suggests tuberculous infection but not active clinical disease. Common false negatives include poor test techniques, miliary TB, sarcoidosis, HIV infection and active malignancies.
TREATMENT OF OCULAR TUBERCULOSIS The treatment of any case of ocular TB depends on several factors including the specific manifestation being treated, the aetiopathogenesis, i.e. whether it is a hypersensitivity reaction or a direct infection, and whether any systemic focus of TB is present.
CORTICOSTEROID THERAPY Manifestations due to purely hypersensitivity phenomena such as phlyctenulosis need only corticosteroid therapy. Most direct infections such as anterior or posterior uveitis, retinal vasculitis or panophthalmitis also need adjunct corticosteroid therapy due to the inflammation they induce. Depending on the site of involvement and severity of the inflammation topical, periocular or systemic corticosteroids may be used.
ANTITUBERCULOSIS THERAPY Along with the appropriate corticosteroid therapy it is necessary to prescribe systemic anti-TB therapy in cases of ocular direct infections as well as in cases where a systemic focus is present. At present no topical anti-TB therapy is available. Systemic therapy allows adequate concentrations of the drug in all ocular tissues and especially in the posterior uvea that is most commonly affected as well as allowing treatment of any systemic foci. Schlaegel was among the first to carry out a therapeutic trial of isoniazid for patients of ocular TB but this is only of historical value. As no recent randomized trials have been conducted to assess the optimum treatment for patients with ocular TB, recommendations described for the treatment of pulmonary and extrapulmonary TB may be used even though intraocular inflammation is not specifically described. The American Thoracic Society (ATS), the Centers for Disease Control (CDC) and the Infectious Diseases Society of America (IDSA) have recommended four drugs – isoniazid (INH), pyrazinamide (PZA), ethambutol (EMB) and rifampicin (RMP) – for an initial 8 weeks followed by INH and RMP either 7 days a week (regimen 1a) or twice weekly (regimen 1b) for a minimum duration of 18 weeks. The efficacy and effectiveness of these regimens has led to a rating of A1 (A ¼ preferred regimen; 1 ¼ based on randomized clinical trials) and A2 (A ¼ preferred regimen; 2 ¼ based on non-randomized clinical trials) for HIV-uninfected and -infected patients, respectively. These principles also apply to extrapulmonary forms of the disease, with evidence suggesting that similar regimens of four drugs for a period of 6–9 months are effective.48 The World Health Organization (WHO) recommendations also require the use of four drugs (INH/RMP/PZA/EMB) for an initial 2 months followed by INH/RMP for 4 months for category I patients (new sputum-positive patients, new sputum-negative patients with extensive lung parenchymal disease and those with severe extrapulmonary disease) as well as category III patients
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(new smear-negative patients with lesser lung parenchymal involvement and patients with less severe extrapulmonary disease).49 Therapeutic failures may occur and may be due to faulty compliance or primary drug resistance. Reports of drug-resistant ocular TB are rare but may be a problem in the future as the multidrugresistant TB epidemic expands.
OCULAR TOXICITY IN ANTITUBERCULOSIS THERAPY Drug-induced ocular toxicity is rare and it is anti-TB therapy that most reports discuss. Ethambutol is most often the offending
REFERENCES 1. Donoghue HC. Ophthalmologic experience in a tuberculosis sanatorium. Am J Ophthalmol 1967;64:742–748. 2. Illingworth RS, Wright T. Tubercles of the choroid. BMJ 1948;2:365–368. 3. Bouza E, Merino P, Munoz P, et al. Ocular tuberculosis: A prospective study in a general hospital. Medicine (Baltimore) 1997;76:53–61. 4. Biswas J. Ocular morbidity in patients with active systemic tuberculosis. Int Ophthalmol 1995–1996; 19(5):293–298. 5. Mehta S. Ocular lesions in acute disseminated tuberculosis. Ocul Immunol Inflamm 2004; 12(4):311–315. 6. Henderly DE, Genstler AJ, Smith RE, Rao NA. Changing patterns of uveitis. Am J Ophthalmol 1987;103:131–136. 7. Schlaegel TF Jr, O’Connor GR. Metastatic nonsuppurative uveitis. Int Ophthalmol Clin 1977; 17(3):87–108. 8. Singh R, Gupta V, Gupta A. Pattern of uveitis in a referral eye clinic in North India. Indian J Ophthalmol 2004;52:121–125. 9. Latanza L, Damiano C, DeRosa C. Three-year experience at the uveitis clinic of the eye department of Cardarelli Hospital, Naples. In: Recent Advances in Uveitis. Amsterdam/New York: Kruger, 1993: 175–178. 10. Beare NA, Kublin JG, Lewis DK, et al. Ocular disease in patients with tuberculosis and HIV presenting with fever in Africa. Br J Ophthalmol 2002;86 (10):1076–1079. 11. Cochereau I, Mlika-Cabanne N, Godinaud P, et al. AIDS related eye disease in Burundi, Africa. Br J Ophthalmol 1999;83:339–342. 12. Mehta S, Gilada IS. Ocular tuberculosis in acquired immune deficiency syndrome (AIDS). Ocul Immunol Inflamm 2005;13(1):87–89. 13. Kurup S, Chan C. Mycobacterium-related ocular inflammatory disease: diagnosis and management. Ann Acad Med Singapore 2006;35:203–209. 14. El-Ghattit, El-Dariny SM, Mahmoud AA, et al. Presumed periorbital lupus vulgaris with ocular extension. Ophthalmology 1999;106:1990–1993. 15. Raina UK, Jain S, Monga S, et al. Tubercular preseptal cellulitis in children: A presenting feature of underlying systemic tuberculosis. Ophthalmology 2004;111(2):291–296.
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drug and toxicity is generally a dose-dependent optic neuritis seen in up to 2% of patients on dosages of 15 mg/kg. The most common presentation is bilateral visual loss with a normal-appearing fundus. Rarely, disc hyperaemia, disc oedema and peripapillary haemorrhages have been seen. Disc pallor suggestive of optic atrophy is seen after 4–6 weeks. Perimetric studies reveal central, paracentral or peripheral scotomas. Loss of or defective colour vision is common especially in the red–green axis. Patients with decreased renal function may be at greater risk due to delayed excretion of the drug. The optic neuritis is usually reversible but full recovery may be prolonged, often over several months. Isoniazid has also been implicated in a few cases of ocular toxicity but aggregate data are not available.
16. Chang WJ, Tse DT, Rosa RH, et al. Periocular atypical mycobacterial infections. Ophthalmology 1999;106:1:86–90. 17. Lamba PA, Srinivasan R. Conjunctival tuberculosis of endogenous origin associated with miliary tuberculosis. Indian J Ophthalmol 1983;31:89–92. 18. Bloomfield SE, Mondino B, Gray GF. Scleral tuberculosis. Arch Ophthalmol 1976;94:754–756. 19. Gupta A, Gupta V, Pandav SS, et al. Posterior scleritis associated with systemic tuberculosis. Indian J Ophthalmol 2003;51(4):347–349. 20. Mehta S. Fundus fluorescein angiography of choroidal tubercles: case reports and review of literature. Indian J Ophthalmol 2006;54:273–275. 21. Salman A, Parmer P, Rajmohan M, et al. Optical coherence tomography in choroidal tuberculosis. Am J Ophthalmol 2006;142:170–172. 22. Gupta V, Gupta A, Arora S, et al. Presumed tubercular serpiginouslike choroiditis: clinical presentations and management. Ophthalmology 2003;110(9):1744–1749. 23. Mehra S, Pattanayak PS, Gupta S. Tuberculoma of orbit. Indian J Ophthalmol 1992;40:90–91. 24. Maurya O, Patel R, Thakur V, et al. Tuberculoma of the orbit—a case report. Indian J Ophthalmol 1990;38:191–192. 25. Brice SE, Oldfield MD, Barker R. Stridor, malaise, and visual loss in a woman from Sierra Leone. Postgrad Med J 2001;77(911):601, 607–608. 26. Renie WA, Murphy RP, Anderson KC, et al. The evaluation of patients with Eales’ disease. 1983; 3(4):243–248. 27. Madhavan HN, Therese KL, Doraiswamy K. Further investigations on the association of Mycobacterium tuberculosis with Eales’ disease. Indian J Ophthalmol 2002;50:35–39. 28. Rosen PH, Spalton DJ, Graham EM. Intraocular tuberculosis. Eye 1990;4:486–492. 29. Gupta A, Gupta V, Arora S, et al. PCR-positive tubercular retinal vasculitis: clinical characteristics and management. Retina 2001;21(5):435–444. 30. Chawla R, Garg S, Venkatesh P, et al. Case report of tuberculous panophthalmitis. Med Sci Monit 2004; 10(10):CS57–59. 31. Amitava AK, Alarm S, Hussain R. Neuro-ophthalmic features in pediatric tubercular meningoencephalitis. J Pediatric Ophthalmol Strabismus 2001;38:229–234. 32. Girgis NI, Sultan Y, Farid Z, et al. Tuberculosis meningitis, Abbassia Fever Hospital–Naval Medical Research Unit No.3–Cairo, Egypt, from 1976 to 1996. Am J Trop Med Hyg 1998;58(1):28–34. 33. Girgis NI, Farid Z, Kilpatrick ME, et al. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10(3):179–183.
34. Kumar R, Singh SN, Kohli N. A diagnostic rule for tuberculous meningitis. Arch Dis Child 1999; 81:221–224. 35. Katti MK. Pathogenesis, diagnosis, treatment and outcome aspects of cerebral tuberculosis. Med Sci Monit 2004;10(9):RA215–229. 36. Thwaites GE, Hien TT. Tuberculous meningitis: too many questions, too few answers. Lancet Neurol 2005;4:160–170. 37. Kennedy DF, Fallon RJ. Tuberculous meningitis. JAMA 1979;241:264–268. 38. Illingworth RS. Miliary and meningeal tuberculosis; difficulties in diagnosis. Lancet 1956;271:646–649. 39. Mehta S, Chauhan V, Hastak S, et al. Choroidal tubercles in neurotuberculosis: prevalence and significance. Ocul Immunol Inflamm 2006;14(6): 341–345. 40. Zumla A, Malon P, Henderson J, et al. Impact of HIV on tuberculosis. Postgrad Med J 2000;76:259–268. 41. Babu RB, Sudharshan S, Kumarasamy N, et al. Ocular tuberculosis in acquired immunodeficiency syndrome. Am J Ophthalmol 2006;142(3):413–418. 42. Torres RM, Calonge M. Macular edema as the only ocular finding of tuberculosis. Am J Ophthalmol 2004;138 (12):1048–1049. 43. Sarvanathan N, Wiselka M, Bibby K. Intraocular tuberculosis without detectable systemic infection. Arch Ophthalmol 1998;116(10):1386–1388. 44. Rathinam SR, Rao NA. Tuberculous intraocular infection presenting with pigmented hypopyon: a clinicopathological case report. Br J Ophthalmol 2004;88(5):721–722. 45. Salman A, Parmar P, Rajamohan M, et al. Subretinal fluid analysis in the diagnosis of choroidal tuberculosis. Retina 2003;23(6):796–799. 46. Arora S, Gupta V, Gupta A, et al. Diagnostic efficacy of polymerase chain reaction in granulomatous uveitis. Tuber Lung Dis 1999;79:229–233. 47. Mehta S. Role of computed chest tomography (CT scan) in tuberculous retinal vasculitis. Ocul Immunol Inflamm 2002;10(2):151–155. 48. American Thoracic Society, CDC, and Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Morb Mortl Wkly Rep 2003 20;52(RR11):1–77. 49. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. WHO/CDS/TB/2003.313. Geneva: World Health Organization, 2003. [online]. Accessed 6 June 2005. Available at URL:http://www.who.int/ docstore/gtb/publications/ttgnp/pdf/2003.313.pdf
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Dermatological manifestations of tuberculosis in adults and children H Francois Jordaan and Johann W Schneider
INTRODUCTION The late eighteenth and early nineteenth centuries are known as the Age of Reason and the era of the establishment of dermatology as a specialty. At that time, Willan and Bateman set forth accurate descriptions of the basic types of skin lesions. Initially skin lesions were grouped into ‘orders’ and ‘genera’. Skin lesions of TB appeared in the order of ‘tubercles’ and in the genus of ‘lupus’. With the Age of Reason came the Industrial Revolution and the three key factors that lead to a rapid increase in the incidence of TB, namely urban congestion, poverty, and a susceptible population. By the midnineteenth century, TB killed about one-quarter of young adults in industrialized countries. The high death rate from birth to the age of 6 or 7 years was due to bovine TB transmitted by raw milk. The second peak in the death rate was between the ages of 25 and 50 years. This was due to human tubercle bacilli transmitted largely by droplet infection. Also by this time, dermatologists had begun to differentiate between localized cutaneous TB and skin manifestations of systemic TB, and to classify skin lesions of TB based on their morphology. Worcester classified TB lesions involving both the skin and deeper tissues as ‘lupus exedens’ and TB confined to the skin as ‘lupus non-exedens’. In 1876 Neligan described cases with localized skin lesions as ‘lupus superficialis’ and ‘lupus serpiginosus’ and cases with skin lesions and ‘scrofula’ (TB of lymph nodes) associated with TB of deeper tissues as ‘lupus devorans’. Fox and Duhring referred to TB of the skin simply as ‘lupus vulgaris’. Robert Koch reported on his bacteriological findings of TB in 1882. He stained and cultured tubercle bacilli and reported the transfer of TB to animals with these cultures. Koch’s postulates provide the key method for identifying the causative agent of all forms of TB of the skin.1 In 1903, Niels Ryberg Finsen was awarded the Nobel Prize for his invention of light therapy for cutaneous TB (lupus vulgaris). It was recently demonstrated that Mycobacterium tuberculosis produces coproporphyrin III. Radiation with light of 400 nm led to the production of singlet oxygen.2 Since these early days, various classifications have been proposed for cutaneous TB. However, it was the classification of Beyt et al.3 and minor modifications of this classification that gained general approval. The global expansion of TB during the past decade confirms that TB is a growing health problem, especially in populations with a high prevalence of human immunodeficiency virus (HIV) infection.4 The acquired immunodeficiency syndrome (AIDS) pandemic and increased number of immunocompromised patients
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contribute significantly to the increased incidence of TB and its cutaneous manifestations.5,6 Many recent publications emphasize this phenomenon and highlight the importance of cutaneous manifestations of TB as an important clinical and diagnostic challenge.6,7 Cutaneous TB can mimic the clinicopathological features of many other skin diseases, and underlying systemic or organ TB can be notoriously difficult to detect, resulting in considerable diagnostic challenges and pitfalls and potential delays in diagnosis and institution of treatment.8,9 Patient immunity to M. tuberculosis, previous infection, and the route of infection determine the clinicopathological features of cutaneous TB in a particular patient. Systemic TB is present in the overwhelming majority of patients, and direct cutaneous or mucosal inoculation with M. tuberculosis is rare.6,10 Cutaneous manifestations of TB include a wide and often overlapping spectrum of papules, pustules, papulonecrotic and papulopustular lesions, nodules, panniculitis, plaques, verrucous lesions, ulcers, chronic sinuses, and scars.11
CLASSIFICATION OF CUTANEOUS TUBERCULOSIS Over the years, a number of classifications of cutaneous TB have been proposed. Accurate classification of the varied expressions of cutaneous TB is relevant in order to improve diagnostic accuracy and appropriate prognostication and treatment of patients.11 The classification of Beyt et al.3 gained general acceptance, and a modification of this classification has been utilized in the latest edition of Rook’s Textbook of Dermatology.12 More recent modifications of the classification adhere to the route of infection, but acknowledge the expanding spectrum of cutaneous TB and include tuberculids as a variant of cutaneous TB rather than a cutaneous hypersensitivity reaction to underlying systemic or organ TB (Table 47.1).13 Complications of Bacillus Calmette–Gue´rin (BCG) vaccination include disseminated infection with spread to the skin,14,15 scrofuloderma,16 papular tuberculids,17 erythema induratum,18 lupus vulgaris,19 lichen scrofulosorum,20 and keloids,11 and should therefore be included in a classification of cutaneous TB (Table 47.1). Considerable clinicopathological overlap and non-specific clinical features complicate the traditional classification of cutaneous TB.3 Overlapping clinicopathological features emphasize that the traditional subtypes of cutaneous TB represent a spectrum with variable and overlapping combinations of clinical and histopathological features, variable success for detecting tuberculous bacilli in skin lesions, and variable demonstration of underlying
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Dermatological manifestations of tuberculosis in adults and children
Table 47.1 Classification of cutaneous tuberculosis Inoculation tuberculosis from exogenous source (primary cutaneous tuberculosis)
Primary tuberculous chancre Verrucosa cutis (warty TB) Some cases of lupus vulgaris-type TB
Table 47.2 A practical guide to the diagnosis and management of cutaneous tuberculosis Definite cutaneous TB Clinical morphology
Secondary tuberculosis from endogenous source
Direct spread to the skin (scrofuloderma-type TB) Autoinoculation (orificial TB)
Histopathology
Haematogenous tuberculosis
Miliary TB Some cases of lupus vulgaris-type TB Tuberculous gumma
Tuberculid-type tuberculosis (tuberculids or eruptive tuberculosis)
Papulonecrotic-type TB Erythema induratum of Bazin/nodular vasculitis-type TB Lichen scrofulosorum-type TB Nodular tuberculid
ZN and/or culture and/or PCR on skin lesion biopsy ZN and/or culture and/or PCR on specimen from origin other than skin Mantoux test result
Phlebitic tuberculid-type TB BCG-related TB
non-cutaneous TB. The clinical management of patients will depend on the level of certainty of the diagnosis of TB rather than the subtype of cutaneous TB. A more useful approach to cutaneous TB from a clinical perspective should combine clinicopathological findings and the results of special investigations to offer practical guidelines and stratification of patients as definitive, probable, and possible cutaneous TB, respectively (Table 47.2).
PATHOGENESIS AND MORPHOLOGY The genus Mycobacterium contains more than 80 species, most of which are harmless environmental saprophytes. The most important obligate human pathogens are M. tuberculosis and Mycobacterium leprae, but others such as Mycobacterium avium and Mycobacterium ulcerans are also significant. These are now best referred to as environmental mycobacteria, also referred to as non-tuberculous mycobacteria (NTM). Cutaneous involvement by M. tuberculosis can follow direct inoculation of organisms from an exogenous source; direct spread of organisms from an endogenous source such as tuberculous lymphadenitis extending to the skin (scrofuloderma) or autoinoculation, e.g. mucocutaneous involvement from pulmonary TB (orificial TB); haematogenous dissemination of organisms from a distant site; or haematogenous spread of mycobacterial components including DNA as seen in the so-called tuberculids.21,22 These various pathogenic mechanisms are further modulated by the number and the virulence of the organisms and the concerned host’s level of immune competence and genetic predisposition to infection. These complex interactions between host
Radiograph findings compatible with TB, e.g. lung, bone Response to anti-TB treatment
Probable cutaneous TB
Possible cutaneous TB
Variable combinations and transitions of papular, nodular, pustular, papulonecrotic, pustulonecrotic, ulcerative, vegetating skin lesions Variable combinations and transitions of granulomatous inflammation, mixed acute and chronic inflammatory cells, necrosis, vasculitis, organization and fibrosis, other non-specific changes – – +a
NEFD
+b
–
NEFD
–
NEFD
+b (only in children <5 years old) +b
NEFD
NEFD
EFD
Other
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–
ZN, Ziehl–Neelsen stain; PCR, polymerase chain reaction; NEFD, not essential for diagnosis; EFD, essential for diagnosis (but not necessarily proof of TB). a When only ZN positive, distinction from environmental (nontuberculous) mycobacteria is necessary by culture and/or PCR. b Any positive establishes the diagnosis of probable TB.
factors on the one hand and the organism and other environmental factors on the other hand result in the wide spectrum of clinicopathological manifestations of cutaneous TB.23 The microscopic hallmark of cutaneous TB is granulomatous inflammation, which may vary from sarcoidal or tuberculoid granulomas to necrotizing, suppurative, or palisading granulomas. Combinations of various patterns of granulomatous inflammation are common. In some cases of erythema induratum of Bazin and papulonecrotic tuberculid, necrotizing vasculitis is present.24,25 The epidermis may be atrophic, hyperplastic, or ulcerated. Lymphocytes, macrophages, plasma cells, and sometimes neutrophils and eosinophils constitute the inflammatory cell population involved. Scarring may be mild, moderate, or marked. Although the histopathological findings are often quite characteristic, they are not diagnostic per se and a specific diagnosis depends on clinicopathological correlation and the demonstration of M. tuberculosis organisms in skin lesions or other organs. The detection of M. tuberculosis organisms in skin lesions depends largely on the type of cutaneous involvement and the adequacy of the diagnostic sample tissue. Organisms are usually easy to detect in skin lesions associated with miliary TB or scrofuloderma, difficult to find in specimens obtained from lupus vulgaris lesions, and absent in tuberculids where demonstration of M. tuberculosis DNA by polymerase chain reaction (PCR) is required.26–29
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The variable and overlapping clinical and pathological features of cutaneous TB often defy the various types of clinical lesions depicted in traditional classification, leading to diagnostic challenges. Despite these limitations, an understanding of the pathogenesis and various morphological patterns of cutaneous TB facilitates the recognition of the various clinical manifestations of the disease (Table 47.1).
PRIMARY CUTANEOUS TUBERCULOSIS Primary cutaneous TB follows the direct inoculation of M. tuberculosis organisms into the skin due to penetrating trauma such as ear piercing, circumcision, tattooing, or injury to laboratory staff.30 The subsequent indurated papulonodular lesion appears within 1–3 weeks and tends to ulcerate, resulting in a primary chancre and regional lymphadenopathy, similar to the pulmonary Ghon complex. A similar picture can follow BCG vaccination.21 Biopsies from a primary chancre reveal mixed acute and chronic inflammation that leads to necrosis, ulceration, and granulomatous inflammation after a
few weeks.31 Organisms are easily demonstrated in tissue sections by Ziehl–Neelsen stain. Underlying systemic TB is absent. Inoculation of M. tuberculosis bacteria into the skin of patients with strong immunity may lead to TB verrucosa cutis.32 This unusual expression of cutaneous TB is characterized initially by a warty indurated nodule that expands in time to form a verrucous plaque. The skin lesions typically involve the dorsum of the hand or fingers following exposure to infected tissues or sputum. Pathological findings include epidermal hyperplasia, hyperkeratosis, papillomatosis, and mixed acute and chronic inflammation with caseating granulomas in the dermis. Ziehl–Neelsen stain of tissue sections will usually show sparse bacilli. Lupus vulgaris can follow inoculation of organisms into the skin of patients with previous or current TB, but, more often, it follows haematogenous or lymphatic dissemination to the skin from underlying and often subclinical TB. Less commonly it may develop at the site of BCG inoculation.33 The skin lesions are characterized by coalescing papules that form a plaque that has traditionally been described as resembling apple jelly nodules on diascopy (Fig. 47.1).
Fig. 47.1 Cutaneous TB, lupus vulgaris variant involving the tip of the nose (A) and the nose and upper lip (B). The nose is a characteristic site of involvement. The differential diagnosis in (B) should include discoid lupus erythematosus. Plaques are often a typical clinical manifestation of lupus vulgaris as demonstrated in this lesion involving the arm and showing an expanding nodular border with central atrophic scarring (C). Note the central atrophy and scarring in this example of lupus vulgaris involving the lateral neck (D).
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Other clinical manifestations include warty plaques, ulceration, cellulitis, and rarely alopecia.34 Although the head and neck and especially the nose are typically involved, lupus vulgaris may less commonly involve the limbs and feet, gluteal area, trunk,35 and penis.36 Disseminated lesions may also occur. Lupus vulgaris is a chronic condition, and it is often characterized by considerable delay in arriving at the correct diagnosis.37 Subsequent scar formation is therefore not uncommon. Squamous cell carcinoma and less commonly basal cell carcinoma, melanoma, and lymphoma may complicate long-standing lupus vulgaris.38,39 Histopathological features include intradermal tuberculoid granulomas with little or no necrosis, mimicking sarcoidosis.40 Pseudoepitheliomatous hyperplasia of the epidermis may simulate squamous cell carcinoma, especially in superficial biopsies. Less frequently, epidermal atrophy and ulceration may be present. Organisms are usually rare and difficult to find in Ziehl–Neelsen-stained sections.
SECONDARY TUBERCULOSIS FROM ENDOGENOUS SOURCE Orificial tuberculosis is characterized by ulceration at mucocutaneous orifices including the mouth, nose, perianal region, and genitalia (Fig. 47.2).41 The clinical lesions follow autoinoculation of the mucocutaneous surface from underlying active TB with abundant organisms. Patients present with persistent and undermined painful ulcers. Biopsies of the ulcers typically show prominent necrosis with
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Fig. 47.2 Orificial TB with involvement of the tongue.
mixed acute and chronic inflammation and inconspicuous granulomas. Ziehl–Neelsen-stained sections reveal abundant organisms. Scrofuloderma represents direct spread to the skin from underlying tuberculous infection such as tuberculous lymphadenitis, arthritis, or osteomyelitis.42,43 Typical lesions include ulcerating nodules, ulcers, draining sinuses, and scarring (Fig. 47.3). Frequently involved sites include the neck and submandibular regions, but many sites could be involved, depending on the location of the focus of TB. Active TB is present and histological findings typically
Fig. 47.3 Cutaneous TB, scrofuloderma variant. Note the extensive ulceration and draining sinuses in the inguinal region (A) and the underlying lymphadenopathy and linear arrangement ulceration on the lateral side of the neck (B) and the superficial scarring (C). The linear arrangement corresponds to the lymphatic drainage in this area.
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demonstrate ulceration, caseating granulomas, abscess formation, and variable number of acid-fast bacilli.
HAEMATOGENOUS TUBERCULOSIS Miliary TB has a poor prognosis if not diagnosed and treated timeously and usually occurs in infants and children and follows haematogenous dissemination of numerous M. tuberculosis organisms from underlying active TB usually in the lung. Typical skin lesions include papules, pustules, vesiculopustular lesions, small ulcers, haemorrhagic lesions, and subcutaneous abcesses.44 Miliary TB may occur in immunocompromised patients, including patients with AIDS.45 Lesions that simulate folliculitis may cause diagnostic problems.46 A high index of suspicion is important to establish a diagnosis. Histopathological features include necrosis, small dermal abscesses, and leucocytoclastic vasculitis, often without granulomatous inflammation.45 Since underlying TB is often not suspected clinically, the histopathological features could be interpreted as non-specific. However, Ziehl–Neelsen stain of tissue sections will usually show numerous acid-fast bacilli. Tuberculous gumma (metastatic tuberculous abscess) follows haematogenous dissemination of organisms from a tuberculous focus elsewhere in the body to the subcutaneous tissue with subsequent development of a subcutaneous abscess.47 Patients with malnutrition and compromised immunity are more frequently affected.48 The clinical features include one or more subcutaneous nodules that may soften because of necrosis. Subsequent chronic ulceration may simulate scrofuloderma. Biopsies from affected sites reveal granulomatous inflammation, often with extensive caseous necrosis, that involves primarily the subcutaneous tissue with extension to the dermis. Ziehl–Neelsen stain typically shows sparse bacilli.
TUBERCULIDS Tuberculids include a spectrum of related and often overlapping clinicopathological manifestations of cutaneous TB that occur in patients with tuberculin hypersensitivity and with underlying and often subclinical tuberculous infection elsewhere in the body.12,29 Mycobacterium tuberculosis organisms are absent in the skin lesions when assessed by Ziehl–Neelsen stains and culture, but M. tuberculosis DNA can be demonstrated by PCR in 25–50% of cases.28,29,49,50 A good clinical response of the skin lesions to anti-TB treatment provides further evidence that the tuberculids are best regarded as a variant of cutaneous TB rather than an immunological reaction to TB elsewhere in the body, including BCG.12,29,51 Clinicopathological variants of tuberculid-type cutaneous TB include papulonecrotic tuberculid (PNT), erythema induratum of Bazin (EIB), lichen scrofulosorum, nodular tuberculid, and nodular granulomatous phlebitis. Concurrent lesions of different expressions of tuberculid-type TB overlapping histopathological features suggest that these clinicopathological variants form part of a single spectrum of disease.12,52 PNT is characterized by recurring crops of skin-coloured or red papules that can show central necrosis, ulceration, crusts, and pustules that heal in time with small depressed scars (Fig. 47.4A–D). The skin lesions can occur in children and in adults and they typically involve the ears and extensor surfaces of the limbs around the elbows and knees.12,21,27 The lesions may be symmetrical and widespread or localized to specific areas such as the penis.53 Occasionally a Koebner phenomenon may occur (Fig. 47.4E). Confluence and
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ulceration of the lesions may occur in patients with AIDS (Fig. 47.4F). PNT may follow BCG vaccination.54 Histopathological features include wedge-shaped necrosis of the upper dermis with the base towards the epidermis which frequently shows ulceration.27,55,56 The area of necrosis is often folliculocentric and flanked by granulomatous inflammation and chronic inflammatory cells (Fig. 47.4).55 Leucocytoclastic vasculitis may be present.24 Ziehl– Neelsen stain for acid-fast bacilli is always negative. Erythema induratum of Bazin or erythema induratum/nodular vasculitis is a form of panniculitis characterized by red violaceous nodules that classically occur on the calves of women especially in winter (Fig. 47.5A and B).57 The nodules may be painful and undergo ulceration that tends to be chronic and to heal with scarring. Biopsies from EIB skin lesions reveal variable features of septolobular panniculitis, necrosis, granulomatous inflammation, and vasculitis of smaller or larger blood vessels (Fig. 47.5C and D).25,57 Acid-fast bacilli are invariably absent. Lichen scrofulosorum typically affects paediatric patients and young adults and is often associated with localized tuberculous lymphadenitis or organ TB, particularly tuberculous osteomyelitis. The condition is characterized by asymptomatic yellowish papules on the trunk (Fig. 47.6).51,58 The skin lesions tend to heal without scarring. Histopathological findings include granulomatous perifolliculitis and involvement of sweat glands by granulomatous inflammation.59 Lichen scrofulosorum has been documented following the administration of BCG and in patients with AIDS.60,61 Nodular tuberculid shows clinicopathological features of EIB and PNT.12 The skin lesions comprise a few to many dull red or bluish-red, and non-tender nodules of approximately 1cm in diameter that show a preference for the legs in children (Fig. 47.7).12 Ulceration is absent. Histopathological features include necrosis, granulomatous inflammation, and occasionally vasculitis, usually in the superficial dermis. Nodular tuberculid has been documented in HIV-infected patients.62
OTHER Phlebitic tuberculid or nodular granulomatous phlebitis is characterized by subcutaneous nodules along the course of leg veins.63 Histopathological examination of skin biopsies shows granulomatous inflammation within the walls of cutaneous veins. More advanced lesions show associated granulomatous panniculitis. Erythema nodosum is not a form of cutaneous TB, but represents a hypersensitivity reaction of unknown pathogenesis. Erythema nodosum can be associated with a wide spectrum of bacterial infections including mycobacteria; fungal infections; viral infections; and chlamydial infections.64 Non-infectious associations include drugs; sarcoidosis; inflammatory bowel disease; Behc¸et’s disease; and underlying neoplastic diseases such as lymphoma, leukaemia, and carcinoma. In more than 30% of cases of erythema nodosum the association remains unknown. Typical skin lesions present as a panniculitis, which manifests as tender, non-ulcerating erythematous nodules and which has a preference for the shins and less commonly the upper limbs, plantar regions, or the trunk. It must be distinguished from erythema induratum. The typical histopathological features include septal panniculitis with limited inflammation of the lobular fat. Necrosis, well-developed granulomatous inflammation, or vasculitis is absent or mild. Patients who present with erythema nodosum should be investigated for known associated diseases including TB, but a diagnosis of TB should not be based solely on the presence of erythema nodosum.
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47
D
E Fig. 47.4 Cutaneous TB, papulonecrotic tuberculid type. Note the characteristic papular lesions with an umbilicated appearance due to central necrosis and ulceration (A, B). Note typical involvement of the ears (C) as well as associated scrofuloderma (D; arrow). A Koebner phenomenon (arrow) may infrequently be present (E). (F) Cutaneous TB, papulonecrotic tuberculid type, in a patient with HIV/AIDS. Note the confluence of papulonecrotic lesions to form larger plaques and erosions. The histopathological features are very characteristic of PNT, but are not diagnostic per se.
DIAGNOSIS A clinical diagnosis of cutaneous TB can be made with reasonable confidence in most instances. The diagnosis should be confirmed by a skin biopsy, microbiological culture in broth-based culture medium, or molecular techniques such as PCR.65 Suitable material for identification of the organism can be obtained by skin biopsy or
fine needle aspiration (FNA) of associated enlarged lymph nodes.66,67 Tuberculin skin testing in suspected cutaneous TB should not be performed in children under the age of 5 years if phlyctenular conjunctivitis is present (Fig. 47.8). The latter is associated with extreme hypersensitivity to tuberculin and a subsequent risk for ulceration and scarring following a tuberculin skin test. A strongly positive tuberculin test is highly suggestive of TB in young children. Ulceration can be prevented in these patients by
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► ►
*
*
* C
*
D
Fig. 47.5 Cutaneous TB, erythema induratum of Bazin/nodular vasculitis type is characterized by indurated and violaceous nodules that occur preferentially on the legs, especially the calves (A, B). The lesions may ulcerate and heal with scarring. Histopathology of erythema induratum of Bazin/ nodular vasculitis-type TB shows typical septolobular panniculitis with necrosis (*), granulomatous inflammation (arrow tip), and vasculitis (arrow) (C, D).
the application of a strong topical steroid to the cutaneous test site. Interpretation of the tuberculin skin test in adults is controversial and fraught with difficulties ascribed to previous BCG and the high prevalence of TB. A tuberculin skin test could, however, be performed in adults in low-TB-incidence settings where BCG is often not administered and TB is clinically suspected. Cutaneous TB is often the first clinical manifestation of underlying systemic and organ TB of, for example, the lung, bones, and urogenital tract.6 Thorough clinical examination and appropriate special investigations to search for systemic or organ TB are therefore mandatory in all patients with cutaneous TB. In patients with possible cutaneous TB based on clinicopathological findings but without demonstrable systemic or organ TB, a therapeutic test
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with the administration of full anti-TB treatment for at least 6 weeks is indicated (see Table 47.2). In the event of a clinical response to anti-TB treatment, a diagnosis of cutaneous TB is confirmed and a full course of treatment is justified. Lack of a clinical response requires clinical reassessment of the patient. In the authors’ experience this scenario is fortunately unusual. The clinical work-up of a patient with suspected cutaneous TB should include at least a thorough clinical examination of the patient and a chest radiograph. Further investigations such as FNA of enlarged lymph nodes, microscopy and culture of different specimens such as sputum, gastric aspirates, urine, endometrial fluid, bone scans, and other appropriate investigations should be directed by the clinical suspicion of underlying organ TB.
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47
Based on the results of clinical examination and additional investigations and tests, it is possible in most cases to classify the patients according to the criteria in Table 47.2, which can be used to determine further management and treatment of the patients.
DIFFERENTIAL DIAGNOSIS
Fig. 47.6 Cutaneous TB, lichen scrofulosorum type shows characteristic small flat-topped and folliculocentric papules. The small black dots (arrows) represent hair follicle infundibulae.
The differential diagnosis for cutaneous TB will vary according to the respective clinical variants and their clinical manifestations. A comprehensive discussion of the differential diagnoses could therefore include a very extensive range of dermatological disorders, which is beyond the scope of this chapter. Box 47.1 presents a short list of relevant and common conditions to consider in the differential diagnosis of the respective variants of cutaneous TB.
TREATMENT
Fig. 47.7 Nodular tuberculid type TB is characterized by dull red or bluish-red, and non-tender nodules of approximately 1 cm in diameter that show a preference for the legs in children.
Fig. 47.8 Phlyctenular conjunctivitis is associated with extreme hypersensitivity to tuberculin and a potential severe skin reaction and ulceration to a tuberculin test.
Cutaneous TB includes all forms of TB affecting the skin – those in which organisms can be identified (tuberculous ulcer, scrofuloderma, orificial TB, TB verrucosa cutis, and lupus vulgaris) as well as those conditions formerly called ‘tuberculids’ (erythema induratum, papulonecrotic tuberculid, and lichen scrofulosorum). In all cases, tissue biopsies for culture should be performed. Often in the later conditions, cultures and PCR studies fail to detect mycobacteria, but anti-TB treatment is still indicated. Despite Finsen being awarded the Nobel Prize for his invention of light therapy for cutaneous TB, there is currently no role for light therapy in the management of cutaneous TB and the cornerstone for therapy remains modern anti-TB drugs. All patients with cutaneous TB should receive multidrug therapy as recommended in their community for active TB. Duration of therapy should be at least 6 months. Single-drug treatments and shorter courses are not recommended. There is no special protocol for the treatment of cutaneous TB. Treatment of patients should be according to standard protocols as defined by the WHO or relevant national TB control programmes. The cost of treatment for TB may be paid for by local health departments, and protocols may vary from community to community, depending on the status of drug resistance in that community at that time. The most appropriate treatment protocol for a particular patient should therefore be determined by the clinician in accordance with official guidelines at that particular time and in that particular region. If cultures grow M. tuberculosis, susceptibility studies should guide anti-TB treatment. Most cases of TB are a manifestation of systemic involvement. The bacillary load in cutaneous TB is less than that in pulmonary TB. Treatment regimens are similar to that of TB in general.68 Fixed dose combination treatment with four drugs for 2 months in the intensive phase and two drugs for 4 months in the continuation phase is the treatment of choice for adults and children over the age of 8 years. A response of skin lesions is usually witnessed within 6 weeks. If there is no visible response after 6 weeks, the patient should be re-evaluated. Careful inquiry about compliance is essential. Children with cutaneous TB are treated with isoniazid, rifampicin, and pyrazinamide for 2 months followed by isoniazid and rifampicin for 4 months (WHO Regimen III – see Chapter 61).69
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Box 47.1 Differential diagnoses of various types of cutaneous tuberculosis
Tuberculous chancre ○ Tularaemia ○ Sporotrichosis ○ Cat scratch fever ○ Mycobacterium marinum infection ○ Syphilis. Tuberculosis verrucosa cutis ○ Blastomycosis ○ Chromoblastomycosis ○ Actinomycosis ○ Leishmaniasis ○ Tertiary syphilis ○ Hypertrophic lichen planus ○ Lichen simplex chronicus ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Bromoderma ○ Hyperkeratotic lesions due to other mycobacteria. Lupus vulgaris ○ Lymphocytoma cutis ○ Spitz naevus ○ Lupus erythematosus ○ Leishmaniasis ○ Rosacea ○ Port-wine stain ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Leprosy ○ Sarcoidosis ○ Psoriasis ○ Bowen’s disease ○ Lichen simplex chronicus ○ Wegener’s granulomatosis ○ Blastomycosis. Tuberculosis cutis orificialis ○ Secondary syphilis ○ Aphthous ulcers ○ Carcinoma ○ Herpes virus infection.
Miliary TB with skin involvement is treated with four drugs in the intensive phase and it is of utmost importance to ensure that the appropriate treatment protocol is initiated immediately (Chapter 61). A diagnosis of multidrug-resistant (MDR) TB should never be made clinically and laboratory confirmation of drug resistance is mandatory. It is difficult to demonstrate acid-fast bacilli in smears or biopsies, or to culture M. tuberculosis from cutaneous TB because most lesions are paucibacillary. A therapeutic trial of anti-TB treatment is frequently used to confirm the diagnosis in difficult cases. Previously there were no clear guidelines on when to expect a response or when to abandon a therapeutic trial. Ramam and co-workers70 showed that, when a therapeutic trial is undertaken in cutaneous TB, 6 weeks of therapy with four drugs appear adequate to prove or disprove the diagnosis. Therapeutic trials of antituberculosis treatment is not recommended in other types of tuberculosis and
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Scrofuloderma ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Tertiary syphilis ○ Sporotrichosis ○ Actinomycosis ○ Acne conglobata ○ Hidradenitis suppurativa. Miliary cutaneous tuberculosis ○ Disseminated BCG infection ○ Bacterial folliculitis ○ Fungal folliculitis ○ Disseminated histoplasmosis ○ Papular and papulopustular syphilides. Tuberculous gumma (metastatic tuberculous abscess) ○ Panniculitis ○ Deep fungal infections ○ Tertiary syphilis ○ Hidradenitis suppurativa. Papulonecrotic tuberculid ○ Pityriasis lichenoides ○ Leucocytoclastic vasculitis ○ Papular urticaria ○ Secondary syphilis ○ Folliculitis ○ Perforating granuloma annulare. Erythema induratum of Bazin/nodular vasculitis ○ Other forms of panniculitis. Lichen scrofulosorum ○ Lichen nitidus ○ Keratosis pilaris ○ Papular or lichenoid sarcoidosis ○ Lichenoid secondary syphilis ○ Drug eruptions ○ Lichen planus. Nodular tuberculid ○ Insect bites ○ Evolving folliculitis ○ Evolving vasculitis ○ Dermal erythema multiforme.
should therefore not be done if any other systemic form of tuberculosis co-exists.
CONCLUSION Cutaneous manifestations of TB are relatively common in countries with a high prevalence of TB and may be the presenting clinical manifestation of the disease. Underlying systemic TB is often subtle and may be difficult to demonstrate. It is therefore of great importance that clinicians are familiar with the clinicopathological spectrum of cutaneous TB and that they maintain a high index of suspicion for underlying TB in patients with skin lesions as described in this chapter. A pragmatic approach to the diagnosis and management of cutaneous TB as outlined in the relevant table should facilitate and simplify optimal clinical care of patients.
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REFERENCES 25. 1. Beutner EH. Tuberculosis of the skin: historical perspectives on tuberculin and Bacillus Calmette Guerin. Int J Dermatol 1997;36:73–77. 2. Moller KI, Kongshoj B, Philipsen PA, et al. How Finsen’s light cured lupus vulgaris. Photodermatol Photoimmunol Photomed 2005; 21:118–124. 3. Beyt BE Jr, Ortbals DW, Santa Cruz DJ, et al. Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease. Medicine (Baltimore) 1981;60:95–109. 4. Zumla A, Malon P, Henderson J, et al. Impact of HIV infection on tuberculosis. Postgrad Med J 2000;76:259–268. 5. Inwald D, Nelson M, Cramp M, et al. Cutaneous manifestations of mycobacterial infection in patients with AIDS. Br J Dermatol 1994;130:111–114. 6. Kivanc-Altunay I, Baysal Z, Ekmekci TR, et al. Incidence of cutaneous tuberculosis in patients with organ tuberculosis. Int J Dermatol 2003; 42:197–200. 7. Hay RJ. Cutaneous infection with Mycobacterium tuberculosis: how has this altered with the changing epidemiology of tuberculosis? Curr Opin Infect Dis 2005;18:93–95. 8. Foo CC, Tan HH. A case of tuberculosis verrucosa cutis–undiagnosed for 44 years and resulting in fixedflexion deformity of the arm. Clin Exp Dermatol 2005;30:149–151. 9. Sharma S, Choudhary R, Juneja M, et al. Cutaneous tuberculosis mimicking sporotrichosis. Indian J Pediatr 2005;72:86. 10. Ho CK, Ho MH, Chong LY. Cutaneous tuberculosis in Hong Kong: an update. Hong Kong Med J 2006;12:272–277. 11. Kakakhel KU, Fritsch P. Cutaneous tuberculosis. Int J Dermatol 1989;28:355–362. 12. Yates VM, Rook GAW. In: Burns T (ed.). Rook’s Textbook of Dermatology. London: Blackwell, 2004: 1–38. 13. Jordaan HF, Schneider JW, Abdulla EA. Nodular tuberculid: a report of four patients. Pediatr Dermatol 2000;17:183–188. 14. Peart LK, Schneider JW, Jordaan HF, et al. Fine needle aspiration biopsy of postvaccination disseminated Mycobacterium bovis infection presenting as a solitary cutaneous papule. Acta Cytol 2005;49:230–231. 15. Antaya RJ, Gardner ES, Bettencourt MS, et al. Cutaneous complications of BCG vaccination in infants with immune disorders: two cases and a review of the literature. Pediatr Dermatol 2001;18:205–209. 16. Atasoy M, Aliagaoglu C, Erdem T, et al. Scrofuloderma following BCG vaccination. Pediatr Dermatol 2005;22:179–180. 17. Figueiredo A, Poiares-Baptista A, Branco M, et al. Papular tuberculids post-BCG vaccination. Int J Dermatol 1987;26:291–294. 18. Inoue T, Fukumoto T, Ansai S, et al. Erythema induratum of Bazin in an infant after Bacillus Calmette-Guerin vaccination. J Dermatol 2006;33:268–272. 19. Handjani F, Delir S, Sodaifi M, et al. Lupus vulgaris following bacille Calmette-Guerin vaccination. Br J Dermatol 2001;144:444–445. 20. Park YM, Kang H, Cho SH, Cho BK. Lichen scrofulosorum-like eruption localized to multipuncture BCG vaccination site. J Am Acad Dermatol 1999;41:262–264. 21. Saxe N. Mycobacterial skin infections. J Cutan Pathol 1985;12:300–312. 22. Pereira J. [Tuberculids]. Rev Port Pneumol 2004;10:97–105. 23. Jepson A, Fowler A, Banya W, et al. Genetic regulation of acquired immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa. Infect Immun 2001;69:3989–3994. 24. Ramdial PK, Mosam A, Mallett R, et al. Papulonecrotic tuberculid in a 2-year-old girl: with
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48. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol 2002;3:319–328. 49. Victor T, Jordaan HF, Van Niekerk DJ, et al. Papulonecrotic tuberculid. Identification of Mycobacterium tuberculosis DNA by polymerase chain reaction. Am J Dermatopathol 1992;14:491–495. 50. Degitz K. Detection of mycobacterial DNA in the skin. Etiologic insights and diagnostic perspectives. Arch Dermatol 1996;132:71–75. 51. Ramdial PK, Mosam A, Pillay T, et al. Childhood Lichen scrofulosorum revisited. Pediatr Dev Pathol 2000;3:211–215. 52. Park YM, Hong JK, Cho SH, et al. Concomitant lichen scrofulosorum and erythema induratum. J Am Acad Dermatol 1998;38:841–843. 53. Israelewicz S, Dharan M, Rosenman D, et al. Papulonecrotic tuberculid of the glans penis. J Am Acad Dermatol 1985;12:1104–1106. 54. Iden DL, Rogers RS III, Schroeter AL. Papulonecrotic tuberculid secondary to Mycobacterium bovis. Arch Dermatol 1978;114:564–566. 55. Jordaan HF, Van Niekerk DJ, Louw M. Papulonecrotic tuberculid. A clinical, histopathological, and immunohistochemical study of 15 patients. Am J Dermatopathol 1994;16:474–485. 56. Wilson-Jones E, Winkelmann RK. Papulonecrotic tuberculid: a neglected disease in Western countries. J Am Acad Dermatol 1986;14:815–826. 57. Rademaker M, Lowe DG, Munro DD. Erythema induratum (Bazin’s disease). J Am Acad Dermatol 1989;21:740–745. 58. Singal A, Bhattacharya SN. Lichen scrofulosorum: a prospective study of 39 patients. Int J Dermatol 2005;44:489–493. 59. Beena KR, Ramesh V, Mukherjee A. Lichen scrofulosorum—a series of eight cases. Dermatology 2000;201:272–274. 60. Kumaran MS, Dogra S, Kaur I, et al. Lichen scrofulosorum in a patient with lepromatous leprosy after BCG immunotherapy. Lepr Rev 2005; 76:170–174. 61. Arianayagam AV, Ash S, Jones RR. Lichen scrofulosorum in a patient with AIDS. Clin Exp Dermatol 1994;19:74–76. 62. Friedman PC, Husain S, Grossman ME. Nodular tuberculid in a patient with HIV. J Am Acad Dermatol 2005;53:S154–S156. 63. Hara K, Tsuzuki T, Takagi N, et al. Nodular granulomatous phlebitis of the skin: a fourth type of tuberculid. Histopathology 1997;30:129–134. 64. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician 2007; 5:695–700. 65. Negi SS, Basir SF, Gupta S, et al. Comparative study of PCR, smear examination and culture for diagnosis of cutaneous tuberculosis. J Commun Dis 2005; 37:83–92. 66. Kathuria P, Agarwal K, Koranne RV. The role of fine-needle aspiration cytology and Ziehl Neelsen staining in the diagnosis of cutaneous tuberculosis. Diagn Cytopathol 2006;34:826–829. 67. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosis-endemic area. Pediatr Infect Dis J 2006;25:142–146. 68. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol 2002;3:319–328. 69. Sehgal VN, Sardana K, Sehgal R, et al. The use of anti-tubercular therapy (ATT) as a diagnostic tool in pediatric cutaneous tuberculosis. Int J Dermatol 2005;44:961–963. 70. Ramam M, Mittal R, Ramesh V. How soon does cutaneous tuberculosis respond to treatment? Implications for a therapeutic test of diagnosis. Int J Dermatol 2005;44:121–124.
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Musculoskeletal and spinal tuberculosis in adults and children Martin Storm and Gert J Vlok
INTRODUCTION World-wide 8 million new cases of TB are reported each year with developing countries carrying most of the burden.1 Musculoskeletal TB remains a relatively common problem in orthopaedic practice in countries with a high TB burden. It is undoubtedly the most common source of vertebral infection in adults and children in both first and third world countries.2 Extraspinal TB is also becoming more prevalent because of an increase in extrapulmonary TB seen mainly due to human immunodeficiency virus (HIV) infection. This ancient disease has been described in an Egyptian mummy as early as 3000 BC,3 in Sanskrit sometime between 1500 and 1700 4 5 BC, and also in the writings of Hippocrates in 450 BC. The classic description of spinal TB was presented by Percival Pott in 1779 and Poncet in the nineteenth century.6 Spinal TB is often referred to as Pott’s disease. The continued evolving nature of TB, and its ability to cause deformity, paraplegia, and related complications, demands a high index of suspicion from the treating physician. Tuberculosis has earned its nickname as the great mimicker and should be ruled out as a diagnostic possibility in the differential diagnosis of several infectious and neoplastic conditions.
INCIDENCE AND EPIDEMIOLOGY Despite the development of effective anti-TB treatment the prevalence of musculoskeletal TB remains around 1–4% of all cases. In the United States, cases of extrapulmonary TB remained essentially unchanged despite a decrease in the number of pulmonary cases from 1965 to 1987. From 1986 to 1995 extrapulmonary cases per year were relatively constant and bone and joint TB made up 9.2–11.5% of extrapulmonary cases.7 This suggests both the resilience of the pathogen and the change in the patient demographics.8 The modern resurgence in the first and third world can further be attributed to the emergence of drug-resistant Mycobacterium tuberculosis strains, global migration patterns, socioeconomic overcrowding, aging populations, and the increased number of patients receiving radiation or immune suppression therapy. The HIV pandemic, with an estimated 40 million patients living with HIV, and more than half situated in sub-Saharan Africa, contributes significantly to the increase in TB patients.8 This general increase is prevailing in both spinal and extraspinal musculoskeletal TB.
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Before the sharp increase in TB cases in the late 1980s and early 1990s, sporadic case reports of musculoskeletal TB from developed countries highlighted the low incidence in these countries, and a lack of experience of health workers in the diagnosis and treatment of this problem.9,10 In recent years, however, the incidence of extrapulmonary TB has increased to as high as 25% in some European countries, and is still showing a steady increase.1,11 Whereas in developed countries musculoskeletal TB is often a disease in older adults,7 it is mainly a disease in children, with 50% of all cases reported in children less than 10 years of age, and young adults in developing countries with a high TB incidence.12 The prevalence of coexisting active pulmonary TB ranges between 29% and 50%.13–15 As with extrapulmonary TB, musculoskeletal TB occurs more often in HIV-infected than in HIVuninfected patients presenting with TB. The spine is involved in approximately 50% of musculoskeletal TB, with the thoracic spine involvement accounting for 25–50%, the lumbar and lumbosacral spine for 25–50%, and the cervical spine for 5–25%.7,16 Extraspinal (also referred to as extra-axial) involvement is most often seen in the peripheral skeleton and usually in the weight-bearing joints. Osteoarticular TB usually affects a single joint or site, but multiple bone sites or joints may be affected. The lower limbs are involved in 72% of cases with the most common sites affected being the hip (50%), knee (20%), and ankle and foot (10%).17 The calcaneus, ankle, midtarsal, and Lisfranc joint are most often affected in the foot. Metatarsal and phalanx involvement are uncommon.18 In 84% of cases of osteoarticular TB both the metaphysis and adjacent joint will be involved,19 and disease may start in either the metaphysis (the majority) or the synovium of the joint and progress to the adjacent structure. Simultaneous metaphyseal and diaphyseal involvement is rare.17 The upper limb is affected in 10–15% of cases. The elbow (10%) and shoulder joints (1–5%) are affected most, and involvement of the phalanges and metacarpals are rare.13,17 Dactylitis (infection of the small tubular bones of the hands and feet) is considered to be a disease of childhood and is rarely seen in adults.20 The hands are affected more often than the feet with the proximal phalanx of the index and middle finger and the second and third metacarpal the most commonly affected.21 Disseminated skeletal TB, where TB lesions simultaneously present in multiple skeletal sites, is relatively rare and is reported in 0.2–10% of osteoarticular TB cases.22,23 This variant is almost exclusively found in young children who are immune immature or immune compromised and the clinical and pathological presentation can vary significantly.
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Primary or isolated involvement of the muscle, bursae, or tendon sheaths is rare (< 0.1%),24 and only a handful of case reports are available in current literature.1,11,25,26 Musculoskeletal disease caused by environmental (non-tuberculous) mycobacteria, such as Mycobacterium avium–intracellulare, has increased.27 This is mainly attributed to the increase in the number of immune-compromised patients receiving radio- or corticosteroid therapy, and the increased prevalence of HIV infection. An association with iatrogenic infection, contamination of instruments, and traumatic inoculation has also been shown.28Mycobacterium avium–intracellulare is rarely seen in the spine (only five reported cases) and must be differentiated from typical TB because treatment regimens are different.27 The epidemiological distribution varies in different geographical areas. Studies conducted in North America concluded that the most common risk factors for extrapulmonary TB were female gender, age 25–39 years, origin from an area of endemicity, being African American, Native American, or Asian, and being infected with HIV.1,29 Similar epidemiological trends have been documented in other large cities in Europe with almost 50% of patients originating from North Africa and sub-Saharan Africa.1 In Southern African countries the risk factors remain the same but infection rates are higher and more than 50% of patients with musculoskeletal TB are under the age of 10 years.
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is the most common, with impairment of function and swelling also common. Constitutional symptoms such as fever, fatigue, night sweats, and weight loss occur in many but not all patients and usually in advanced disease. The diagnosis is often delayed because of the chronic nature of the disease and low clinical suspicion especially in areas with low incidence of TB. A delay in diagnosis of between 16 and 19 months has been reported in several series.38,39 Patients often present to the orthopaedic surgeon in the advanced stage of disease with low-grade pain, deformity, or neurological compromise (reported between 12% and 43%). In spinal TB back pain and rigidity or stiffness of the spine due to muscle spasm are often the presenting complaints. Children may present with an acute kyphosis or gibbus, although a gibbus of some degree occurs in most patients (Figs 48.1 and 48.2). A visible dissecting abscess with or without sinus tract formation may be present. Paraspinal cold abscesses may present a mass at a distant site from the vertebral involvement because pus can dissect along tissue planes. A psoas abscess originating as a paraspinal abscess may, for example, protrude under the inguinal ligament and present as a groin mass. Weakness and paralysis of the lower extremities may occur early during the course of the disease.7 During the late stages of the disease the two main complications remain: deformity and
PATHOGENESIS The main causative organism is M. tuberculosis complex, subspecies M. tuberculosis. However, the subspecies M. bovis Bacillus Calmette–Gue´rin (BCG) has caused osteomyelitis after BCG immunization. Environmental mycobacteria, especially M. avium– intracellulare, rarely cause skeletal involvement and then mainly in immune-compromised hosts. Several possibilities for the transfer of the tuberculous bacillus into the musculoskeletal system have been proposed. The most common mechanism is haematogenous spread from a primary or reactivated focus in another body part, mainly the lungs. In spinal TB, retrograde venous spread through the paravertebral venous plexus of Batson has been proposed,30,31 but it is generally accepted that haematogenous spread occurs mainly via the arterial route.32,33 Direct extension from an underlying pleural infection site can also infiltrate the adjacent spinal structures.20 Lymphatic spread, direct inoculation, and congenital transfer via the umbilical vein or amniotic fluid has also been described.34 Trauma has also been implicated in the pathogenesis of muscle, bone, and joint disease and a history of trauma can be elicited in 30–50% of patients.35–37 Coexistent pulmonary TB is seen in less than 50% of cases but clinicians must be aware of the possible reactivation of old lung lesions.20 Through a delayed hypersensitivity reaction, the bone, muscle, tendon, and cartilage is destroyed by caseous necrosis. Joint destruction leads to fibrous ankylosis, and associated ‘cold’ abscesses and sinus tract formation are common. The result of local destruction is far reaching and the effect on each anatomical area will be discussed in the following sections.
CLINICAL PRESENTATION Musculoskeletal TB is a chronic infection with an insidious onset and slow progression. Symptoms are non-specific and are often present for a long time before the diagnosis is suspected. Local pain
Fig. 48.1 Lateral view of a patient with clearly visible gibbus.
Fig. 48.2 Lateral radiograph showing gibbus formation and destruction of anterior elements of the vertebra.
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paraplegia. In some cases patients may present with back pain only and show no signs of systemic disease.40 Hip pain combined with a flexion contracture can indicate the presence of a psoas abscess or associated hip involvement.40 In cervical spine involvement atlantoaxial instability, torticollis, hoarseness, and dysphagia can be the presenting symptom. Retropharyngeal and mediastinal paraspinal abscesses can lead to airway obstruction. These patients can present with inspiratory stridor (Millar asthma).20,34,40 Lymphadenopathy is common in cervical spine TB in children. Osteomyelitis may present with deep bone pain, a swollen red mass over the limb, and the inability to weight bear. Articular involvement is associated with firm doughy swelling or effusion, stiffness, reduced range of motion, and inability to weight bear. Muscle, tendon, tendon sheath, or bursal involvement usually presents with localized pain, reduced power, reduced range of motion, and inflammatory changes.
SPINAL TUBERCULOSIS (TUBERCULOUS SPONDYLITIS) LOCAL PATHOPHYSIOLOGY The spinal focus is mainly secondary to haematogenous spread from a pulmonary or other focus. The infection originates in the anterior inferior half of the vertebral body and four distinct patterns have been described.40
Paradiscal pattern This pattern is found in over 50% of all spinal TB cases. The primary source of infection begins in the vertebral metaphysis and erodes into the vertebral end plate with the resulting disc space narrowing. This pattern of infection will spare the disk until late in its course and will usually result in a sequestrated disc. The resulting disc herniation can be one of the causes of spinal cord compression and possibly result in neurological compromise.
Anterior pattern In this type of involvement the pus and the necrotic tissue dissects beneath the anterior longitudinal ligament. Devascularization of the vertebral body and surrounding structures ensues with necrosis and abscess formation along the spinal column. Further progression will lead to collapse of the vertebral body and kyphotic deformity. Dissection into the surrounding soft-tissue structures with abscess and sinus formation is also seen. Central pattern This involves the entire vertebral body and significant destruction and deformity results because of this pattern. Posterior pattern This involves the posterior soft-tissue and bony elements of the spine. Paraspinal abscess formation involving the posterior elements is quite common and occurs in 50–70% of all cases. These abscesses are more frequently found in the cervical area. Paraspinal abscesses form a fusiform mass in the lumbosacral spine but tend to be more ovoid (Fig. 48.3A) or ‘nest shaped’ (Fig. 48.3B) in the cervical spine. In the lumbar sacral spine cold abscesses dissect in the muscular sheath of the iliopsoas muscle, creating a diagnostic psoas shadow on abdominal radiograph. Large epidural abscesses are, however, uncommon.20,34,41,42 Skip lesions, affecting vertebrae at multiple levels with no apparent connection, are seen in 10–25% of patients and may appear in different stages of development at different levels (Fig. 48.4).19 Rare cases of pachymeningitis or myelitis have also been reported. Direct infiltration of the dura can cause irreversible neurological damage.34 DIAGNOSIS The timeless question remains: ‘TB or not TB?’ Spinal TB is still known as the great mimicker. It can present in unusual ways both clinically and radiographically.
Fig. 48.3 (A) Fusiform tuberculous abscess mass in the thoracic spine. (B) Nest-shaped mass in the lower cervical spine.
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Routine chest radiographs should also be done to exclude active or reactivated pulmonary TB.
Computed tomography (CT) CT scanning can detect bony changes of spinal TB, but it has been surpassed by magnetic resonance imaging and is now infrequently used in the evaluation and follow-up of this condition. Early marrow changes in the vertebrae are difficult to see with CT.46 Contrasted CT shows enhancement of the inflammatory paravertebral or epidural abscess wall. CT is of value in evaluating the early lesion and the extent of bony destruction of the spine and threedimensional reconstruction can be used for surgical planning in the advanced or severely deformed case. CT also facilitates image-guided percutaneous biopsy to establish diagnosis or for drainage of intradiscal or paravertebral abscesses.32,44
Fig. 48.4 Tuberculous skip lesion.
Plain radiography Plain radiography remains the first line of special investigations employed to make a diagnosis. The classical picture of spinal TB includes destruction of two adjacent vertebral bodies with sparing of the disc space, anterior vertebral scalloping, gibbus formation (kyphosis), and soft-tissue shadows with or without calcification.34,43 Paravertebral cold abscesses found in the cervical spine are usually nest-shaped while thoracolumbar abscesses are fusiform in shape (Fig. 48.3A and B). The iliopsoas shadow is usually clearly visible in the case of a psoas abscess. Posterior vertebral involvement is present in 20–50% of patients.19 Several authors warn against a too ‘rigid’ approach to radiograph evaluation and diagnosis. Govender and Leong44 studied a series of 997 cases and concluded that spinal TB presented in the classical radiographic manner in only 6.9% of all cases, while Pertuiset et al.45 found it in only 48% of 103 cases. Radiographic presentation of spinal TB and pyogenic spondylitis can be similar, although some features such as involvement of the posterior elements of the vertebrae, late preservation of the adjacent intervertebral disc, and calcifications are usually indicative of TB.46 Case reports of tuberculous granulomas that mimic neoplasms, later diagnosed as TB, and vice versa are available.23,47–49 Other atypical presentations of spinal TB include single vertebral infection, isolated posterior involvement sparing the vertebral body, skip lesions, and so-called ‘ivory vertebra’.19 This highlights the fact that a diagnosis on spinal radiograph evaluation alone must be considered with caution. The differential diagnosis to be considered in suspected spinal TB is diverse especially in areas where TB is uncommon. The radiographic appearance can be similar to infections caused by pyogenic organisms, syphilis, Salmonella typhi, brucellosis, actinomycosis, and blastomycosis. Malignant tumours such as Ewing’s sarcoma, osteosarcoma, multiple myeloma, and mixed metastasis can also be included in the differential diagnosis. Finally, radiographic features may represent benign conditions such as haemangioma, giant cell tumour, aneurysmal bone cyst, and histiocytosis X.
Magnetic resonance imaging (MRI) MRI with gadolinium DTPA enhancement has become a powerful tool in the diagnosis of spinal TB. Where available, MRI should be performed when an infected spine is suspected. Information on the condition of the spinal cord, soft tissue, and bony elements can be obtained from this one non-invasive investigation. The pathological changes are evident on MRI before they become visible on plain radiographs. The lesions present as hypointense on T2 images and as hyperintense on T1 images. Enhancement is typically seen on the rim around intraosseous abscesses, and postcontrast images with fat suppression show paravertebral soft-tissue abscesses and epidural extension by the peripheral-enhancing rim, corresponding with peripheral inflammatory changes, while central necrosis remains hypointense (Fig. 48.5). Although rare, these findings can also be consistent with neoplasm or pyogenic infection. Poor prognostic findings on MRI include myelomalacia, atrophy of the spinal cord, cord signal change, and formation of a syrinx.50 Bone scintigraphy Bone scintigraphy with technetium-99m, gallium-67, and indium111 enhancement can also be used, and has a sensitivity of 92% and 88.5%, respectively. They do not, however, have the specificity for routine use as a diagnostic tool.34,42 Other available investigations Blood investigations such as the erythrocyte sedimentation rate (ESR), white cell count, differential cell count, and C-reactive protein (CRP) are all non-specific and not very useful. An ESR of more than 100 mm/h Westergren is usually indicative of myeloproliferative disease, TB, or pyogenic discitis. Once again exceptions seem to be the rule where spinal TB is concerned and patients may present with a marginally raised ESR. If the ESR is initially elevated it can be useful in following treatment. A raised white cell count, chronic anaemia, raised CRP, and neutrophilia indicative of chronic disease can also be found. Mantoux tuberculin skin test will be positive in the majority of patients.50 Furthermore serum electrophoresis, Bence Jones protein analysis, alkaline phosphatase, and calcium, magnesium, and phosphate levels can assist with the exclusion of other possible lytic conditions. Bacteriological and histological confirmation Definitive diagnosis still relies on the bacteriological and/or histological confirmation of M. tuberculosis inside the lesion in question. Govender and Leong44 proposed CT-guided fine needle aspiration, core biopsy under radiographic guidance, or open biopsy combined with anterior surgery to address the problem of an elusive diagnosis.
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Fig. 48.5 (A) Nest-shaped abscess in lower cervical spine. (B) MRI with anterior and intraspinal extension of pus and necrotic material. (C) MRI showing anterior and intraspinal extension of pus with classic preservation of the disc spaces.
It must be borne in mind that obtaining a biopsy has morbidity and can be technically complicated. The yield, especially in percutaneous procedures, is variable (20–88%) and therefore planned biopsy is not always successful.34 The site of biopsy is of utmost importance. Unless the biopsy is taken from the granulomatous area where the cyst is visible on radiograph or the directly adjacent synovium, the positive yield diminishes significantly.20 The biopsy is followed by Ziehl– Neelsen staining, culture and susceptibility testing, histology, and polymerase chain reaction (PCR) evaluation to confirm the diagnosis. Following diagnosis, treatment needs to be directed according to the drug susceptibility test result.
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It must be reiterated that none of the special investigations employed to aid in diagnosis is absolute, and all the results should be scrutinized together to come to a conclusion. Controversy remains as to whether chemotherapy should be started in the presence of ‘good’ clinical and radiological suspicion of spinal TB, or whether the patient should first be subjected to biopsy. The answer will depend on the type of practice the physician finds him/herself in. In a developed environment where biopsy is feasible and available, it is ideal to obtain a definitive diagnosis prior to commencing chemotherapy. In developing countries, and TB-endemic areas with an obvious lack of specialized facilities, and with proof of previous TB contact,
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treatment should not be withheld from a patient who has the risk of developing complications such as deformity and paraplegia. A gibbus in a child from a TB-endemic area is usually due to TB and should be managed as such if no specialized investigations are available.
NEUROLOGICAL COMPROMISE The most serious complication of spinal TB is neurological compromise. The incidence of complete or incomplete paraplegia ranges between 12% and 43% of all patients in areas where the disease is endemic.40 It is most common in the mid- and low thoracic region. This neurological compromise develops either because of direct compression of the neural elements by bony fragments, disc sequestration, pus, or fibrotic tissue or rarely because of direct dural invasion by caseous necrosis. In active disease pressure on or thrombosis of the critical spinal arteries can also cause ischaemia of the spinal cord that in turn results in paraplegia. The spinal canal can accommodate occlusion of up to 75% before clinical neurological deficit appears.51 This type of cord compression can lead to progressive neurological deterioration or, in the case of the cervical spine, sudden fatal spinal cord damage. Neurological compromise is more prevalent in children under the age of 10 years, but the severity of neurological complications is comparatively lower in the child.34 Sorrell and Butler described paraplegia as early if it occurred within 2 years of disease onset, or late if it occurred after this time frame, while Hodgson and co-workers40 on the other hand classified paraplegia according to what they found in spinal decompression surgery. They described two groups: (1) paraplegia of active disease and (2) paraplegia of healed disease. Paraplegia of active disease included two subtypes. The first was with external pressure on the cord causing inflammatory changes and oedema of the meninges, and the second was caused by penetration of the dura by the infection itself, or thrombosis or pressure on critical spinal arteries. Paraplegia of healed disease also included two subtypes. The first was with transection of the cord because of the bony ridge, and the second was due to constriction of the cord because of fibroses, granulation tissue, or stretching of the cord over the internal gibbus. This distinction is very important with regards to the management of spinal TB. Several methods of grading or classifying neurological compromise have been described. The most commonly used are the Frankel/Tuli system (Table 48.1), which has good clinical reference, and the American Spinal Injury Association (ASIA) grading system, which is more comprehensive and is commonly used for statistical analyses. These scoring systems are used to define specific outcome measures and aids in management algorithms. Table 48.1 Frankel grading system of neurological compromise in spinal tuberculosis Frankel grade
Lesion
A B C D E
Complete neurological injury Preserved sensation only Preserved motor—non-functional Preserved motor—functional Normal motor function
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DEFORMITY Kyphotic deformity is an important complication of spinal TB. This is usually (90%) the result of collapse of the anterior spinal elements. The regions of the thoracic–lumbar junction and lumbar spine are more prone to these deformities. The degree of deformity is more severe in children or where two or more vertebrae are involved. Although chemotherapy may eradicate the disease, vertebral collapse may continue for some time thereafter, until the vertebral bodies in the region of the kyphosis meet anteriorly, or until granulation tissue matures into the bony fusion.52 The loss of one whole vertebral body may result in a kyphotic deformity of 30 –35 in the thoracic spine, and 5 in the lumbar spine, with most of this collapse occurring during the first 18 months of the disease process. Kaplan used a simple classification system to grade kyphotic deformity as follows: mild, kyphotic angulation up to 30 ; moderate, between 30 and 60 ; and severe, more than 60 .40 The kyphotic deformities progress in two distinct phases. Phase I (disease phase) occurs during the first 18 months of active disease. This is followed by the healed phase (phase II). The pattern is distinct for adults and children. Adults usually present with a lesser deformity, and progression during phase I is mild (usually < 30 ). No progression is seen in phase II.52 It must be noted, however, that in a 30-year followup of 60 patients by Luk34 at Hong Kong University Hospital, 25 patients progressed to kyphosis of more than100 with late onset paraplegia. Once again it is evident that there are always exceptions to the well-accepted dogma. Children present with greater deformities and a variable progression pattern during both phase I and phase II. The progressive changes during phase II of the disease is of utmost importance in the management of these patients. After disease eradication approximately 45% of children show improvement of their deformity, approximately 40% show deterioration, and no change is seen in the remaining 15%.19,52 Progression of deformity presents in two patterns: the first is a continuous steady deterioration and the second only presents with deterioration after a lag period of 3–6 years. Clinical follow-up should be structured in such a way that late progression in these children is not missed. A formula for predicting progression in mobile kyphosis not treated surgically has been developed.52 Using this formula Y ¼ A þ BX, where Y is the final angle of deformity, A a constant of 5.5, B a constant of 30.5, and X the amount of initial loss of vertebral body height measured in tenths, the deformity was predicted with 90% accuracy in this series. This allows surgeons to select those patients who will require surgery to prevent a severe kyphosis and potential late neurological deficit. Progression of deformity in surgically treated patients is not due to posterior element overgrowth as suggested by certain authors. The main reasons for progression of deformity in this group were graft dislodgment, graft slippage, graft fracture, and graft resorbtion.53 Spontaneous improvement of deformity is unique in spinal TB. It is most prevalent in children and can be attributed to regeneration of the vertebral bodies and/or overgrowth of the anterior fusion mass. Scoliotic lumbar and thoracic curves have also been reported in the setting of spinal TB and could be attributed to vertebral destruction and/or contraction of the iliopsoas and paravertebral muscles secondary to fibrosis.40
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Reactivation of spinal TB in the adult or child can lead to acute severe progression. Patients must continuously be monitored for the so-called ‘spine at risk’ signs on radiograph. These include: 1. separation of facet joints; 2. posterior retropulsion of diseased vertebra; 3. lateral translation; and 4. the toppling sign. Patients demonstrating these warning signs are at risk for further structural deterioration, neurological deficit, and chest complications. Surgical intervention is indicated in these patients.
MANAGEMENT The following treatment modalities are at our disposal for spinal TB:
anti-TB chemotherapy; bed rest and bracing; and surgical treatment: ○ aspiration; ○ debridement only; ○ anterior debridement and strut grafting instrumented fusion; ○ posterior debridement, grafting instrumented fusion; and ○ combined anterior and posterior strut grafting instrumented fusion.
Medical treatment All spinal TB patients should receive anti-TB chemotherapy. Surgery is used as an adjunct to this therapy. The aim of anti-TB treatment is to cure the TB and to prevent further complications such as paraplegia, deformity, and sinus or abscess formation. This implies that the patient is pain free, there is restoration of the normal physical activity, healing of any sinus tracts and abscesses, a normal central nervous system, and the diseased area is clinically and radiologically healed. A four-drug treatment regimen, including isoniazid, rifampicin, pyrazinamide, and ethambutol, is recommended in the intensive phase of treatment in adults and children, with two drugs (isoniazid and rifampicin) in the continuation phase in drug-susceptible cases. (See treatment chapters.) In case of drug-resistant TB, the treatment regimen should be adjusted appropriately. (See drug-resistant chapters.) Directly observed treatment is strongly recommended to ensure adherence in order to improve clinical outcome, to prevent relapse, and to prevent the emergence of drug resistance.50 The optimal duration of anti-TB treatment in spinal TB is controversial. The 12th British Medical Research Council (MRC) study of 1993 found that 6- to 9-month ambulatory treatment was effective with regard to disease eradication. This confirmed previous studies by the MRC in 1986 in Hong Kong and 1989 in Madras. Upadhyay et al.53 used 6 months of three-drug therapy in conjunction with radical surgery and produced results comparable to 12 or 18 months of anti-TB treatment without surgery. Current World Health Organization guidelines recommend 6- to 9-month rifampicin-based treatment regimens for the management of spinal and other osteoarticular TB.54,55 The British and American Thoracic Societies also recommend 6 months of treatment for spinal TB. A literature review by van Loenhout-Rooyackers et al.56 in 2002 found that 6 months of therapy is probably sufficient for patients with spinal TB. However, subsequent publications showed a high relapse rate in patients receiving 6-months of chemotherapy
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compared with no relapses when treated for 9 months or more.57,58 Follow-up MRI findings suggested that there was incomplete resolution in 50% of cases after 6 months of treatment even though there was apparent disease resolution clinically.58 Although 9 months of anti-TB chemotherapy should be sufficient in the majority of drugsusceptible spinal TB cases, longer treatment duration with four drugs in the intensive phase for 3–4 months followed by three drugs in the continuation phase for 14–15 months (total of 18 months) is still regarded as the standard of care by many surgeons in endemic areas.44 Treatment is usually stopped after a minimum period of 12–18 months following clinical and radiological proof of disease arrest.
Bed rest and bracing British MRC studies also investigated the use of extended bed rest and bracing in treatment protocols. Bracing and bed rest yielded no significant improvement with regards to disease eradication. It was, however, noted that unbraced patients showed a higher incidence of progressive kyphosis and late progressive neurological compromise. Further well-structured studies are still needed to evaluate the role of bracing. Custom fit bracing has evolved remarkably in the modern era. Compliance with the wearing of braces is a problem in subSaharan countries. This may be due to poor patient education or the warm climate. In our unit bracing is still employed in both surgically (short-term) and medically (long-term) managed patients. The aim of bracing is to arrest curve progression, provide pain relief, and encourage early ambulation. Surgery The aims of surgery can be summarized as: (1) the relief of neurological symptoms and (2) the prevention of progression or correction of deformity. Specific indications for surgery abound with each author adding another modification to the list. Indications for surgery can be roughly divided into absolute and relative and these differ from author to author. Some of these indications include the following. Absolute indications
A marked neurological deficit, especially related to severe kyphosis or retropulced bone or disc. Large abscesses causing respiratory obstruction. Neurological deficit that has worsened despite adequate chemotherapy. Continued progression of kyphosis or instability, despite adequate chemotherapy, especially where three or more vertebra are involved, or with posterior element involvement.
Relative indications
Inability to obtain adequate material for culture/diagnosis. Neurological deficit in a patient where the prolonged bed rest may lead to other problems. Persistence of pain or spasticity due to demonstrable mechanical block. Pain related to instability.
Tuli59 described the middle path regimen where patients with neurological deficit were initially treated with a trial of chemotherapy for 3–4 weeks. Only patients who failed to respond to this initial trial of chemotherapy underwent anterior decompression and fusion. All patients without neurological compromise received standard anti-TB chemotherapy and in this group surgery was reserved to posterior element lesions, persistent active infections, instability, pain, and occurrence of neurological deficit.
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In the latter group only 6% of patients required surgery compared with 60% of patients in the first group. The decision to proceed to surgery is multifactorial. It depends on the clinical condition of the individual patient, the facilities available, the proposed procedure, and the skill and experience of the attending surgeon. Different opinions therefore exist as to when, and which patients should be selected for surgery. A few indications, however, are commonly found in the literature. These are: 1. uncertain diagnosis; 2. draining of large abscesses; 3. failure of conservative treatment; 4. progression of neurological deficit; and 5. impeding or progressive kyphosis. In these circumstances surgery is mandatory. In active disease anterior radical surgery, as described by Hodgson and Stock (the Hong Kong procedure), still remains the gold standard.60 Anterior procedures utilize a transthoracic and/or retroperitoneal approach to expose the anterior diseased vertebra. The local cold abscess is drained, necrotic tissue is removed, the affected vertebra are resected, and the spinal cord is decompressed. The resulting defect is structurally stabilized using rib graft (Kalafong procedure), autograft (iliac crest), vascularized fibula, or structural allograft as described by Govender and Leong.44 Structural allograft is preferred, as rib allografts are more prone to slippage, fracture, and subsidence, resulting in a progressive kyphosis. In adults the fusion can be augmented with anterior instrumentation.61 Posterior fusion, as described by Albee and Hibbs in 1911, is another option for surgery. This approach alone has failed to produce fusion in certain case series because of the active disease and the unsuccessful consolidation of the anterior elements. Although some authors feel that there is no place for posterior fusion in the modern management of spinal TB, it still has a place in stabilizing the occipitocervical junction, and it can also be used in combination with anterior surgery where two or more levels are affected or where there is posterior element involvement. Combination surgery can be done simultaneously or staged.61 Undertaking major surgery of this kind in the immune-compromised HIV-infected patient is controversial. Proper preoperative preparation and good patient selection produced good results in HIVinfected patients treated surgically using radical debridement with instrumentation.44 The use of metal implants in active disease does not increase the risk of prolonged infection as M. tuberculosis has shown no biofilm production or adherence to metallic implants.62 In established deformity complicated by neurological or respiratory compromise (so-called end-stage spinal TB), the prognosis for improvement is poor. The impeding cardiopulmonary compromise and severe deformity makes surgery daunting. Surgery in these cases is technically difficult, has a high complication rate, and requires prolonged postoperative immobilization. Surgery is usually staged and is only indicated for patients in whom the deformity is severe, active disease still present, and total paraplegia or death imminent because of chest complications.
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reaching the bone or joint through haematogenous spread. Direct inoculation or reactivation of an old primary focus may also be the source of infection.41 Tuberculous arthritis most commonly results from metaphyseal tuberculous osteomyelitis crossing the epiphyseal plate into the joint. Tubercle bacilli may also primarily be deposited in the synovium causing tuberculous synovitis, which can spread transphyseally to the metaphysis. Tuberculous arthritis (30%), which involves both bony elements and synovial joints, is the second most common site of infection after the spine and is followed by osteomyelitis (19%). Isolated soft-tissue involvement, such as tenosynovitis, bursitis, myositis, and panniculitis, is rare. Concomitant osseous and articular involvement is present in approximately 85% of cases and 15% of cases exhibit bony involvement only. The weight-bearing joints, such as the hip, knee, and ankle, are mostly affected, although the elbow and shoulder joints are not exempt from infection.17,18,41,63
TUBERCULOUS ARTHRITIS The most common presentation of patients with osteoarticular TB is that of a chronic monoarthritis, although multiple joints may be involved in approximately 10% of cases.64 Clinical signs usually include pain (80%), loss of function (80%), swelling (30%), sinus tract formation (20%), and abscess formation (20%). Frequently a history of trauma can also be elicited. In one-third to half of these patients the diagnosis of TB at another extraskeletal site can readily be made.17 Plain radiography is the appropriate initial imaging modality for the evaluation of musculoskeletal TB. The radiographic findings vary with the site and age of the lesion. The radiographic findings are progressive and include periarticular soft tissue swelling, joint effusion, osteopenia, subchondral cystic erosion (lytic lesions – Fig. 48.6), with eventually joint space narrowing, collapse, sclerosis, deformity, and finally ankylosis.50 The triad of periarticular osteopenia, subchondral erosions, and joint space narrowing is termed Phemister’s triad and is characteristic of tuberculous arthritis.20 Chronic infection may also lead to early physeal closure with resultant leg length discrepancy or deformity. Sequestrum formation is also occasionally found in advanced lesions.20,50 Early during the disease process radiographs may be normal, and even in well-established disease it may be difficult to distinguish from degenerative arthritis, pyogenic infection, inflammatory disease, or neoplasm. In late stage osteoarticular TB the radiographic findings may also be confused with pigmented villonodular synovitis, rheumatoid arthritis, or haemophilia.19
OSTEOARTICULAR TUBERCULOSIS Extraspinal TB accounts for 40–50% of all musculoskeletal cases. The pathophysiology is similar to spinal TB with the TB bacilli
Fig. 48.6 Radiograph of left ankle: cystic (lytic) lesions around subtalar joint.
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Ultrasound evaluation may be helpful for evaluating effusion and synovitis, and CT may be employed to differentiate between osteoarticular TB and neoplasm. On MRI, findings in tuberculous arthritis are non-specific. Aspiration or synovial biopsy is required for final diagnosis. Blood investigations also differ depending on age, site, and severity of infection and are usually not helpful. In children inflammatory markers are less pronounced with more than 50% presenting with an ESR below 50 mm/h. The white cell count can be marginally raised (> 12,000). Mild to moderate anaemia is common. A positive Mantoux tuberculin skin test is found in 60–85% of patients.17 Once again the diagnosis relies on evaluation of all the available data and definite diagnosis depends on identification of the TB bacillus in synovial fluid or tissue biopsy, or characteristic histological findings. The goals of treatment in osteoarticular TB are to eradicate the disease while maintaining a mobile and pain-free joint. Antituberculosis chemotherapy is compulsory for all patients and should be continued for 6–9 months. Some surgeons still prefer to continue treatment for 12–18 months in osteoarticular TB, but 6–9 months of treatment has been shown to be as effective as longer durations of treatment. Bracing and traction is used in the acute phase for pain relief, and physical therapy is used to optimize mobility after treatment has commenced. If a satisfactory pain-free range of motion cannot be obtained by conservative measures, surgery is indicated. In joints such as the hip and elbow spontaneous ankylosis is not well tolerated and surgical arthrodesis or osteotomy can be used to stabilize the joint in a functional position. In certain instances prosthetic application may be of value.50
Chronic tuberculous rheumatism (Poncet’s disease) This is a rare condition that presents as a polyarthritis associated with visceral TB in which there is no evidence of bacteriological involvement of the joints themselves.65 The pathogenesis is uncertain. Multidrug chemotherapy for the underlying TB leads to fairly rapid resolution of the arthritis.22 TUBERCULOUS OSTEOMYELITIS Solitary are now more common than multifocal lesions.66 Intercurrent active pulmonary lesions are found in less than 50% of cases. Tuberculous osteomyelitis may affect any bone, including tubular and flat bones and often affects bones of the extremities. The tubercle bacillus implants in the medulla of the metaphysis and less commonly the diaphysis, the latter more often in adults, with subsequent formation of a granulomatous lesion. As the infected focus enlarges, caseation and liquefaction necrosis occurs with resorption of bone trabeculae.64 Transphyseal spread to the joint or erosion through the cortex with formation of a paraosseous mass may occur. Plain radiograph findings show soft-tissue swelling, minimal periosteal reaction (although layered and extensive periosteal reaction may occur in young children with multiple bone lesions or dactylitis67), osteolysis with minimal reactive change, periarticular osteopenia, and erosions.64 Sclerosis is mainly seen in adults. Tuberculosis osteomyelitis may present in unusual ways that can be markedly difficult to diagnose.
Closed cystic tuberculosis These are well-defined cystic lesions in bone without surrounding sclerosis, periosteal reaction, or generalized osteopenia.
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No abscess or sinus tract formation is seen. This subtype is usually found in males less than 15 years old and has shown a predilection for long bones. The lesions need to be differentiated from Brodie’s abscess, bone cyst, non-ossifying fibroma, and enchondroma.22
Multiple (cystic) bone tuberculosis or disseminated skeletal tuberculosis Multiple bone TB occurs mainly in immune immature children or immune-compromised children or young adults. Incidence ranges between 5% and 10% of tuberculous osteomyelitis.22,35 This entity affects multiple areas of the skeleton with a tendency to symmetrical involvement of the long bones. Cystic lesions can simultaneously occur in the flat bones such as the skull. Dactylitis is sometimes present. Radiologically the lesions are round or oval and cystic in appearance, with clearly defined margins. Periosteal reaction, although uncommon in other forms of osteoarticular TB, is common and presents as smooth, layered, periosteal reaction which can be extensive in the long bones overlying the multiple cystic lesions.67 Sclerosis may be present on healing. Tuberculous dactylitis Tuberculous dactylitis is infection of the small bones of the hands and feet and occurs mainly in children. In children, often multiple bones are affected, whereas in adults it is usually restricted to one bone. A metacarpal or a proximal phalanx is most frequently affected. There is soft-tissue swelling around the affected bone. Periosteal reaction is common. A cyst-like cavity forms within the diaphysis of the bone due to expansion of caseous material, eventually causing widening of the bone and cortical erosions.13,22,68 This wind-blown widening of the bone with lucent lesion is classically referred to as ‘spina ventosa’. Differential diagnosis is congenital syphilis, haematological bone disease, such as leukaemia or haemoglobinopathies, and, in adults, sarcoidosis.46 Closed multiple diaphysitis Closed multiple diaphysitis is a very rare entity and is almost exclusively found in severely immune-compromised children. It presents as painful swelling of forearms and legs, as well as general ill health. Radiographs reveal generalized thickening and sclerosis of the affected limbs with no sequestrum formation. Treatment consists of multidrug chemotherapy combined with surgical curettage of the lesion. SOFT-TISSUE TUBERCULOSIS: TUBERCULOUS MYOSITIS, BURSITIS, AND TENOSYNOVITIS Extension of osteoarticular TB into the soft tissue can lead to cold abscesses, sinus tracts to the skin surface, or secondary bursitis or synovitis. Primary bursitis or tenosynovitis following haematogenous spread is rare. Isolated skeletal muscle involvement is rare (incidence < 0.0006%)24 and only a handful of cases have been reported.14,24 Treatment consists of multidrug chemotherapy combined with surgical drainage of the abscess, bursectomy, or synovectomy. Management of extraspinal musculoskeletal TB is mainly by chemotherapy (see Management of spinal TB), but drainage and/ or curettage and other surgical procedures may be indicated in some cases.
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Musculoskeletal and spinal tuberculosis in adults and children
REFERENCES 1. Salliot C, Allanore Y, Lebrun A, et al. Disseminated extrapulmonary tuberculosis revealed by humeral osteomyelitis with chronic unremarkable pain. Joint Bone Spine 2005;72:263–266. 2. Press Release. Geneva: WHO, 1996. 3. Zimmermann M. Pulmonary and osseous tuberculosis in an Egyptian mummy. Bull NY Acad Med 1979;55:604–608. 4. Goldsmith R. The challenge of tuberculosis. Curr Opin Orthop 2000;14:18–25. 5. Hippocrates. The genuine works of Hypocrates. 1849. 6. Paradisi F, Corti G. Skeletal tuberculosis and other granulomatous infections. Bailliere’s Clin Rheumatol 1999;13:163–177. 7. Davidson PT, Quoˆc Leˆ H. Musculoskeletal tuberculosis. In: Schlossberg D (ed.). Tuberculosis and Nontuberculous Mycobacterial Infections, 4th edn. Philadelphia: WB Saunders, 1999: 204–220. 8. Colmegna I, Koehler JW, Garry RF, et al. Musculoskeletal and autoimmune manifestations of HIV, syphilis and tuberculosis. Curr Opin Rheumatol 2006;18:88–95. 9. Herbst A, Simon A, Nemati M. A 15 year old girl with large lumbosacral abcess. Eur J Pediatr 1999;158:1003–1004. 10. Ceverien C, Nowak G. Osteomyelitis of the lower cervical spine caused by Mycobacterium tuberculosis. Pediatr Infect Dis 1998;17:170–172. 11. Ramos J, Esteban J. Extrapulmonary tuberculosis, experience in a general hospital. Rev Clin Esp 1995;195:546–549. 12. Ludwig B, Lazarus AA. Musculoskeletal tuberculosis. Dis Mon 2007;53:39–45. 13. Subasi M, Bukte Y, Kapukaya A, et al. Tuberculosis of the metacarpals and phalanges of the hand. Ann Plast Surg 2004;53:469–472. 14. Abdelwahab IF, Kenan S. Tuberculous abscess of the brachialis and biceps brachii muscles without osseous involvement. J Bone Joint Surg 1998; 80-A:1521–1524. 15. Goldblatt M, Cremin B. Osteoarticular tuberculosis: its presentation in coulored races. Clin Radiol 1978;29:669–677. 16. Watts HG, Lifeso RM. Tuberculosis of bones and joints. J Bone Joint Surg Am 1996;78(2):288–299. 17. Teklali Y, Alami ZFE, Madhi TE, et al. Peripheral osteoarticular tuberculosis in children: 106 casereports. Joint Bone Spine 2003;70:282–286. 18. Dhillon MS, Nagi ON. Tuberculosis of the foot and ankle. Clin Orthop Related Res 2002;398:107–113. 19. Griffith JF, Kumta SM, Leung PC, et al. Imaging of musculoskeletal tuberculosis: a new look at an old disease. Clin Orthop Related Res 2002;398:32–39. 20. Yao DC, Sartoris DJ. Musculoskeletal tuberculosis. Radiol Clin North Am 1995;33:679–689. 21. Hardy J, Hartmann J. Tuberculous dactylitis in childhood: A prognosis. J Pediatr 1947;30:146–156. 22. Babhulkar S, Pande SK. Unusual manifestations of osteoarticular tuberculosis. Clin Orthop Related Res 2002;398:114–120. 23. Ip M, Tsui E, Wong K, et al. Disseminated skeletal tuberculosis with skull involvement. Tuber Lung Dis 1993;74:211–214. 24. Ashworth M, Meadows T. Isolated tuberculosis of a skeletal muscle. J Hand Surg 1992;17B:235.
25. Davies P. The worldwide increase in tuberculosis: how demographic changes, HIV infection and increasing numbers in poverty are increasing tuberculosis. Ann Med 2003;35:235–243. 26. Frieden T. Tuberculosis. Lancet 2003;362:887–899. 27. Mehta JB, Emery MW, Girish M, et al. Atypical Pott’s disease: localized infection of the thoracic spine due to Mycobacterium avium intracellulare in a patient without human immunodeficiency virus infection. South Med J 2003;96:685–688. 28. O’Brian R, Geiter L, Snider D. The epidemiology of non-tuberculous mycobacteria disease in the United States. Am Rev Respir Dis 1987;135:1007–1014. 29. Yang Z, Kong Y, Wilson F. Identification of risk factors for extrapulmonary tuberculosis. Clin Infect Dis 2004;38:199–205. 30. Ruiz A, Post JD, Ganz WI. Inflammatory and infectious processes of the cervical spine. Neuroimaging Clin North Am 1995;5:401–425. 31. Tuli SM. General principles of osteoarticular tuberculosis. Clin Orthop 2002;398:11–19. 32. Sta¨bler A, Reiser MF. Imaging of spinal infection. Radiol Clin North Am 2001;39:115–135. 33. Hetem SF, Schils JP. Imaging of infections and inflammatory conditions of the spine. Semin Musculoskelet Radiol 2000;4:329–347. 34. Luk KD. Spinal tuberculosis. Curr Opin Orthop 2000;11:196–201. 35. Rathakrishnan V, Mohd TH. Osteo-articular tuberculosis. Skelet Radiol 1989;18:267–272. 36. Golden MP, Vikram HR. Extrapulmonary tuberculosis: an overview. Am Fam Physician 2005;72:1761–1768. 37. Davidson GS, Voorneveld CR, Krishnan N. Tuberculous infections of skeletal muscle in a case of dermatomyositis. Muscle Nerve 1994;17:730–732. 38. Chen W-J, Wu C-C, Jung C-H, et al. Combined anterior and posterior surgeries in the treament of spinal tuberculous spondylitis. Clin Orthop Related Res 2002;398:50–59. 39. Enarson D, Fujii M, Nakielna E. Bone and joint tuberculosis, a continuing problem. Can Med Assoc J 1979;120:139–145. 40. Bailey HL, Gabriel M, Hodgson AR, et al. Tuberculosis of the spine in children. Operative findings and results in one hundred consecutive patients treated by removal of the lesion and anterior grafting. J Bone Joint Surg Am 1972;54:1633–1657. 41. Soler R, Rodriquez E, Remuinan C, et al. MRI of musculoskeletal extraspinal tuberculosis. J Comput Assist Tomogr 2001;25(2):177–183. 42. Smith D, Smith F, Douglas J. Tuberculous polyradiculopathy: the value of magnetic resonance imaging of the neck. Tubercle 1989;70:213–216. 43. Murandali D, Gold WL, Vellend H, et al. Multifocal osteoarticular tuberculosis: report of four cases and review of management. Clin Infect Dis 1993;17:204–209. 44. Govender S, Leong JCY (eds). Inflammatory Diseases of the Spine. Singapore: TTG Asia Media Printers, 2003. 45. Pertuiset E, Beaudreuil J, Liote´ F, et al. Spinal tuberculosis in adults. A study of 103 cases in a developed country, 1980-1994. Medicine (Baltimore) 1999;78:309–320. 46. De Vuyst D, Vanhoenacker F, Gielen J, et al. Imaging features of musculoskeletal tuberculosis. Eur Radiol 2003;13:1809–1819. 47. Boumpas DT, Vieras F, Acio E, et al. Skeletal tuberculosis resembling metastatic disease on bone scintigraphy. J Nuclear Med 1987;28(9):1507–1509.
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48. Hardoff R, Efrat M, Gips S. Multifocal osteoarticular tuberculosis resembling skeletal metastatic disease: evaluation with Tc-99m MDP and Ga-67 citrate. Clin Nucl Med 1995;20(3):279–281. 49. Abdelwahab IF, Kenan S, Hermann G, et al. Atypical skeletal tuberculosis mimicking neoplasm. Br J Radiol 1991;64:551–555. 50. Spiegel DA, Singh GK, Banskota AK. Tuberculosis of the musculoskeletal system. Techniques Orthop 2005; 20(2):167–178. 51. Fang D, Leong J. Tuberculosis of the upper cervical spine. J Bone Joint 1983;65:47–50. 52. Rajasekaran S. The problem of deformity in spinal tuberculosis. Clin Orthop Related Res 2002; 398:85–92. 53. Upadhyay SS, Sell P, Saji MJ, et al. 17-year prospective study of surgical management of spinal tuberculosis in children. Hong Kong operation compared with debridement surgery for short- and long-term outcome of deformity. Spine 1993; 18:1704–1711. 54. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Geneva: WHO, WHO/CDS/TB/2003.313. 55. World Health Organization. Guidance for national programmes on the management of tuberculosis in children. Geneva: WHO, WHO/HTM/TB/ 2006.371. 56. Van Loenhout-Rooyackers JH, Verbeek AL, Jutte PC. Chemotherapeutic treatment of spinal tuberculosis. Int J Tuberc Lung Dis 2002;6:259–265. 57. Ramachandran S, Clifton IJ, Collyns TA, et al. The treatment of spinal tuberculosis: a retrospective study. Int J Tuberc Lung Dis 2005;9:541–544. 58. Cormican L, Hammal R, Messenger J, et al. Current difficulties in the diagnosis and management of spinal tuberculosis. Postgrad Med J 2006;82:46–51. 59. Tuli S. Results of treatment of spinal tuberculosis by ‘Middle path’ regimen. J Bone Joint 1975;57B: 13–23. 60. Hodgson AR, Stock FE. The Classic: Anterior spinal fusion. A preliminary communication on the radical treatment of Pott’s disease and Pott’s paraplegia. 1956. Clin Orthop Relat Res 2006;444: 10–15. 61. Fukuta S, Miyamoto K, Masuda T, et al. Two-stage (posterior and anterior) surgical treatment using posterior spinal instrumentation for pyogenic and tuberculotic spondylitis. Spine 2003;28:E302–E308. 62. Ha K-Y, Chung Y-G, Ryoo S-J. Adherence and biofilm formation of Staphylococcus epidermidis and Mycobacterium tuberculosis on various spinal implants. Spine 2004;30:38–43. 63. Dhillon MS, Sharma S, Gill S, et al. Tuberculosis of bones and joints of the foot: an analysis of 22 cases. Foot Ankle 1993;14-9:505–513. 64. De Backer AI, Mortele´ KJ, Vanhoenacker FM, et al. Imaging of extraspinal musculoskeletal tuberculosis. Eur J Radiol 2006;57:119–130. 65. Isaacs AJ, Sturrock RD. Poncet’s disease—fact or fiction? Tubercle 1974;55:135–142. 66. Teo HE, Peh WC. Skeletal tuberculosis in children. Pediatr Radiol 2004;34:853–860. 67. Schaaf HS, Donald PR. Multiple bone tuberculosis and dactylitis. Arch Pediatr Adolesc Med 2000;154: 1059–1060. 68. Benkeddache Y, Gottesman H. Skeletal tuberculosis of the wrist and hand: a study of 27 cases. J Hand Surg 1982;7:593–600.
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Tuberculosis of endocrine glands in adults and children Ertan Bulbuloglu and Harun Ciralik
INTRODUCTION Tuberculosis is a common disease in the developing world and its incidence is slowly increasing in developed countries. Thus, it is expected that with extrapulmonary TB’s increased prevalence in the world, there is a consequential increase of TB of the endocrine glands. It was recently reported that active TB was present in 871 patients (6.5%) of 13,492 who were autopsied, where extrapulmonary TB was seen in 261 patients (30%).1 The most common endocrine glands involved were the adrenal gland (6.7%), thyroid (1.9%), pancreas (1.5%), ovary (0.9%) and testis (0.3%).1 Thus, TB may affect many of the endocrine glands including the pituitary, thyroid, parathyroid, adrenal pancreas, ovary and testis, which can occur in one of three ways: direct, indirect or due to anti-TB therapy (Table 49.1).2
PITUITARY TUBERCULOSIS EPIDEMIOLOGY Pituitary TB is extremely rare.2–30 Pituitary involvement was observed in 4% of patients with TB in the preantibiotic era,30 while it accounts for approximately 0.15% of all intracranial tumours and 0.6% of all intracranial TB in the postantibiotic era.5,17 Pituitary TB was first reported in 1940 by Coleman et al., although many cases have been reported since then. The atypical and selective involvement of the pituitary gland by Mycobacterium tuberculosis remains unclear.6,10,16,18,23 It is probable that invasion can result by haematogenous spread or directly from basal TB meningitis or paranasal sinus.6,10,15,16,18,24 Common sites associated with pituitary TB are lung, lymph nodes, para-nasal sinus, middle ear and gastrointestinal tract.10,16,18,24,29 Previous or actual TB infection elsewhere was present in only 20 patients in published cases. Among reported cases, the male–female ratio was 26:40 (average age, 34 years for men versus 29 years for women, range 8–55 years). Most cases have been reported from India (40 cases). There have been no reported endocrine TB cases associated with human immunodeficiency virus (HIV). Pituitary TB is extremely rare in children.
SYMPTOMS AND SIGNS Usually dull, continuous and insidious headache and panhypopituitarism are common.2–30 Clinical features of endocrinopathy due to hypopituitarism may be present in patients with pituitary TB.22 Only two acromegaly cases (one with pituitary adenoma) have
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been reported (Fig. 49.1A).14,22 Hyperprolactinaemia (amenorrhoea, infertility, galactorrhoea) is found when the mass compresses the dopaminergic axis.6,8,15 Endocrinological disturbances have been found in 36 out of 56 patients from published cases. Suprasellar extension of pituitary TB commonly manifests with hypothalamic dysfunction and impairment of the visual acuity and fields.2–29 Third and sixth cranial nerve palsy and diabetes insipidus may be seen.16 Rarely, signs of meningitis and confusion can be seen.25,28 Tuberculosis vasculitis may cause atrophic changes in the optic nerves,2,29 and can present as apoplexy-like, with intense headache, sudden neurological deficits like ptosis or visual impairment and altered sensorium.20,30 Alternatively, it may present with pituitary cachexia involving amenorrhoea, asthenia and marked rapid weight loss.15 Erythrocyte sedimentation rate (ESR) may increase and a tuberculin skin test may be positive.16
DIFFERENTIAL DIAGNOSIS Although pituitary adenomas are the most common mass lesions in the sella, the differential diagnosis of pituitary TB from adenomas is difficult. Non-adenomatous sellar lesions are also difficult to diagnose.10,12,16,18,29 In particular, other granulomatous and infectious processes should be considered in the differential diagnosis of pituitary TB.12,13,22,24 Sarcoidosis can infiltrate the pituitary gland and hypothalamus with varying degrees of hypopituitarism and diabetes insipidus, with or without associated symptoms of an intrasellar mass.5,12,22 Giant cell granuloma or granulomatous hypophysitis is a rare disease which can present with a sellar/suprasellar mass and hypopituitarism.5,13,22,24 Histiocytosis X can present with signs of hypopituitarism, diabetes insipidus and an enhancing suprasellar mass, hypothalamic lesions and a thickened stalk on magnetic resonance imaging (MRI).13,22,24 Lymphocytic hypophysitis is a rare, but increasing disorder which affects women in late pregnancy or postpartum period and can present with an enlarging intrasellar or suprasellar mass with varying degrees of pituitary insufficiency.13 Diffuse lymphocytic and plasma cell infiltration of the pituitary can resolve spontaneously in some patients.13,24 For those cases which do not need surgical decompression, conservative followup could be considered.13,24 Infectious pituitary abscesses are rare and can present with symptoms indistinguishable from pituitary tumours, headache, visual disturbances and endocrinopathy.13 Pituitary abscesses may originate from a variety of bacterial organisms and fungal infections.13,18 Signs of systemic involvement or specific imaging findings may provide clues, but surgical biopsy is essential for an accurate diagnosis.13
Table 49.1 Effect of tuberculosis on endocrine glands.. direct, indirect and due to antituberculosis treatment Thyroid
Parathyroid
Adrenal
Pancreas
Testis and ovary
Endocrine abnormalities due to TB of endocrine glands
Sellar mass with/without headache, ophthalmopathy, hypopituitarism. Confirmation tests: MRI/CT scan/ biopsy
Solitary node/multinodular/ mass; painless or painful thyromegaly with or without lymphadenopathy; euthyroid/ hyperthyroidism, abscess/ sinus, etc. Confirmation test: FNAC/ biopsy
Parathyroid gland TB and parathyroid adenoma and primary hyperparathyroidism. Confirmation tests: FNAC/biopsy
Adrenal mass with or without decreased serum cortisol level, increased ACTH level. Confirmation tests: low-dose ACTH stimulation test, CT adrenals with or without FNAC.
Abdominal mass with or without ascites/obstructive jaundice/pancreatic abscess, gastrointestinal bleeding, pancreatitis/secondary diabetes, splenic vein thrombosis. Confirmation tests: CT scan/ USG abdomen FNAC/biopsy
Endocrine abnormalities due to active TB
Hypothalamus–pituitary–adrenal axis is active; growth retardation (following TB meningitis); hyponatraemia without oedema (SIADH); polyuria, polydipsia (diabetes insipidus). Confirmatory tests: clonidine/ insulin tolerance test for GH insufficiency. Plasma osmolality and urinary osmolality for SIADH. Dehydration test for diabetes insipidus
Increased thyroid hormone level
Hypercalcaemia. Confirmatory test: low 1,25 (OH)2 D3 and low parathormone
Increased cortisol level. Adrenal enlargement
Adnexal mass with or without abdominal pain/ infertility/menstrual abnormalities/ascites/ raised serum CA125. Confirmatory test: MRI, CT scan/biopsy. Scrotal mass with or without painless or painful abscess/fistula/ azoospermia. Confirmation tests: USG FNAC/biopsy. Gonadal dysfunctions, decreased dehydroepiandrosterone and testosterone levels; hypogonadotropic hypogonadism increased oestradiol and prolactin level
Thyroid binding globulin rises (with rifampicin, isoniazid, pyrazinamide); thyronine response unit decreases; goitrogenic (with para-amino salicylic acid)
Masks hypercalcaemia and hypercalciuria
Increases steroid metabolism; precipitates Addisonian crisis
Anti-TB therapy interacts adversely with oral antidiabetic therapy; insulin resistance
Failure of oral contraceptives
Effect of anti-TB therapy on endocrine system
ACTH, adrenocorticotropic hormone; CT, computed tomography; FNAC, fine needle aspiration cytology; GH, growth hormone; MRI, magnetic resonance imaging; SIADH, syndrome of inappropriate antidiuretic hormone secretion; USG, ultrasound-guided. Adapted from Arya (1999).2
Tuberculosis of endocrine glands in adults and children
Pituitary
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Rights were not granted to include this content in electronic media. Please refer to the printed book.
Fig. 49.1 (A) Preoperative MRI of sella shows a macroadenoma. (B) Haematoxylin þ eosin stain. Arrow: granuloma; short arrow: adenoma cells. Gazioglu N, Ak H, Oz B, et al. Silent pituitary tuberculoma associated with pituitary adenoma. Acta Neurochir 1999;141(7):785–6.
INVESTIGATIONS Radiological findings are rarely characteristic and it is difficult to differentiate pituitary TB from sellar lesion-like adenoma.6–30 Radiological features such as leptomeningeal enhancement and other parenchymatous brain tuberculomas are helpful in diagnosing pituitary TB.16 Intrasellar TB on computed tomography (CT) appears as an iso- to hyperdense mass which enhances brilliantly after contrast administration. Rarely they may present with peripheral ring enhancement.16,18,29 Contrast MRI characteristically demonstrates thickened infundibulum and hypophyseal stalk. Pituitary haemorrhage, abscess, adenoma and calcification are rarely shown.16,18,29 Suprasellar extension is more common than sphenoid sinus, nasopharynx or cavernous sinus invasion in pituitary TB.16 Hydrocephalus is uncommon but may be present with TB meningitis.28 Chest and head radiograph may be used.15,16,19 Polymerase chain reaction (PCR) was positive in only two cases; one was from pituitary tissue and the other from cerebrospinal fluid (CSF).13,23
PATHOLOGY There has been evidence of necrotizing and non-necrotizing granulomatous inflammation (Fig. 49.1B). Acid-fast bacilli (AFB) are rarely seen and were observed in only one case at histopathology.15
MANAGEMENT Management should include appropriate hormonal replacement, especially cortisol, thyroxine, antidiuretic and gonadal hormones, and comprehensive anti-TB therapy and surgery.7,15,30 The role of surgery in pituitary TB is tissue diagnosis and decompression.15,16,18,29 Early surgical decompression of pituitary TB with apoplexy-like appearance prevents persistent neuro-ophthalmic deficit.30 Although a subfrontal approach for excision is recommended,2,4 the preferred route is the transsphenoidal route,5–22 which prevents CSF contamination by TB material.15,16,29 Although response to anti-TB therapy in pituitary TB is good, there is no agreement on regimen and duration of this treatment.6–30 A combination of bactericidal drugs such as rifampicin, isoniazid, pyrazinamide and streptomycin is preferred as they penetrate the
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blood–brain barrier effectively, regardless of the presence of inflammation. Duration from at least 3 months to 2 years has been proposed.6–13,15–30 If isolated pituitary TB is removed completely, anti-TB therapy is unnecessary.14 If there is pituitary TB with adenoma, anti-TB therapy may be given after radiotherapy.15 Three out of 56 patients died during treatment. Hormone serum levels should be monitored.
COMPLICATIONS If surgery is carried out by a skilled surgeon, complications can be minimal; however, transient or permanent diabetes insipidus, CSF rhinorrhoea,12 monohormonal or polyhormonal deficiencies5 and visual field defects26,29 have been known to occur.
TUBERCULOSIS OF THE THYROID GLAND EPIDEMIOLOGY Tuberculosis of the thyroid gland is a rarely encountered condition even in countries with a high TB prevalence,31–37 and was considered non-existent in the middle of the nineteenth century. Thyroid TB was first recognized on autopsies of thyroid in symptom-free miliary TB cases in 1862 by Lebert.31–34 Bruns reported the first clinical case of primary thyroid TB in 1893.31,33,34 Coller and Huggins described five cases in 1926 in a series of thyroid-operated patients.31–34 Thereafter, sporadic cases have been reported, the majority being discovered at postmortem examinations during the past decade. Up to now there have been 73 cases published in the English literature.32 Thyroid TB rates are 0.1–0.003%, 0.2% and 14% in postmortem studies, chronic thyroiditis specimens and miliary TB, respectively.33 However, its true incidence is unknown. The rarity of this entity is not clear but could be explained by colloid material possessing bactericidal action, extremely high blood flow and an excess of iodine, enhanced destruction of tubercle bacilli by increased physiological activity of phagocytes in hyperthyroidism or anti-thyroid binding capacity roles of thyroid hormones.32–34
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Tuberculosis of endocrine glands in adults and children
Thyroid TB may be primary or secondary to other sites.31–37 During the past decade, the increasing incidence of extrapulmonary forms was reportedly greater than that of the pulmonary forms alone. Of the 73 cases reported in the literature, only 11 had associated pulmonary forms.32 Infection spreads to the thyroid by the lymphogenous or haematogenous route or directly from adjacent organs.32–34 According to studies on thyroid TB, there is a slight female predominance. The ages of patients reported have ranged from 9 to 83 years, with a median age of 40 years for men and 43 years for women.34 There has been a case report of a 9-year-old patient but no known HIV-infected case.32
SYMPTOMS AND SIGNS The diagnosis of thyroid TB is difficult since there is not any specific symptom. It may be asymptomatic or may present with non-specific manifestations.32–37 It may be seen as an isolated nodule or as a diffuse or multinodular goitre.32–37 The presence of satellite adenopathy may indicate malignant aetiology, and an abscess or chronic sinus may also be present.32–34,37 The symptoms of mass effect such as dysphagia or transient paralysis may be found.32–34,37 Hyperthyroidism due to parenchymal damage and increased release of thyroid hormones may be seen, whereas hypothyroidism is seen as a result of total destruction of the gland.32–37 Thyroid TB has been known to cause pyrexia of unknown origin or lethargy, and can mimic cancer or thyroiditis.32–37 Although normal thyroid function is the most frequent laboratory finding, thyroid function abnormalities may also be seen. Only five cases have been reported with thyrotoxicosis.32 A high ESR and a positive tuberculin skin test may suggest the tuberculous aetiology.32–37
INVESTIGATIONS Fine needle aspiration cytology (FNAC) is a useful method for diagnosing thyroid TB despite a paucity of evidence in the literature.32–37 Thyroid TB was diagnosed by FNAC in 0.6–1.15% of cases with thyroid lesions.37 Nearly half of reported cases have been diagnosed with FNAC, and the diagnosis must be substantiated by histopathological findings and/or identification of AFB.32,36 CT scan and ultrasonography (US) may be useful.36
DIFFERENTIAL DIAGNOSIS Thyroid TB should be distinguished from thyrotoxicosis, acute thyroiditis, thyroid cancer, Riedel thyroiditis and thyroid nodules.32–37 Lymphocytic infiltration and granulomas may also be seen in sarcoidosis, subacute thyroiditis and autoimmune thyroiditis.33–37 The most distinct feature of subacute thyroiditis is the giant cell granuloma, its resemblance to the granulomatous tissue reaction in thyroid TB causing the term pseudotuberculous thyroiditis to become more widespread.33,34,37 Sometimes thyroid TB is mistaken for carcinoma.33 However, there have been reports of TB thyroiditis coexisting with thyroid carcinoma in the same patient.34 A differentiation from thyroid cancer is essential to avoid unnecessary thyroid surgery.32,33
PATHOLOGY Morphological variations of thyroid TB include multiple tubercles in cases of miliary TB, solitary and merging tubercles, caseation
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necrosis or cold abscesses, and cicatrized tuberculous foci.32–34 The histological diagnosis is based on the presence of epithelial cell granulomas with peripheral lymphocytic cuffing, Langhans giant cells and central caseation necrosis.32–37 Rarely, AFB has been observed at histopathology.32,34
MANAGEMENT Following diagnosis, surgery has a limited role with surgical removal of the affected parts of the thyroid gland or surgical drainage.32–37 If surgery is required, early anti-TB drugs remain the keystone of treatment, avoiding total destruction of the thyroid gland and consequentual hypothyroidism.32–37 Thyroid hormone serum levels should be monitored.32,34 Although no specific study on the efficacy of the various regimens of thyroid TB treatment has been conducted, the same regimens can be used effectively in thyroid as used in any other extrapulmonary TB.36 If the affected thyroid gland is removed, there is no need for treatment.32
COMPLICATIONS Despite adequate treatment, recurrence and failure rates are about 1% owing to drug-resistant TB. When hypothyroidism occurs, treatment is directed according to thyroid-stimulating hormone levels.32
TUBERCULOSIS OF PARATHYROID GLAND EPIDEMIOLOGY Tuberculosis of the parathyroid gland is very rare even in countries with a high TB prevalence. Primary parathyroid TB is unknown, but coexistence of TB with adenoma in parathyroid glands has been reported.38,39 Two cases of parathyroid gland involvement from adjacent thyroid lobe and lymph nodes have also been reported.38,39 Parathyroid TB is expected to result in the gland’s hypofunction, as granulomatous inflammation of endocrine glands has almost invariably the same result. However, these two cases had hyperfunction, which could be explained by a pre-existent parathyroid adenom or that not all parathyroid glands are affected by TB inflammation in the same manner.38,39 Tuberculosis organisms may spread from an adjacent focus or distant haematogenous dissemination.38,39
SYMPTOMS AND SIGNS Symptoms and signs are shown in Table 49.2. Patients with parathyroid TB may manifest constitutional symptoms such as fever, anorexia, weight loss, malaise and fatigue and/or hyperparathyroidism due to adenoma in parathyroid glands.38,39
DIFFERENTIAL DIAGNOSIS Primary hyperparathyroidism is common in industrialized nations, while rates of detection have increased in developing nations. Likewise, TB is a problem in both industrialized and developing nations. Thus, we will probably see more coexistence of these two diseases in same population. Hypercalcaemia is a common electrolyte disorder and primary hyperparathyroidism, granulomatous diseases and malignancies are the most common in aetiology.38,39 A patient with two concurrent underlying diseases
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Table 49.2 Symptoms and signs of tuberculosis of the parathyroid gland Reference
Age/ sex
Symptoms, signs and tests
Investigations
Tuberculosis elsewhere
Endocrinology before/after treatment
Surgery
Jakob et al.38
35/F
Generalized body ache, increased serum calcium and parathormone
Thyroid lobe
Kar et al.39
36/F
Generalized bone ache, anaemia, muscular weakness, increased serum calcium and parathormone
Subperiosteal bone resorption, MIBI scintigraphy Ultrasonography and CT scan, chest radiograph
Primary hyperparathyroidism/ symptom free Primary hyperparathyroidism/ symptom free
Parathyroidectomy with adjoining right thyroid lobe Parathyroidectomy with adjoining right lymph nodes
capable of causing hypercalcaemia is rare and poses both a diagnostic and therapeutic challenge. Also, the mass, abscess, inflammation and malignancy of the neck region are important in differential diagnosis.
Lymph node
There was non-necrotizing granuloma in the parathyroid tissue and lymph node of one patient and necrotizing granuloma in the parathyroid tissue of another patient, with parathyroid adenoma in both of them.38,39
metastatic neoplasia, haemochromatosis and congenital adrenal hyperplasia–adrenoleucodystrophy.42–44 A study has shown interestingly that 11% of patients with adrenal TB had antibodies.45 Adrenal TB is an uncommon clinical condition, and adrenal dysfunction as a result of TB is a rarer combination.41–45 Although only 0.03% involvement of adrenal gland has been reported in extra-adrenal with extrapulmonary TB,46 it remains the most commonly involved endocrine organ in TB.46–48 In one study of patients with active TB, endocrine TB involvement was 9.5%, adrenal gland involvement 6.5% and single organ involvement 25%.48 The primary source of TB is usually the lung.46–48 Postmortem studies usually confirm that TB may exclusively involve the adrenal glands.46–48 Nevertheless, despite advances in diagnostic techniques, premortem diagnosis of isolated adrenal TB remains extremely rare, and has been reported in only six studies.46–51 Adrenal TB is extremely rare in children. Male predominance and a mean age of 61 years have been reported.1 In HIV-infected patients adrenal insufficiency and adrenal gland involvement by Mycobacterium avium–intracellulare and M. tuberculosis is more commonly seen. However, the risk of adrenal insufficiency is not increased in coinfected patients.52
MANAGEMENT
SYMPTOMS AND SIGNS
In both patients, diagnosis was made with histological examination of surgically removed tissue. The patients were given triple antiTB treatment for the first 3 months and then a two-drug regimen for 3 months for the first patient and 6 months for the other. Outcome was good in both patients.38,39
It is believed that > 90% of the adrenal gland must be destroyed before the clinical features of adrenal insufficiency are manifested.50,51,53 Active pulmonary TB may be associated with Addison’s disease characterized by enlarged adrenal glands, with or without normal adrenocortical functions.53 Because it is frequently unrecognized in its early stages, Addison’s disease due to TB can present with chronic adrenal insufficiency and rarely with lifethreatening acute adrenal insufficiency.50,51–53 Also, TB-related sudden death has been reported.54 However, when coexisting with Cushing’s syndrome, the typical symptoms related to Cushing’s syndrome might be partially masked by the adrenal insufficiency as a result of adrenal TB.55 Addison’s disease due to adrenal TB may manifest with diverse and non-specific clinical and/or biochemical features (Table 49.3).
INVESTIGATIONS Biochemical parameters (serum calcium, alkaline phosphatase, parathyroid hormone phosphorus, etc.), ultrasonography, CT scan, MIBI scintigraphy, bone radiograph and bone densitometry could show primary hyperparathyroidism and complications. Chest radiography, tuberculin skin test and ESR may be useful. PCR, FNAC and AFB may help to diagnose TB.38,39
PATHOLOGY
ADRENAL TUBERCULOSIS EPIDEMIOLOGY Primary adrenal insufficiency (Addison’s disease) is a rare endocrine disease in which there is destruction of the adrenal cortex with resultant inadequate secretion of the adrenal cortical hormones – cortisol, aldosterone and androgens.41–43 The prevalence of Addison’s disease has been reported to be 39–110 per million population.42,43 The commonest causes of Addison’s disease are autoimmune disease and adrenal TB.41–43 Between 1930 and 1950, adrenal TB accounted for 70–80% of cases of Addison’s disease.44 Currently in developed countries, idiopathic adrenal atrophy is responsible for 68–94% of the cases and adrenal TB for 18–30% of the remaining cases.45 In contrast, in developing countries, the most common cause of Addison’s disease is TB.41–45 Others are fungal infection,
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DIFFERENTIAL DIAGNOSIS Other causes of adrenal insufficiency as well as atrophy, calcification and mass lesions of the adrenal gland are important in the differential diagnosis.44,46,51 Primary adrenal insufficiency is almost certainly present when a high corticotropin (ACTH) level is associated with a low cortisol response to ACTH challenge.56 Low levels of plasma ACTH indicate secondary (pituitary) or tertiary (hypothalamic) causes that can
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Table 49.3 Presented symptoms, signs and biochemical abnormalities due to adrenal tuberculosis Symptom
Sign
Biochemical abnormality
Fatigue Muscular weakness
Postural hypotension Sinus tachycardia Weight loss Extra-adrenal TB source signs Generalized pigmentation, darkened skin creases, pigmented buccal mucosa and nail beds
Decreased cortisol level Low ACTH-stimulated cortisol responses Hyponatraemia, hyperkalaemia, hypoglycaemia, eosinophilia
Malaise Abdominal pain Vomiting Diarrhoea Behaviour changes Headache Sweating
Lymphocytosis Increased erythrocyte sedimentation rate and C-reactive protein level
Fever Positive tuberculin skin test (PPD) Associated thyroiditis
be differentiated by corticotropin-releasing hormone (CRH)stimulation testing. ACTH and aldosterone levels are also helpful in distinguishing primary from secondary adrenal insufficiency.56 CT and MRI are important in the differential diagnosis of primary adrenal insufficiency. Typically, autoimmune adrenal insufficiency is associated with atrophy of the adrenal glands, whereas disorders such as TB, fungal infections, amyloidosis, bilateral haemorrhage, primary tumour and metastatic disease are associated with adrenal enlargement.48,49 Long-standing TB, however, may also cause adrenal atrophy and calcification.50 Similar findings have been described with adrenal blastomycosis and histoplasmosis, but TB is rarely unilateral. Tuberculosis should still be considered in the aetiology of adrenal insufficiency, particularly in endemic areas.40–42 Adrenal TB or other causes may be identified by percutaneous needle biopsy of an enlarged adrenal gland.43–49 The finding of incidental masses in the adrenals has increased (from 0.35% to 5% of patients) in recent decades with the increased usage of CT and MRI. These are excellent methods for detecting an adrenal mass, but percutaneous biopsy could be required to differentiate lesions except myelolipomas, cysts, haemorrhages, phaeochromocytomas and adrenal metastases.43,49
INVESTIGATIONS Specific diagnostic tests should be performed when symptoms or signs suggest the possibility of Addison’s disease with TB, e.g. decreased serum cortisol level; however, a single normal serum cortisol level does not rule out Addison’s disease, although a high value would make the diagnosis very unlikely. The low-dose ACTH stimulation test using 1 mg of ACTH has been used to diagnose subclinical adrenal dysfunction.40–43,48,53 CT scan of the abdomen in adrenal TB shows typical features of shrunken and calcified adrenals (Fig. 49.2A) in the chronic stage and enlarged in the active stage (Fig. 49.2B).43,49 A normal CT finding is also possible in a biochemically proven case of Addison’s disease.15 MRI signs of adrenal TB are usually of bilateral, but asymmetrical enlargement. They tend to be heterogeneous with low attenuation areas of caseating necrosis and calcification.43,49,51 FNAC may be used to confirm the diagnosis of adrenal TB in acute cases.49,51 Bacteriological techniques and PCR could be used in some doubtful cases. A positive tuberculin skin test result would suggest TB but require further investigation. Radiography could show adrenal calcification or another focus in the lung.46,53
Increased urea nitrogen level and creatinine Hypercalcaemia
PATHOLOGY Adrenal TB shows necrotizing granulomatous inflammation including epithelioid histiocytes, giant cells and caseous necrosis. Sometimes bacilli can be evident. Caseous necrosis has been found in about 70% of cases, and thus is an important sign for the diagnosis of adrenal TB.1 However, typical granulomatous inflammation with Langhans giant cells has been found in less than half of cases, which may be related to the local suppressive effect of steroids secreted into the adrenal cortex. If Addison’s disease occurs, Langhans giant cells are more commonly seen (Fig. 49.2C).1,46,53
MANAGEMENT Treatment of acute adrenal insufficiency must not be delayed. High doses of intravenous steroids and fludrocortisone should be given.46,53,56 Intravenous doses may be replaced by oral maintenance doses in 3–5 days.46,53,54 Antituberculosis therapy is common practice for treating patients with TB–Addison’s disease for 1 year with isoniazid for inactive TB.15 However, the dual and triple (isoniazid (5 mg/kg), rifampicin (10 mg/kg) and pyrazinamide (25 mg/kg)) therapies are given for 12– 18 months.46,48,53 Antituberculosis therapy is known to increase the degradation of corticosteroids. Initiation of anti-TB therapy may lead to overt manifestations of subclinical adrenocortical insufficiency. Addisonian crisis has also been reported with the initiation of rifampicin therapy.56 Corticosteroids can cause immunosuppression and exacerbation of old TB foci.56 Significant increases in catecholamine levels with the severity of the disease suggest that the stress of infection plays a role in induction of enzymes responsible for catecholamine synthesis with subsequent stimulation of ACTH and cortisol synthesis.56 Patients should have regular follow-up visits with 3-month intervals.53 Addison’s disease due to TB is usually irreversible.46,46,53 Except for a few cases most studies have shown no improvement in adrenal corticosteroid production after anti-TB treatment.53,57 Histopathological evaluation of resected bilateral adrenal glands revealed no remaining vital adrenal tissue.1,53,57 Thus improvement after anti-TB therapy could not be expected.53,57 However, it is unclear whether anti-TB therapy prevents adrenocortical failure in the patients with enlarged adrenal glands but normal adrenal function.53,57 Obviously, diagnosis of this kind of abnormality is very difficult to make unless adrenal imaging is routinely performed.53,57 Therefore, prospective studies are needed to determine the effectiveness of anti-TB therapy in patients with normal
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Fig. 49.2 (A) Calcified adrenals on CT. (B) Lobulated, right adrenal depicting a 6 3.5 2 cm homogeneous mass and left adrenal gland showing a nodular irregularity. (C) Histopathological evaluation of the resected material. Large areas of caseous necrosis and granulomatous inflammation comprising Langhans giant cells and epithelioid histiocytes in adrenal tissue. Serter R, Koc G, Demirbas B, et al. Aral Acute adrenal crisis together with unilateral adrenal mass caused by isolated tuberculosis of adrenal gland. Endocr Pract. 2003 Mar-Apr;9(2):157–61.
adrenal function or subclinical adrenal failure and enlarged adrenal glands due to non-viable necrotic and caseous tissue.53
PANCREATIC TUBERCULOSIS EPIDEMIOLOGY Pancreatic TB is a rare entity in developed countries, occurring mostly in the setting of HIV infection or immunosuppression for transplantation.58–61 There has been an increase in the number of
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immunocompetent patients, originating mostly from developing countries.58–61 In a large portion of those cases, there is neither concomitant disease elsewhere nor evidence of miliary dissemination.58 Moreover isolated pancreatic TB is of lesser prevalence. The most common location of a pancreatic mass has been reported in the head or body; however, occasionally isolated involvement of the pancreatic tail has also been described.62 The pancreas is in the retroperitoneum and protected from direct environmental exposure. Purified lipases, pancreatic extracts and DNAses appear to have antimycobacterial effects.63 Thus, the pancreas is relatively
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resistant to mycobacterial invasion.63 The true incidence of pancreatic TB is unknown. In a MEDLINE search for English language articles from 1966 to 2004 using the MeSH terms ‘tuberculosis’ and ‘pancreas’ a total of 116 reports of pancreatic TB were identified in immunocompetent individuals worldwide.64 Mean age range was 40–45,64 and there was a slight male predominance.65 In another study 14 out of 62 cases (23%) were HIV-infected.66 Forms of mycobacterial infection of the pancreas have been described as: 1. miliary TB (M. tuberculosis); 2. spread to the pancreas from coeliac and other retroperitoneal lymph nodes (M. bovis); 3. primary localized pancreatic TB due to M. tuberculosis, which may reflect a point of origin from the intestinal tract;67,68 and 4. toxic-allergic reaction of the pancreas in response to TB elsewhere.69
SYMPTOMS AND SIGNS Common symptoms are abdominal pain (75%), anorexia with weight loss (69%), fever and night sweats (50%) and back pain and jaundice (31–40%).64–66 Infrequently, pancreatic TB may present as acute pancreatitis with radiographic findings.64–66 Other rare manifestations include obstructive jaundice, gastrointestinal bleeding via direct invasion of a peripancreatic artery, pancreatic abscess, chronic pancreatitis, diabetes, a pancreatic mass mimicking malignancy, pancreatic abscess, splenic vein thrombosis and ascites.64–66 Iron deficiency anaemia, lymphocytopenia, elevated transaminases and alkaline phosphatase have been seen in approximately 50% of cases.64–66 Most patients have a high sedimentation rate and C-reactive protein and the tuberculin skin test has been positive in over two-thirds of cases.61
DIFFERENTIAL DIAGNOSIS Pancreatic TB may be especially confused with carcinoma of the pancreas. There are no clear differences in the radiological appearances of cystic neoplasm and TB abscess of pancreas; both have septa within the mass, cyst with internal echoes and nearby hypodense lymphadenopathy.71 A calcified rim of cyst wall and mural nodulars are characteristic findings for cystic neoplasms, but these may occasionally be present in TB.70,71,73 A diagnosis of TB can be suggested only in the presence of ancillary findings such as pulmonary TB, pleural effusion, enlarged coeliac lymph nodes, lesions in other solid viscera, ascites, mural thickening in the ileocaecal region or a positive tuberculin skin test.71 Interestingly abdominal pain is more frequent at the time of presentation with pancreatic TB than with pancreatic cancer. The presence of fever with a pancreatic mass favours TB; however, non-Hodgkin’s lymphoma should also be considered in this clinical scenario. A firm diagnosis can only be made with the help of histopathological or microbiological evidence of the disease. Most patients have been diagnosed at laparotomy or FNAC. Another diagnostic option is initiating treatment with anti-TB therapy and evaluating the response to therapy.71,72
INVESTIGATIONS Ultrasound and CT scan may show a diffusely enlarged pancreas, a mass lesion, or focal hypoechoic or hypodense lesions usually in the pancreatic head region.74 These finding are non-specific and may be seen with focal pancreatitis of any aetiology, such as in pancreatic
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carcinoma.74 There are no pathognomonic CT features of TB, although ‘ring enhancement’ or low-density areas within enlarged lymph nodes is accepted as a characteristic feature.73 Associated findings may include splenic vein thrombosis, focal hepatic or splenic lesions, bowel thickening in the ileocaecal region and ascites.71–73 Calcification in the gland has been reported in pancreatic TB.75 Chest radiography and sputum smears for AFB are mostly negative. Endoscopic retrograde cholangiopancreatography (ERCP) may show displacement and stenosis of the main duct or involvement of the common bile duct leading to intrahepatic biliary dilatation.64,74 The success rate of image-guided percutaneous FNAC or biopsy in diagnosing pancreatic TB is less than 50%.64,65 Endoscopic ultrasound FNA cytology/biopsy has proved to be an excellent tool for the cytological diagnosis of pancreatic and peripancreatic masses.64,65 However, the potential risk of tumour dissemination sometimes prevents physicians from performing FNAC. Although spillage of tumour cells by FNAC has not been reported, PCR has proved important for rapid diagnosis. Also, PCR of ascites has been reported.64,65 Laparoscopy might prove helpful if TB cannot be confirmed by FNAC or core biopsy. However, the diagnosis has been made in most cases by laparotomy or at necropsy.64,65 Also, it appears hypointense on fat-suppressed T1-weighted images and hyperintense on T2-weighted images, and shows heterogeneous enhancement after Gd-DTPA injection on MRI.75
PATHOLOGY The presence of caseating granulomatous inflammation with or without necrosis is the commonest finding on histopathological examination. Caseating granulomas are seen in 75–100% of cases.64 AFB are identified in only 20–40% of cases.64
MANAGEMENT Response to anti-TB therapy is very favourable.58–62,66 The most frequently used combinations were isoniazid/rifampicin/ pyrazinamide/streptomycin or ethambutol and isoniazid/rifampicin/ streptomycin (older studies).62,64–66 The duration of the therapy was usually 6–12 months.58–66 Recurrences are rare. Laparotomy should be indicated to establish a diagnosis in most of the suspected cases. Other indications for an exploration are secondary complications, such as compression of common bile duct, or gastrointestinal bleeding. The role of resection (e.g. pancreatoduodenectomy) is very limited. Imaging-guided drainage may be useful in cases that present with an abscess.58,62,64
TUBERCULOSIS OF TESTIS EPIDEMIOLOGY Epididymo-orchitis is a rare manifestation of genital TB which usually results from retrograde infection from prostate and seminal vesicles.77–82 The infection affects epididymis first, then testis is usually involved by direct spread.77–82 Rarely it may be caused by haematogenous dissemination, bacillus Calmette–Gue´rin (BCG) and venereal transmission.77–82 Also, isolated testicular TB is extremely rare. Men aged 20–50 years are affected most commonly.80 Isolated testis involvement with ectopic testis has been reported in children.82 Testicular TB in patients with acquired immunodeficiency syndrome is rarely seen.82
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SYMPTOMS AND SIGNS Testicular TB presents with a painless or slightly painful scrotal mass.77–82 The presence of an abscess or scrotal sinus formation should alert the clinician to TB, especially as such sinus tracts are known to occur as a result of caseous material reaching the scrotal skin; thus a chronic draining sinus should be regarded as having a tuberculous origin until proven otherwise. Patients may have systemic manifestations such as fever and sweats. Chest radiographs have failed to reveal any active pulmonary disease and urine analysis and a plain abdominal radiograph excluded tuberculous infection of urinary tract.77–82
DIFFERENTIAL DIAGNOSIS Testicular tumours, acute infections, infarction, granulomatous orchitis and testicular TB should be considered. The presence of epididymal involvement in conjunction with a testicular lesion is suggestive of an infection rather than a tumour, because testicular TB is nearly always caused by epididymitis. Sometimes the epididymides may be enlarged because of coincidental epididymitis or direct tumour invasion – especially in lymphoma, but also in germ cell tumours. Skin thickening and a large volume of peritesticular fluid tend to indicate a non-neoplastic process. Differentiating TB epididymitis from non-tuberculous epididymitis is important for disease management. Generally, the sonographic findings of non-tuberculous epididymitis consist of diffuse enlargement of the epididymis and a uniform decrease in its echogenicity. Heterogeneous enlargement of the epididymis may distinguish TB from non-tuberculous epididymitis. Also, Doppler sonography may show more signal tuberculous orchitis rather than non-tuberculous orchitis.77–82
The ultimate prognosis is determined by the degree of systemic illness.
TUBERCULOSIS OF OVARIES EPIDEMIOLOGY The tubes are almost always involved in TB of the female genital tract, but the ovarian parenchyma is affected in only 9–11% of cases. Ovarian involvement appears to be fairly common in developing countries and may be usually due to haematogenous or lymphatic spread and occasionally to peritoneal dissemination.83,84 Isolated ovarian involvement is extremely rare.83
SYMPTOMS AND SIGNS Tuberculosis of ovaries in the absence of endometrial and tubal involvement can pose problems in diagnosis. Patients may present with non-specific lower abdominal pain, infertility, menstrual abnormalities, abdominal distension, ascites, and postmenopausal and intermenstrual bleeding. Systemic constitutional symptoms of weight loss, feeling unwell and night sweats may be present. Involvement of the ovaries may result in a unilateral or bilateral adnexal ovarian mass. Fistula formation to the bowel, skin or vagina may be seen. An adnexal mass and a raised serum CA125 level can be mistaken for ovarian cancer and can result in unnecessary surgical intervention.83 Pelvic examination may reveal mass or ascites. ESR is usually raised.83 A tuberculin skin test may be helpful.83 Chest radiography is aimed at demonstrating current or past tuberculous lesions in the lungs. Tuberculosis peritonitis may accompany TB of the ovaries. The definite diagnosis is usually made postoperatively.83,84
INVESTIGATIONS Scrotal US is helpful in assessing for complications of testicular TB, such as fistula or abscess formation.80 The most characteristic US pattern of testicular TB is the presence of heterogeneously or homogeneously nodular and multiple small hypoechoic nodules in an enlarged testis. Scrotal skin thickening, scrotal abscesses and scrotal sinus tract are other US features. Colour Doppler sonography may help in the diagnosis.77–82 A renal US for evaluating the upper tracts for evidence of TB is also warranted. FNAC is very successful for diagnosis of TB.77–81
DIFFERENTIAL DIAGNOSIS Acute and chronic bacterial pelvic infections, sarcoidosis, Crohn’s disease, actinomycosis, leprosy, granuloma inguinale, lymphogranuloma venereum, syphilis, histoplasmosis, brucellosis, berylliosis silicosis, tularaemia, foreign body reaction, other intra-abdominal diseases and rarely schistosomiasis and filariasis should be kept in mind.83,84
INVESTIGATIONS PATHOLOGY The diagnosis of TB depends upon the demonstration of epithelioid granuloma, necrosis and/or AFB.77–82
COMPLICATIONS Complications of advanced testicular TB are scrotal abscess and fistula formation. Severe immunosuppression increases that complication. Both complications are usually treated by scrotal surgery. If epididymis is affected, patients may become infertile, because of either extensive duct destruction or obstruction of the vas deferens.77–82
TREATMENT Standard short-course anti-TB treatment is usually sufficient.77 Ulcerative lesions and sinus could improve in the seventh month.77
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MRI, CT scan and US are helpful. Cystic or both solid and cystic adnexal masses, unilateral or bilateral, are accompanied by ascites, omental or mesenteric infiltrations and peritoneal thickening. These findings closely resemble those of peritoneal carcinomatosis from ovarian cancer. Calcifications may be found in adnexal masses and suggest TB, but are not frequently observed, especially in active inflammation. Lymph node enlargement and dense adhesion with the adjacent organs is common, and the latter may reflect a late fibrotic process of this infection. Loculated fluid collections with internal septations are often found adjacent to the masses or in the cul-de-sac. Laparoscopic findings may include ovarian mass, adhesions, tubal abnormalities and ascites. Tissues of ovaries can be obtained at laparoscopy or laparotomy for culture and PCR. If the patient does not have tubal involvement, hysterosalpingogram may not reveal a typical tubal pattern.83,84
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PATHOLOGY Microscopy demonstrates the typical caseous granulomatous lesions with giant epithelioid cells. AFB can provide a quick diagnosis.83,84
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in isolated TB of the ovaries. If it is not isolated, therapy is the same as that for genital TB. Surgery should be recommended in persistent disease, multidrug resistance or coexistence with malignancy.83,84
MANAGEMENT
COMPLICATIONS
First, three- or four-drug therapy for 2 months and maintenance with ethambutol and streptomycin for 4 months is recommended
Patients may present with infertility, menstrual abnormalities, ascites, and hydronephroses.83
REFERENCES 1. Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol 2001; 54(5):633–639. 2. Arya V. Endocrine dysfunctions in tuberculosis. Int J Diab Dev Countries 1999;19:71–77. 3. Oliver LC. A pituitary tuberculoma. Lancet 1952; 1(14):698–699. 4. Brooks MH, Dumlao JS, Bronsky D, et al. Hypophysial tuberculoma with hypopituitarism. Am J Med 1973;54(6):777–781. 5. Eckland DJ, O’Neill JH, Lightman SL. A pituitary tuberculoma. J Neurol Neurosurg Psychiatry 1987;50:360–361. 6. Esposito V, Fraioli B, Ferrante L, et al. Intrasellar tuberculomas: case report. Neurosurgery 1987; 21:721–723. 7. Delsedime M, Aguggia M, Chiado Cuttin I, et al. Isolated hypophyseal tuberculoma: case report. Clin Neuropathol 1988;7:311–313. 8. Taparia SC, Tyagi G, Singh AK, Gondal R, Prakash B. Sellar tuberculoma. J Neurol Neurosurg Psychiatr 1992;55:629. 9. Ghosh S, Chandy MJ. Intrasellar tuberculoma. Clin Neurol Neurosurg 1992;94:251–252. 10. Ranjan A, Chandy MJ. Intrasellar tuberculoma. Br J Neurosurg 1994;8:179–185. 11. Pereira J, Vaz R, Carvalho D, et al. Thickening of the pituitary stalk: a finding suggestive of intrasellar tuberculoma? Case report. Neurosurgery 1995; 36:1013–1016. 12. Petrossians P, Delvenne P, Flandroy P, et al. An unusual pituitary pathology. J Clin Endocrinol Metab 1998;83:3454–3459. 13. Ashkan K, Papadopoulos MC, Casey AT, et al. Sellar tuberculoma: report of two cases. Acta Neurochir (Wien) 1997;139:523–525. 14. Gazioglu N, Ak H, Oz B, et al. Silent pituitary tuberculoma associated with pituitary adenoma. Acta Neurochir (Wien) 1999;141:785–786. 15. Basaria S, Ayala AR, Guerin C, et al. A rare pituitary lesion. J Endocrinol Invest 2000;23(3):189–192. 16. Sharma MC, Arora R, Mahapatra AK, et al. Intrasellar tuberculoma: an enigmatic pituitary infection: a series of 18 cases. Clin Neurol Neurosurg 2000;102(2):72–77. 17. Sinha S, Singh AK, Tatke M, et al. Hypophyseal tuberculoma: direct radiosurgery is contraindicated for a lesion with a thickened pituitary stalk: case report. Neurosurgery 2000;46:735–738. 18. Patankar T, Patkar D, Bunting T, et al. Imaging in pituitary tuberculosis. Clin Imaging 2000;24(2):89–92. 19. Manghani DK, Gaitonde PS, Dastur DK. Pituitary tuberculoma: A case report. Neurol India 2001; 49:299–301. 20. Kumar N, Singh S, Kuruvilla A. Pituitary tuberculoma mimicking adenoma: magnetic resonance imaging. Australas Radiol 2001;45:244–246. 21. Arunkumar MJ, Rajshekhar V. Intrasellar tuberculoma presenting as pituitary apoplexy. Neurol India 2001;49(4):407–410. 22. Sharma MC, Vaish S, Arora R, et al. Composite pituitary adenoma and intrasellar tuberculoma: report of a rare case. Pathol Oncol Res 2001;7(1):74–76. 23. Stalldecker G, Diez S, Carabelli A, et al. Pituitary stalk tuberculoma. Pituitary 2002;5:155–162.
24. Paramo C, de la Fuente J, Nodar A, et al. Intrasellar tuberculoma—a difficult diagnosis. Infection 2002; 30(1):35–37. 25. Domingues FS, de Souza JM, Chagas H, et al. Pituitary tuberculoma: an unusual lesion of sellar region. Pituitary 2002;5(3):149–153. 26. Satyarthee GD, Mahapatra AK. Diabetes insipidus in sellar-suprasellar tuberculoma. J Clin Neurosci 2003; 10(4):497–499. 27. Singh S. Pituitary tuberculoma: magnetic resonance imaging. Neurol India 2003;51(4):548–550. 28. Andronikou S, Furlan G, Fieggen AG, et al. Two unusual causes of pituitary stalk thickening in children without clinical features of diabetes insipidus. Pediatr Radiol 2003;33(7):499–502. 29. Desai KI, Nadkarni TD, Goel A. Tuberculomas of hypophysitis cerebri: A report of five cases. J Clin Neurosci 2003;10:562–566. 30. Deogaonkar M, De R, Sil K, Das S. Pituitary tuberculosis presenting as pituitary apoplexy. Int J Infect Dis 2006;10(4):338–339. 31. Klassen KP, Curtis GM, Ohio C. Tuberculous abscess of the thyroid gland. Surgery 1945;17:552–559. 32. Bulbuloglu E, Ciralik H, Okur E, et al. Tuberculosis of the thyroid gland: review of the literature. World J Surg 2006;30:149–155. 33. Al-Mulhim AA, Zakaria HM, Hadi MSAA, et al. Thyroid tuberculosis mimicking carcinoma: report of two cases. Surgery Today 2002;32:1064–1067. 34. Simkus PE. Thyroid tuberculosis Medicina 2004; 40:201–204. 35. Unnikrishnan AG, Koshy GR, Rajaratnam S, et al. Suppurative neck abscess due to tuberculous thyroiditis. J Assoc Physicians India 2002;50:610–611. 36. El Malki HO, El Absi M, Mohsine R, et al. La tuberculose de la thyroide. Diagnostic et traitment. Ann Chir 2002;127:385–387. 37. Mondal A, Patra DK. Efficacy of fine needle aspiration cytology in the diagnosis of tuberculosis of the thyroid gland: a study of 18 cases. J Laryngol Otol 1995;109:36–38. 38. Jakob PM, Sukumar GC, Nair A, et al. Parathyroid adenoma with necrotizing granulomatous inflammation presenting as primary hyperparathyroidism. Endocr Pathol 2005;16(2): 157–160. 39. Kar DK, Agarwal G, Metha B, et al. Tuberculous granulomatous inflammation associated with adenoma of parathyroid gland manifesting as primary hyperparathyroidism. Endocr Pathol 2001;12(3): 355–359. 40. Wolfgang O. Adrenal insufficiency. N Engl J Med 1996;335:1206–1212. 41. Willis AC, Vince FP. The prevalence of Addison’s disease in Coventry, UK. Postgrad Med J 1997; 73(859):286–288. 42. Kong MF, Jeffcoate W. Eighty-six cases of Addison’s disease. Clin Endocrinol 1994;41(6):757–761. 43. Wilms GE, Baert AL, Kint EJ, et al. Computed tomographic findings in bilateral adrenal tuberculosis. Radiology 1983;146:729–730. 44. Betterle C, Dal Pra C, Mantero F, et al. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002;23:327–364. 45. Benini F, Savarin T, Senna GE, et al. Diagnostic and therapeutic problems in a case of adrenal tuberculosis and acute Addison’s disease. J Endocrinol Invest 1990;13(7):597–600.
46. Serter R, Koc G, Demirbas B, et al. Acute adrenal crisis together with unilateral adrenal mass caused by isolated tuberculosis of adrenal gland. Endocr Pract 2003;9(2):157–161. 47. Guttman PH. Addison’s disease: a statistical analysis of 566 cases and a study of the pathology. Arch Pathol 1930;10:742–785. 48. Vita JA, Silverberg SJ, Goland RS, et al. Clinical clues to the cause of Addison’s disease. Am J Med 1985; 78(3):461–466. 49. Liatsikos EN, Kalogeropoulou CP, Papathanassiou Z, et al. Primary adrenal tuberculosis: role of computed tomography and CT-guided biopsy in diagnosis. Urol Int 2006;76(3):285–287. 50. Llewelyn M, Adler M, Steer K, et al. Acute adrenal insufficiency precipitated by isolated involvement of the adrenal gland by tuberculosis. J Infect 1999; 39(3):244–245. 51. Efremidis SC, Harsoulis F, Douma S, et al. Adrenal insufficiency with enlarged adrenals. Abdom Imaging 1996;21(2):168–171. 52. Hawken MP, Ojoo JC, Morris JS, et al. No increased prevalence of adrenocortical insufficiency in human immunodeficiency virus-associated tuberculosis. Tuber Lung Dis 1996;77(5):444–448. 53. Kelestimur E. The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J Endocrinol Invest 2004;27(4):380–386. 54. Alkhuja S, Miller A. Tuberculosis and sudden death: a case report and review. Heart Lung 2001; 30(5):388–391. 55. Kwon HS, Kim SI, Yoo SJ, et al. Adrenal tuberculosis in Cushing’s disease with bilateral macronodular adrenocortical hyperplasia. Endocr J 2006;53(2):219–223. 56. May ME, Vaughn ED, Carey RM. Adrenocortical insufficiency-clinical aspects. In: Vaughan ED Jr, Carey RM (eds). Adrenal Disorders. New York: Thieme, 1989: 171–189. 57. Bhatia E, Jain SK, Gupta RK, et al. Tuberculous Addison’s disease: lack of normalization of adrenocortical function after anti-tuberculous chemotherapy. Clin Endocrinol (Oxf) 1998; 48(3):355–359. 58. Demir K, Kaymakoglu S, Besisik F, et al. Solitary pancreatic tuberculosis in immunocompetent patients mimicking pancreatic carcinoma. J Gastroenterol Hepatol 2001;16:1071–1074. 59. Jaber B, Gleckman R. Tuberculous pancreatic abscess as an initial AIDS-defining disorder in a patient infected with the human immunodeficiency virus: case report and review. Clin Infect Dis 1995;20:890–894. 60. Coelho JC, Wiederkehr JC, Parolin MB, et al. Isolated tuberculosis of the pancreas after orthotopic liver transplantation. Liver Transpl Surg 1999;5:153–155. 61. Schneider A, von Birgelen C, Duhrsen U, et al. Two cases of pancreatic tuberculosis in nonimmunocompromised patients. A diagnostic challenge and a rare cause of portal hypertension. Pancreatology 2002;2:69–73. 62. Woodfield JC, Windsor JA, Godfrey CC, et al. Diagnosis and management of isolated pancreatic tuberculosis: recent experience and literature review. ANZ J Surg 2004;74:368–371. 63. Knowles KF, Saltman D, Robson HG, et al. Tuberculous pancreatitis. Tubercle 1990;71:65–68. 64. Ahlawat SK, Charabaty-Pishvaian A, Lewis JH, et al. Pancreatic tuberculosis diagnosed with endoscopic ultrasound guided fine needle aspiration. JOP 2005;10;6(6):598–602.
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65. Chaudhary A, Negi SS, Sachdev AK, et al. Pancreatic tuberculosis: still a histopathological diagnosis. Dig Surg 2002;19(5):389–392. 66. Evans JD, Hamanaka Y, Olliff SP, et al. Tuberculosis of the pancreas presenting as metastatic pancreatic carcinoma. A case report and review of the literature. Dig Surg 2000;17(2):183–187. 67. Small G, Wilks D. Pancreatic mass caused by Mycobacterium tuberculosis with reduced drug sensitivity. J Infect 2001;42:201–202. 68. Karia K, Mathur SK. Tuberculous cold abscess simulating pancreatic pseudocyst. J Postgrad Med 2000;46:33–34. 69. Stock KP, Riemann JF, Stadler W, et al. Tuberculosis of the pancreas. Endoscopy 1981;13:178–180. 70. Franco-Paredes C, Leonard M, Jurado R, et al. Tuberculosis of the pancreas: report of two cases and review of the literature. Am J Med Sci 2002;323:54–58. 71. Liu Q, He Z, Bie P. Solitary pancreatic tuberculous abscess mimicking pancreatic cystadenocarcinoma: A case report. BMC Gastrenterol 2003;3:1.
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72. Bornman PC, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system: Pancreatic tumours. BMJ 2001;322:721–723. 73. Martin I, Hammond P, Scott J, et al. Cystic tumours of the pancreas. Br J Surg 1998;85:1484–1486. 74. D’Cruz S, Sachdev A, Kaur L, et al. Fine needle aspiration diagnosis of isolated pancreatic tuberculosis. A case report and review of literature. JOP 2003; 4(4):158–162. 75. Hulnick DH, Megibow AJ, Naidich DP, et al. Abdominal tuberculosis: CT evaluation. Radiology 1985;157:199–204. 76. De Backer AI, Mortele KJ, Bomans P, et al. Tuberculosis of the pancreas: MRI features. AJR Am J Roentgenol 2005;184(1):50–54. 77. Garbyal RS, Gupta P, Kumar S, Anshu. Diagnosis of isolated tuberculous orchitis by fine-needle aspiration cytology. Diagn Cytopathol 2006;34(10):698–700. 78. Goodman P, Maklad NF, Verani RR, et al. Tuberculous abscess of the testicle in AIDS: sonographic demonstration. Urol Radiol 1990;12(1):53–55.
79. Kumar PV, Owji SM, Khezri AA. Tuberculous orchitis diagnosed by fine needle aspiration cytology. Acta Cytol 1996;40(6):1253–1256. 80. Gemmel C, Jacek G, Lucking HC, et al. [Scrotal abscess with inguinal lymph node swelling in an 86-year-old man.] Dtsch Med Wochenschr 2004; 129(39):2032–2034. [In German.] 81. Muttarak M, Peh WC. Case 91: Tuberculous epididymo-orchitis. Radiology 2006;238(2):748–751. 82. Debnath PR, Tripathi R, Agarwal LD, et al. Tuberculosis in transverse testicular ectopic testis, a diagnostic dilemma: case report. Indian J Tuberc 2006;53:27–29. 83. Steller J. [Ovarian tuberculosis.] Gynakol Geburtshilfliche Rundsch 2001;41(4):236–239. [In German.] 84. Parikh FR, Nadkarni SG, Kamat SA, et al. Genital tuberculosis—a major pelvic factor causing infertility in Indian women. Fertil Steril 1997; 67(3):497–500.
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Surgery in the management of tuberculosis Phillip S Barie and Soumitra R Eachempati
Tuberculosis, the leading cause of death from infectious disease world-wide, has infected an estimated one-third of the world’s population. Approximately 2 million people die each year from TB. Ninety-five per cent of cases and 98% of deaths occur in developing countries.1 Most disease in human beings is caused by Mycobacterium tuberculosis, with a few cases being caused by Mycobacterium bovis. Without therapy, exposure to TB leads to active disease in 5–15% of those infected within 2 years, with the highest incidence of disease in infancy, between ages 15 and 25 years, and among elderly patients. Children aged 4–15 years are relatively safe from developing disease. Younger patients develop more hilar adenopathy; older patients may have few symptoms. In the United States, high-risk patient populations include immigrants from developing countries, the urban poor, migrant farm workers, prison inmates, homeless persons, abusers of injectable drugs and patients infected with the human immunodeficiency virus (HIV) (the reservoir in which coinfection with multidrug-resistant (MDR) infections has emerged). Outbreaks of TB have been reported in the community (e.g. New York City; Newark, NJ; Miami), hospitals, homeless shelters and prisons. Aside from HIV infection, high-risk circumstances for the development of MDRTB include exposure to a known case of MDR-TB; exposure to a person with active TB who has experienced treatment failure or relapse, exposure to active MDR-TB or travel in a known high-prevalence area; and exposure to a person whose sputum is still culture-positive after 2 months of combination chemotherapy. World-wide, it has been estimated that 9% of all new adult cases of TB (31% in Africa) in 2000 were associated with HIV infection, whereas 12% of deaths were so associated.2 Approximately 15,000 new cases of TB in the USA were reported to the US Centers for Disease Control and Prevention (CDC) during 2002,3 although the incidence is declining further after the immigration- and HIV-related increase of more than a decade ago (1985–1992). In 2004, only 14,511 confirmed TB cases were reported to the CDC, which was a 3.3% decrease from 2003.4 The rate of 4.9 cases/100,000 population was the lowest since reporting began in 1953.4 Most cases in the USA occur in foreign-born persons.4 Whereas the incidence of TB among US-born persons was recently only 2.6 cases/100,000 population, and continues to decrease, among foreign-born persons in the USA the rate is nearly ninefold higher (22.5 cases/100,000 population). Most clinical cases of TB occur due to reactivation of latent disease in a setting of impaired immunity such as HIV, aging, alcoholism or a major stressor such as trauma or major surgery.5 The normal rate of reactivation of latent disease is 0.2% per year;
however, in the presence of HIV infection it is 5% per year.5 Pulmonary infection is the usual initial clinical manifestation, with lymphatic or haematogenous spread of infection occurring subsequently. After inhalation, the pathogenesis of TB develops predictably. Alveolar bacteria grow freely or after phagocytosis by macrophages (usually subpleural, or mid-lung). Lympho-haematogenous spread of infected macrophages to mediastinal lymph nodes and extrapulmonary sites occurs subsequently. The cellular immune response (skin test positivity) usually takes 3–8 weeks to become manifest. With a high inoculum and a brisk immune response, necrosis of the primary complex will occur, leading to the typical caseating lung granuloma. Tuberculosis, which has protean manifestations and can affect almost any tissue or organ system (Box 50.1), has extrapulmonary manifestations in between one-fifth and one-quarter of cases.1 This percentage increases in the presence of HIV infection. Primary non-pulmonary TB is recognized, most often of the gastrointestinal tract, but the incidence has decreased markedly in developed countries where milk is pasteurized. Surgeons in developing countries treat patients with TB routinely. Surgeons in the developed world see patients with TB less frequently, but it is essential for them to recognize its manifestations, as untreated patients with active TB threaten public health. Surgeons may be asked to intervene to diagnose TB (e.g. tissue biopsy), treat it in conjunction with antimicrobial chemotherapy (e.g. resection of primary pulmonary MDR-TB) or to treat its complications (e.g. severe kyphosis of the spine). Unfortunately, many surgical manifestations are described only in case reports or small series, owing to their rarity. Moreover, surgical diagnostics and therapeutics for TB are seldom subjected to the rigor of a randomized, prospective trial. Reported experience, although largely uncontrolled, is substantive for management of pulmonary TB and its complications (the modern origins of thoracic surgery can be traced to the management of TB nearly a century ago), and for the management of TB of the spine; therefore this chapter will necessarily focus in those areas.
PULMONARY MANIFESTATIONS Surgery may assist with both the diagnosis and treatment of pulmonary TB. Diagnostic considerations for tuberculous mediastinal lymphadenitis are listed below. Lung histology obtained by transbronchial lung biopsy may identify TB in up to 58% of smearnegative cases.6 Percutaneous biopsy of parenchymal lesions may yield the diagnosis in up to 90% of cases, particularly if the target
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Box 50.1 Manifestations of tuberculosis that may require biopsy or surgical therapy
Cutaneous ○ Erythema nodosum ○ Metastatic skin infections (with severe immunocompromise) ○ Surgical site infection. Lymphadenopathy ○ Cervical ○ Mediastinal ○ Retroperitoneal. Abdomen ○ Abdominal wall abscess ○ Peritoneal involvement ○ Intestinal obstruction ○ Intestinal perforation ○ Diarrhoea ○ Gastrointestinal haemorrhage ○ Perirectal abscess ○ Perianal fistula. Solid organ tuberculoma (spleen, liver, pancreas, thyroid, breast). Thorax. Oesophagus ○ Mural abscess ○ Oesophago-pleural fistula. Lungs ○ Empyema ○ Cavernous tuberculoma ○ Bronchopleural fistula ○ Haemoptysis ○ Tuberculoma caused by multidrug-resistant pathogens. Pleura ○ Pleural effusion. Pericardium ○ Pericarditis. Genitourinary system ○ Haematuria ○ Granulomatous pyelonephritis ○ Chronic cystitis ○ Penile ulcers ○ Ureteral or urethral strictures ○ Scrotal masses ○ Epididymitis ○ Prostatitis ○ Endometritis. Musculoskeletal ○ Spinal (Pott’s disease) ○ Osteomyelitis (Poncet’s disease) ○ Arthritis ○ Infected total joint prosthesis. Vascular ○ Pseudoaneurysm ○ Arteriovenous fistula ○ Arterial thrombosis ○ Venous thrombosis. Neurological ○ Brain abscess (solitary or military) ○ Meningitis ○ Tuberculoma.
is a tuberculoma. If distinction from malignant disease is needed, video-assisted thoracoscopic surgery (VATS) may accomplish the task with reduced chest tube drainage, shorter hospital stay and less postoperative pain. Closed needle biopsy is established as the most useful procedure for the diagnosis of tuberculous pleuritis, but the
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yield is at most 80%;7 VATS may eventually supplant pleural biopsy as well. The surgical treatment of pulmonary TB provided the basis for the development of the field of thoracic surgery.8,9 Prior to the development of anti-TB drugs, pulmonary TB was treated surgically by opening the tuberculous cavity (‘cavern’) to air by a procedure called a cavernostomy. Subsequent to this, surgical attempts at reducing the volume of the affected lung or ‘collapse therapy’ were employed. Artificial pneumothorax was first advocated in 1822 by Carson.10 It was employed widely in the first half of the twentieth century, usually as an adjunct to bed rest. Artificial pneumothorax was ineffective in 25% of cases owing to an inability to establish or maintain lung collapse, probably secondary to the pleural adhesions characteristic of TB. The first thoracoscopic procedure, performed in 1912 by Jacobaeus using a modified cystoscope to lyse pulmonary adhesions, was the forerunner of today’s VATS procedures.11 Empyema complicated artificial pneumothorax in 20% of cases, which was abandoned when extrapleural pneumothorax (plombage) and more effective forms of collapse therapy were developed. Plombage was developed around the turn of the twentieth century to compress diseased lung.9 An apical extrapleural cavity was created and filled with air, or later with fat, paraffin, bone fragments, plastic spheres, gauze or oil, all with limited success. All such materials tended to migrate or become infected. In addition, large peripheral TB cavities tended to have a pleural-based blood supply, which, when divided during the plombage procedure, resulted often in necrosis, fistula formation and empyema. Thus, use of the extrapleural space was soon abandoned. Attempts to recreate plombage using the posterior subperiosteal extrapleural plane were perhaps more successful, but the advent of anti-TB chemotherapy made pulmonary resection possible, and extraperiosteal plombage was reserved for patients in whom resection was impossible. Thoracoplasty, or resection of multiple ribs to collapse underlying tuberculous cavities, was conceived in the 1880s for the management of empyema,9,12 and went through several iterations over a 50-year period as pulmonary physiology became better understood and mechanical ventilation became possible. Early attempts, resecting multiple ribs anteriorly or laterally, produced pulmonary dysfunction reminiscent of modern conceptions of flail chest caused by trauma. Wilms in 1873 reported on paravertebral thoracoplasty with mortality much lower than previously.13 Alexander, of the University of Michigan, is regarded as the modern father of thoracoplasty, having perfected (operative mortality 2%) the posterolateral method of thoracoplasty as a three- or four-stage procedure by 1935.12,14 However, as with plombage, modern chemotherapy made thoracoplasty obsolete for the management of TB. Although lung resection for bronchiectasis and carcinoma was already technically successful in the late nineteenth century, early results of resection for TB were disappointing. Although the operation had been described for TB in 1897, the mortality rate of pulmonary lobectomy for TB was reported to be 20% as late as 1940.15 After 1940, mass ligation of the pulmonary hilar vessels in favour of ligation of individual vessels made the operation a bit safer, but the problem of failed bronchial stump healing persisted, and the contralateral lung often became infected during surgery owing to lateral positioning and cross-contamination (split-lung ventilation techniques had yet to be developed). The 1945 introduction of streptomycin allowed resection of localized pulmonary
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TB with excellent results, but TB frequently has a regional rather than a lobar distribution within lung, making the disease less amenable to anatomic resection. Consequently, techniques of wedge resection and segmental resection were developed in addition to lobectomy and pneumonectomy. By the 1960s, chemotherapy had become so effective that resectional surgery for TB also seemed destined for the history books.9 However, the emergence of MDR strains has kept surgery as part of the armamentarium for pulmonary TB. Currently, the indications for surgery for pulmonary TB include: 1. MDR-TB;8,16 2. complications of TB such as bronchopleural fistula, haemoptysis, or empyema; and 3. when lesions in the lung are indistinguishable between cancer and tuberculoma. Airway strictures may be amenable to dilation and stenting.17 Some authors advocate a more liberal use of pulmonary resection for eradication of disease even when not caused by MDR pathogens, especially for persistent positive sputum (after 6 months of documented chemotherapy), as might be the case with a thick-walled abscess that impedes drug penetration; however, this is not employed in most locales. Atypical mycobacterial infections are also candidates for surgical resection. There are three principal selection criteria for surgical resection of MDR-TB.18,19 First, drug resistance must be so severe or extensive that medical therapy alone is highly likely to result in failure or relapse. Second, the disease must be sufficiently localized to permit resection with adequate residual pulmonary reserve (see below). Third, there must be sufficient drug activity (albeit possibly with second-line agents) to facilitate healing of the bronchial stump (see below). All patients must be evaluated preoperatively to ensure that their cardiovascular, pulmonary and nutritional status is sufficient to undergo major surgery, so as to minimize the potential for major complications (Box 50.2).19 Particular consideration is paid to performance of pulmonary function testing to establish that the patient will have adequate pulmonary reserve to enjoy a reasonably active lifestyle after surgery. If the patient will not have a residual forced expiratory volume (1 second; FEV1) of > 800 mL, resectional surgery should be a last resort. Bronchoscopy should be performed before surgery (in theatre, immediately preoperative, is acceptable)
Box 50.2 Thoracic complications of surgical therapy of pleuropulmonary tuberculosis
a
Acute respiratory failure. Atelectasis.a Bronchopleural fistula. Empyema. Haemorrhage. Persistent intrapleural cavity. Pleural effusion.a Pulmonary embolism. Pulmonary hypertension. Recurrent laryngeal nerve injury. Superficial surgical site infection.a Wound dehiscence. Minor complication.
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to determine that no endobronchial lesion exists (e.g. tuberculous bronchitis); endobronchial disease increases substantially the risk of postoperative bronchial stump dehiscence and bronchopleural fistula.20 A dual-lumen endotracheal tube with an endobronchial blocker facilitates surgery by collapsing the affected lung while permitting ventilation of the contralateral lung without the risk of contamination. Patients must receive chemotherapy prior to therapeutic surgery, usually for a minimum of 3 months.21 Ideally, patients will be rendered sputum culture-negative prior to surgery. If positive sputum cultures persist, the patient probably has MDR-TB. A more urgent operation may be required for massive haemoptysis or bronchopleural fistula. The therapeutic surgical goal is to excise all gross disease, whether by wedge or segmental resection (in some cases), lobectomy or pneumonectomy.9 Lesions amenable to wedge resection must be less than 3 cm in maximum diameter, and either be located in the peripheral one-third of lung parenchyma or be close to a major fissure. Pneumonectomy should be performed only if the entire lung is involved or if the remaining lung will be too small in volume to expand to fill the hemithorax. Dense adhesions often make dissection easier in the extrapleural plane, especially at the apex of the lung, but the subclavian vessels and brachial plexus are at risk in that dissection plane. Resection has been reported in several series to have an operative mortality rate of 0–4%, and a postoperative complication rate of 9–26%.19,22,23 After induction of general anaesthesia, bronchoscopy is performed. After bronchoscopy, the single-lumen endotracheal tube is changed to a double-lumen tube, with the position verified by repeat bronchoscopy. The patient is positioned for a formal fifthinterspace posterolateral thoracotomy, with careful attention to padding and avoiding pressure points during what is often a prolonged operation. Rib resection may be necessary for adequate exposure. Muscle-sparing thoracotomy with preservation of muscle for flaps is ideal for thoracotomy for TB. The serratus anterior and latissimus dorsi muscles are elevated and preserved if possible; the latter muscle is a useful flap for protecting the bronchial stump closure (Figs 50.1–50.4).20 Indications for a muscle flap include persistent sputum positivity at the time of surgery, bronchopleural fistula and anticipation of a residual space after lobectomy.22 Extrapleural dissection may be performed if intrapleural adhesions are extensive, as is common. A latissimus dorsi flap is created by freeing it from its extensive origin along the spine and the posterior iliac crest to its insertion on the humerus, preserving its blood supply in the form of the thoracodorsal artery. After complete mobilization, the muscle is transected inferiorly and brought superiorly on its humeral attachment (Fig. 50.2). It may be necessary to resect a 2to 3-cm portion of the anterior second or third rib to facilitate passage of the muscle into the hemithorax (Fig. 50.3). The muscle is sutured to the bronchial stump and hilum (Fig. 50.4), with the remaining muscle used to fill as much space as possible, if needed. If the latissimus dorsi was divided during a previous thoracotomy, a pedicle of gastrocolic omentum based on the right gastroepiploic artery can be harvested by coeliotomy with the patient supine before the thoracotomy is started. As another alternative, the first rib can be resected to collapse a small apical cavity after upper lobectomy.20
EMPYEMA Uncomplicated pleural effusion secondary to pulmonary TB usually responds to chemotherapy; tube thoracostomy is therefore
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3
Latissimus dorsi muscle
Fig. 50.3 The latissimus dorsi flap is passed through the third interspace to be positioned at the hilum to buttress the bronchial stump closure. Reprinted from Pomerantz L, Mitchell JD. Surgery of pulmonary mycobacterial disease. In Kaiser L, Kron IL, Spray TL, eds. Mastery of thoracic surgery. Second edition. Philadelphia, Lippincott, Williams & Wilkins 2007:295–300.
Fig. 50.1 The outline of the latissimus dorsi muscle is shown with the patient positioned for right posterolatereral thoracotomy. Reprinted from Pomerantz L, Mitchell JD. Surgery of pulmonary mycobacterial disease. In Kaiser L, Kron IL, Spray TL, eds. Mastery of thoracic surgery. Second edition. Philadelphia, Lippincott, Williams & Wilkins 2007:295–300.
Fig. 50.4 The latissimus dorsi flap is being sutured to the right mainstem bronchus after a pneumonectomy. Reprinted from Pomerantz L, Mitchell JD. Surgery of pulmonary mycobacterial disease. In Kaiser L, Kron IL, Spray TL, eds. Mastery of thoracic surgery. Second edition. Philadelphia, Lippincott, Williams & Wilkins 2007:295–300.
Fig. 50.2 Lung parenchyma is visible through a right fifth-interspace posterolateral thoracotomy. The latissimus dorsi muscle has been mobilized as a pedicle flap on its humeral insertion. A portion of the third rib (3) has been resected to facilitate positioning of the flap within the right hemithorax. Reprinted from Pomerantz L, Mitchell JD. Surgery of pulmonary mycobacterial disease. In Kaiser L, Kron IL, Spray TL, eds. Mastery of thoracic surgery. Second edition. Philadelphia, Lippincott, Williams & Wilkins 2007:295–300.
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contraindicated. In contradistinction, surgical intervention is usually required for tuberculous empyema. Empyema usually results from bronchopleural fistula, leading to direct inoculation of the pleural cavity. Secondary infection of the pleural cavity may also occur after collapse therapy. Thick pus and dense encapsulation make medical management challenging and seldom successful; the risk of induced drug resistance is increased. Tube thoracostomy
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has a limited role, unless the patient is unfit for surgery.19 Decortication is indicated when thoracocentesis fails to yield fluid or does not change the radiographic appearance, the extent of pleural involvement is equivalent to at least one-quarter of the pleural surface and it is believed that the residual lung will re-expand.20 Decortication should be undertaken relatively soon after the patient has received the requisite chemotherapy. Surgical decortication by VATS is the procedure of choice at present, regardless of the aetiology of the empyema, if the empyema is diagnosed early; otherwise, established fibrosis will require a thoracotomy. When the decorticated lung cannot expand to fill the entire hemithorax, the Eloesser-type technique (window thoracotomy) is recommended to allow mechanical toilet followed by thoracoplasty and myoplasty.24 Although this approach is successful in controlling infection (and the underlying bronchopleural fistula), a decrement of lung function is the price paid. If possible, decortication followed by cavity obliteration by collapsing the parietal wall without rib resection may preserve lung function better while also enhancing cosmesis. Decortication is technically impossible after a window thoracotomy or thoracoplasty.
SPINAL TUBERCULOSIS Tuberculous involvement of the spine has been known since the time of Hippocrates. Prior to the advent of antimicrobial therapy, the treatment of TB of the spine was bed rest, often in a plaster cast, with attention to diet and exposure to sunlight and fresh air. Posterior laminectomy for debridement was the mainstay of therapy in the late 1800s, but was unsatisfactory because anterior disease was not addressed and spinal instability was increased. Posterior fusion, introduced in 1911, did not prevent progression of kyphosis or address the lesion that caused paralysis, and was soon abandoned.25 Tuberculosis of the spine is by far the most common granulomatous infection affecting the spine,26 which may also be caused by fungi or bacteria of the order Actinomycetales (e.g. Actinomyces, Arachnia and Nocardia). Tuberculosis affecting bone is uncommon, representing 5–10% of cases of TB. Fifty per cent of these cases affect the spine. The incidence varies widely world-wide, being far more common in less developed countries where public health services are rudimentary. In affluent countries, the incidence has decreased markedly in the past 30 years, and tuberculous spondylitis is now rare. Spinal TB may occur from haematogenous spread from extraaxial primary lesions, which may be quiescent.26 Pulmonary and genitourinary sources are the most common source of bacteraemia. Spinal TB may also arise from other skeletal lesions, or from direct extension from visceral lesions (e.g. perforation of intestinal TB into the retroperitoneum). The typical lesion in the spine from TB is infection of the vertebral body with associated destruction that produces kyphosis.25 Although disease is too extensive to permit localization in more than 50% of cases, there are three major localized types: peridiscal (33%), central (12%) and anterior (2%).25 Less common manifestations include tracking of abscess along the psoas muscle or in the spinal canal without bony involvement.27 Complications of spinal TB most commonly present as paraplegia; a neurological deficit may develop in up to one-half of cases of spinal TB, being more common in older children and adults than in children under 10 years of age. Acute paraplegia may arise from direct pressure on the spinal cord from an epidural granuloma or abscess, from sequestered bone and disc or from pathological subluxation or
50
dislocation of bone. In chronic cases, pressure on the cord may result from epidural granuloma, from fibrosis or by a ridge of bone protruding as a result of progressive kyphosis. Epidural granuloma is analogous to a pyogenic abscess. Most commonly the granuloma arises directly from adjacent infected bone, usually anteriorly (90%). Epidural granuloma without bony involvement, arising by direct haematogenous seeding, is reported but rare, as are other non-bony causes of neurological deficits (e.g. intradural tuberculoma, tuberculous arachnoiditis).26 Secondary pyogenic bacterial infection may occur through sinus tracts or as a complication of surgical debridement. Presenting manifestations are variable.25 Classically, spine pain is accompanied by weight loss, malaise and fever. Tenderness, spinal deformity and neurological deficits may be appreciated by physical examination. The location of pain correlates with the level of involvement, most commonly of the thoracic spine, less commonly of the lumbar spine and rarely of sacrum or cervical spine. Patients may present with an abscess in one of many locations, including the groin or buttock. Children under the age of 10 years tend to have more extensive disease with large abscesses but a lower (20%) incidence of paraplegia, whereas adults have more localized disease, less pus, but a much higher incidence of paraplegia (80%). Diagnostic certainty is achieved only by biopsy and culture, or occasionally after aspiration or drainage of an abscess; unfortunately, the sensitivity of culture is low and reporting may take weeks. Findings on plain radiographs vary depending on the pathological type and chronicity of infection.25 Peridiscal involvement (more common in lumbar spine) may cause disc space narrowing with bone destruction thereafter, similar to pyogenic infection. Central involvement (more common in thoracic spine) has the appearance of neoplasm, with bony destruction followed by collapse. The earliest manifestation may be rarefaction of bone regardless of type. Radionuclide imaging is insensitive for TB of the spine, whereas computed tomography can delineate soft-tissue and bony changes.25 Granulation tissue cannot be distinguished from an abscess. Magnetic resonance imaging is therefore the imaging modality of choice. Antituberculosis chemotherapy has made surgery less necessary for patients with TB of the spine,28 and lowered the mortality rate of indicated surgery by 90% or more,26 by reducing the risk of dissemination and the development of chronic sinuses. Among ambulatory patients, randomized trials demonstrate equivalent results for chemotherapy and surgical debridement.25 Surgery in these patients is commonly reserved for when biopsy is required or for the management of neurological impairment, abscesses or sinuses. Among patients with neurological impairment, surgery is indicated in several subgroups of patients.25 First, in those whose neurological deficits are severe or when mild defects worsen while receiving therapy; second, those patients with acute infection and paraplegia due to vertebral collapse; and third, those patients who have had TB treated and subsequently have spinal cord compression from a gibbus in the spinal canal. Additional indications for surgery include failure to respond to appropriate chemotherapy, instability after healing or recurrence of disease or of neurological complications.25 Chemotherapy is indicated in all surgical cases except for late-onset paraplegia from progressive deformity in the presence of healed, inactive disease. Chemotherapy is usually started preoperatively, but may be started after surgery when biopsy is needed. An operation may be performed to drain abscesses, debride sequestered bone and disc, decompress the spinal cord or stabilize the spine. Early operation is less technically demanding.25,26
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Infections tend to dissect along natural tissue planes, and the fibrosis associated with more protracted infection is more difficult to dissect. Some evidence suggests that the prognosis for neurological recovery is correlated inversely with the duration of neurological symptoms, also arguing for earlier operation.25 Drainage of a tuberculous abscess was described first by Pott in 1779. In general, abscess drainage is indicated for large lesions, sepsis or a neurological deficit. Paravertebral abscess of the thoracic spine can be drained effectively by a costotransversectomy, whereas psoas abscess can be drained via a retroperitoneal/flank approach. Retropharyngeal abscess has been reported to complicate TB of the cervical spine, and can be drained transorally when arising from C1 or C2,29 or through the anterior or posterior of the neck when arising from the lower cervical spine, depending on the presentation. Incisions may be closed in layers or left open at the discretion of the surgeon. Simple debridement of the spine, still advocated by some, has largely been supplanted by anterior radical debridement and strut graft fusion (the Hong Kong operation).25 An anterior approach allows the most affected area to be dealt with directly. Sequestered bone and caseous material are debrided back to bone above, below and back to the posterior longitudinal ligament, or into the dura in cases of neurological impairment when spinal cord decompression is indicated. Insertion of the strut graft corrects angular deformity. Autogenous bone graft (usually harvested from ribs or, ideally, iliac crest) at the time of primary debridement is effective; fusion with bone grafting is more likely to lead to stable bony fusion (at 10 years) than either debridement with chemotherapy or medical management alone. Operative mortality is proportional to the degree of neurological impairment, ranging from 2% for mild defects to 10% for severe impairment.30 In general, children enjoy a better prognosis than adults. The thoracic spine may be approached via costotransversectomy, transpleural approach or anterolateral extrapleural approach. No studies have demonstrated an advantage to the extrapleural approach versus a thoracotomy, but either is probably superior to costotransversectomy. Isolated reports of VATS for thoracic spine TB are appearing,31 but whether the approach is additive to knowledge and experience, or merely a technical tour de force, remains to be determined. Laminectomy (posterior approach) for TB, first described by McCuen in 1882, has been largely abandoned owing to instability and further risk of neurological injury, and is now believed to be contraindicated by most authorities in most circumstances. Although immediate relief is afforded and the approach is advocated by some,32 paraplegia recurs without rigid fixation; even if posterior fusion is performed, progressive kyphosis may not be controlled. Rare cases of involvement of the neural arch causing posterior cord compression or posterior epidural tuberculoma may be amenable to laminectomy. Disease of the cervical spine merits special consideration.33 The incidence of cord compression is very high (40%), especially in adults, and aggressive management is required. The principles are similar to those outlined for the Hong Kong approach. Disease of C1–C2 may be approached transorally with or without a posterior occiput-to-C2 fusion. Lesions of C3–C7 may be approached through either the anterior or posterior triangle of the neck, with the latter possibly preferred because abscesses may track there preferentially. Cervical disease complicated by kyphosis may require staged procedures. Anterior reconstruction should be followed by posterior stabilization and fusion. Cervical laminectomy is contraindicated because subluxation and further neurological deficits may occur.
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ABDOMINAL TUBERCULOSIS It has been estimated that 80% of patients who die of pulmonary TB will have some form of abdominal involvement. The most common forms of abdominal TB are tuberculous peritonitis, intra-abdominal lymphadenopathy and ileocaecal disease (which may cause obstruction, perforation with superimposed bacterial peritonitis or haemorrhage), although involvement of nearly every intra-abdominal organ has been reported. Intra-abdominal organs may acquire TB by haematogenous spread during the initial bacteraemic phase, or secondarily by ingestion of infected sputum or milk. The bacteria then stimulate inflammatory reactions in lymphoid tissue and submucosal tissue, such as Peyer’s patches, to produce the diagnostic caseating granulomas. Most cases of abdominal TB can be treated medically if found early; most surgical interventions are limited to diagnostic procedures or treatment of complications. The abdominal manifestations of abdominal TB are protean.34–38 The most common abdominal manifestation of TB is tuberculous peritonitis, which is manifest by ascites in 97% of cases.34 The most common symptoms are increased abdominal girth, fever and weight loss.34 Diagnostic staining of ascitic fluid reveals acid-fast bacilli initially in only 25% of patients; however, culture is diagnostic in 83% of patients but requires 1 L of peritoneal fluid.34 An ascitic fluid/blood glucose ratio of less than 0.96 helps to distinguish TB from other causes of ascites. Adenosine deaminase concentrations above 30 U/L have 93% sensitivity and 96% specificity for diagnosing tuberculous ascites. Upon inspection of the peritoneum at laparotomy or laparoscopy, thickening of the peritoneum and studding with tubercles is found. Multiple fibrous adhesions and thickened omentum or bowel can also be seen, leading to potential misdiagnosis as carcinomatosis.39 In such patients, abdominal pain, anorexia and weight loss may be the presenting symptoms. Intestinal involvement by TB most commonly occurs in the ileum or ileocaecal area; however, any area of the gastrointestinal tract has the potential for infection. Gastroduodenal involvement presents most commonly with gastric outlet obstruction.40 Tuberculosis of the oesophagus is rare, but has been reported to cause intramural abscess formation, and pneumopericardium from oesophago-pericardial fistula.41,42 The most common symptoms caused by intestinal involvement are abdominal pain, weight loss and diarrhoea. Often the pain is located in the right lower quadrant mimicking acute appendicitis. There are three main pathological manifestations of intestinal TB. Hyperplastic lesions occur as a result of intense inflammatory reactions in the submucosal lymphoid tissue. This leads to thickened bowel wall and can result in intestinal obstruction.43 Tuberculosis has been reported to be the cause of 1.1% of primary cases of appendicitis in India.44 Isolated perianal disease has been reported.45 Ulcerogenic lesions can occur anywhere in the gastrointestinal tract and are often in ‘skip’ patterns.46 These lesions often are the cause of gastrointestinal bleeding in these patients. Sclerotic lesions occur after stimulation of fibrotic reactions in the intestinal wall, producing single or multiple strictures that can be reminiscent of Crohn’s disease.47 Perforation of any tuberculous intestinal lesion is possible, leading to superimposed bacterial peritonitis.27,38 Lymph nodes can also be enlarged in both the mesentery and retroperitoneum, with no other signs of abdominal involvement by TB. This clinical picture may be similar to lymphoma or regional metastasis from carcinoma of the pancreas, or may manifest as intestinal obstruction due to extrinsic compression. Fine
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needle aspiration (FNA), either percutaneously or endoscopically assisted, or laparoscopy-assisted methods may all be used to obtain samples for diagnosis. Solid organs such as the liver, spleen or pancreas also can be affected by tuberculomas or abscesses, including transplanted solid organs (as a consequence of therapeutic immunosuppression).48,49 Evidence suggests that the transplant candidate with skin test positivity can be treated safely with isoniazid and rifampicin without harm to organ function (a particular concern for patients with tenuous hepatic function who are awaiting liver transplantation).50 Likewise, the incidence of active TB following therapeutic immunosuppression for solid organ transplantation has been estimated to be 2%, but therapy is safe for organ function.51–53
GENITOURINARY MANIFESTATIONS Genitourinary involvement by TB is common, constituting about 30% of non-pulmonary TB. Tuberculosis can produce necrosis of the adrenal glands with adrenal insufficiency, which may be diagnosed radiographically as calcifications in the adrenal glands. Involvement of the kidney by TB may produce haematuria, ‘sterile’ pyuria or renal failure. Renal failure may be caused either by intrinsic infection of the renal parenchyma or by obstructive uropathy.54 The obstructive uropathy is caused by fibrotic strictures of the ureter and collecting system. Bladder dysfunction may occur secondary to ulceration of the urothelium with formation of ulcers and fibrosis of the underlying muscle. Infection of the male sexual reproductive organs may produce infertility. Tuberculosis may produce tuberculous epididymitis with painful scrotal masses. In the female genital tract, tuberculous endometritis is reported as a cause of vaginal bleeding,55,56 often requiring hysterectomy for treatment. The diagnosis of TB in the genitourinary system can be identified by cultures, which may take 6–8 weeks to yield organisms. Surgical treatment of urinary tract TB includes procedures to drain hydronephrosis such as percutaneous nephrostomy or ureteral stenting, drainage of abscess, urethral reconstruction and occasional partial nephrectomy.
TUBERCULOUS LYMPHADENITIS Tuberculous lymphadenitis accounts for a large proportion of lymphadenopathy in endemic countries.1 In the West, TB-associated lymphadenopathy is observed most frequently in patients with HIV infection. The cervical lymph nodes are affected most frequently in both HIV-infected and -uninfected populations, accounting for 67–90% of cases. The diagnosis can be made by FNA in approximately 85% of cases. Complete resolution of symptoms and adenopathy can be achieved in 65–74% of patients with oral antimicrobial therapy. Importantly, complications of chronic wounds and draining sinuses can occur after biopsy of a tuberculous lymph node, and can be avoided by performing the least invasive procedure to obtain a diagnosis.57–59 Drains should not be used postoperatively. Histological confirmation is required most commonly for mediastinal lymphadenopathy in the immunocompromised host. Fibreoptic bronchoscopic transbronchial needle biopsy is an encouraging development,60 but, until its role is defined completely, nodal sampling via mediastinoscopy or mediastinotomy will continue to play a role.61 Experience with VATS for the diagnosis of TB remains limited.62
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CARDIOVASCULAR MANIFESTATIONS Vascular involvement by TB occurs most commonly after direct extension of pulmonary TB. Tuberculous pseudoaneurysm of the aorta has been reported,63,64 as has its successful repair by open and endovascular techniques.65,66 False aneurysms of the pulmonary artery, supracoeliac aorta and the femoral artery have also been reported.67–69 Unfortunately, these false aneurysms can rupture with serious consequences, depending on location;70–72 tuberculous aortoenteric fistula with recurrent gastrointestinal haemorrhage has been reported, as has psoas abscess and palsy of the recurrent laryngeal nerve.70–72 Tuberculosis may induce a hypercoagulable state characterized by acquired protein S deficiency.73 Both aortic and venous thrombotic disease without direct involvement of the vessel by a tuberculoma have been reported,73,74 although direct extension has also been reported to cause venous thrombosis.75 Tuberculosis may also involve the pericardium primarily.42,76
MISCELLANEOUS MANIFESTATIONS OF SURGICAL RELEVANCE Neurological manifestations other than spinal cord involvement have been reported. Mass lesions may be recognized as brain abscess or may mimic neoplasm.77,78 As with the systemic circulation, extrinsic disease has been reported to cause venous thrombosis, for example of the sagittal sinus.79 Reports of primary infection of soft tissue (e.g. salivary glands, thyroid, breast)80,81 are numerous, but too scattered to allow definitive recommendations for surgical therapy, which must be individualized. Tuberculosis can also cause surgical site infection on a delayed basis, or infect previously implanted orthopaedic hip or knee prostheses.82,83 Several reports describe tuberculous deep incisional surgical site infection of the sternum following coronary artery bypass grafting.84,85 In none of these cases was there a history of active or recently treated TB, highlighting that the tubercle bacillus can become established in the hypoxic, ischaemic milieu of the fresh or remotely created surgical incision in the aftermath of major surgical stress.
PRECAUTIONS FOR THE SURGICAL STAFF Hospital workers have an increased risk of infection with TB due to the increased likelihood of exposure to infected patients. The most common mode of transmission is through infected droplet nuclei produced by coughing. Particles larger than 5 mm are unlikely to reach an alveolar location suitable for attachment and granuloma formation. However, reports exist of transmission of TB to healthcare workers through exposure to body fluids in theatre as well as at autopsy.86,87 The first step to assuring the safety of healthcare personnel in theatre is an appropriate assessment of the risk posed by the patient. This includes a thorough history of cough and vaccinations, and assessment of risk factors such as HIV infection. Also, in those patients with a prior history of TB treatment, confirmation that the patient is no longer infectious is required unless the surgery is an emergency or for MDR-TB that cannot be eradicated medically. If a patient has been treated previously for TB, three negative sputum specimens and clinical improvement indicates a non-infectious
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88,89
Box 50.3 Guidelines for prevention of transmission of tuberculosis to theatre and perioperative personnel
Educate and train all operating room (OR) personnel regarding TB exposure and transmission. Adequately assess patient risk. Patients suspected of TB infection should wear masks during transport to theatre.a Minimize theatre staff if possible. Schedule as last case of the day. Delay elective procedures if possible until patient becomes non-transmissible. Use a theatre with an anteroom if possible. Respiratory protection for theatre staff is mandatory – masks to be used should not be valve masks, but must meet US Centers for Disease Control and Prevention (CDC) and Occupational Health and Safety Administration (OSHA) standards. Avoid or minimize procedures with a high risk of transmission, such as bronchoscopy, endotracheal intubation or suctioning. Hold postoperative recovery in negative-pressure isolation rooms. A high-efficiency particulate air (HEPA) filter should be placed between patient and anaesthesia apparatus to prevent contamination of equipment.b
a Surgical masks are appropriate for preventing release of droplet nuclei. Infected patients do not need to wear particulate masks, as they do not need to protect themselves. Also, valve masks are inappropriate. b HEPA Corp., Anaheim, CA; http://www.hepa.com Adapted from Tait AR. Occupational transmission of tuberculosis: implications for anesthesiologists. Anesth Analg. 1997;85:444–451 and Centers for Disease Control and Prevention. Guidelines for preventing transmission of Mycobacterium tuberculosis in health care facilities. MMWR 1994;43:1.
patient.88–90 The suggested guidelines for prevention of TB transmission are listed in Box 50.3. Elimination of TB in the USA will require incremental improvement in laboratory services to support diagnosis and treatment, prevention and control. An integrated system would ensure prompt and reliable laboratory testing and flow of information among laboratories, clinicians and infection control officials.91 Challenges to the creation of such a system are several, including establishment of lines of communication, expedited reporting of laboratory results, evidence-based implementation of new laboratory tests, maintaining proficiency of staff and laboratory expertise considering the decreasing numbers of specimens for testing and upgrading laboratory information systems.
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CONCLUSIONS Most forms of TB are managed by administration of a multidrug regimen of oral antimicrobial agents (isoniazid, rifampicin, ethambutol, pyrizanimide).92 However, there are several instances in which a surgeon may come in contact with a patient who has TB, either to establish the diagnosis or to treat a complication of infection. Surgeons everywhere must be aware of the signs and symptoms of TB, and have some level of suspicion in certain patients. Effective mechanisms are in place in most medical centres to prevent the transmission of TB to healthcare workers and to other patients. An understanding of the mode and risk of transmission of TB is mandatory for all practising surgeons.
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prospective clinical study. J Neurosurg Spine 2007;6:222–228. Kamath MP, Bhojwani KM, Kamath SU, et al. Tuberculous retropharyngeal abscess. Ear Nose Throat J 2007;86:236–237. Karaeminogullari O, Aydinli U, Ozerdemoglu R, et al. Tuberculosis of the lumbar spine: outcomes after combined treatment of two-drug therapy and surgery. Orthopedics 2007;30:55–59. Jayaswal A, Upendra B, Ahmed A, et al. Videoassisted thoracoscopic anterior surgery for tuberculous spondylitis. Clin Orthop Relat Res 2007;460:100–107. Lee JS, Moon KP, Kim SJ, et al. Posterior lumbar interbody fusion and posterior instrumentation in the surgical management of lumbar tuberculous spondylitis. J Bone Joint Surg Br 2007;89:210–214. Moon MS, Moon JL, Kim SS, et al. Treatment of tuberculosis of the cervical spine: operative versus nonoperative. Clin Orthop Relat Res 2007;460:67–77. Aston NO. Abdominal tuberculosis. World J Surg 1997;21:492–499. Ibrahim M, Osoba AO. Abdominal tuberculosis: Ongoing challenge to gastroenterologists. Saudi Med J 2005;26:274–280. Badaoui E, Berney T, Kaiser L, et al. Surgical presentation of abdominal tuberculosis: a protean disease. Hepatogastroenterology 2000;47:751–755. Ohene-Yeboah M. Case series of acute presentation of abdominal TB in Ghana. Trop Doct 2006; 36:241–243. Clarke DL, Thomson SR, Bissetty T, et al. A single surgical unit’s experience with abdominal tuberculosis in the HIV/AIDS ERA. World J Surg 2007; 31:1087–1096. Geisler JP, Crook DE, Geisler HE, et al. The great imitator: Miliary peritoneal tuberculosis mimicking stage III ovarian cancer. Eur J Gynaecol Oncol 2000;21:115–116. Rao YG, Pande GK, Sahni P, et al. Gastroduodenal tuberculosis management guidelines, based on a large experience and a review of the literature. Can J Surg 2004;47:364–368. Eroglu A, Kurkcuoglu C, Karaoglanoglu N, et al. Esophageal tuberculosis abscess: An unusual cause of dysphagia. Dis Esophagus 2002;15:93–95. Al-Ajmi J, Al-Soub H, El-Deeb Y. Pyopneumopericardium due to esophago-pericardial fistula in patient with tuberculous pericarditis. Saudi Med J 2007;28:969–970. Brandt MM, Bogner PN, Franklin GA. Intestinal tuberculosis presenting as a bowel obstruction. Am J Surg 2002;183:290–291. Agarwal P, Sharma D, Agarwal A, et al. Tuberculous appendicitis in India. Trop Doct 2004;34:36–38. Akgun E, Tekin F, Ersin S, et al. Isolated perianal tuberculosis. Neth J Med 2005;63:115–117. Engin G, Balk E. Imaging findings of intestinal tuberculosis. J Comput Assist Tomogr 2005;29:37–41. Sibartie V, Kirwan WO, O’Mahony S, et al. Intestinal tuberculosis mimicking Crohn’s disease: Lessons relearned in a new era. Eur J Gastroenterol Hepatol 2007;19:347–349. Saluja SS, Ray S, Pal S, et al. Hepatobiliary and pancreatic tuberculosis: A two decade experience. BMC Surg 2007;7:10. Koseoglu F, Emiroglu R, Karakayali H, et al. Prevalence of mycobacterial infection in solid organ transplant recipients. Transplant Proc 2001; 33:1782–1784. Jahng AW, Tran T, Bui L, et al. Safety of treatment of latent tuberculosis infection in compensated cirrhotic patients during transplant candidacy period. Transplantation 2007;83:1557–1562. Malhotra KK. Challenge of tuberculosis in renal transplantation. Transplant Proc 2007;39:756–758.
52. Chan AC, Lo CM, Ng KK, et al. Implications for management of Mycobacterium tuberculosis infection in adult-to-adult live donor liver transplantation. Liver Int 2007;27:81–85. 53. Avery RK. Infections after lung transplantation. Semin Respir Crit Care Med 2006;27:544–551. 54. Wise GJ, Marella VK. Genitourinary manifestations of tuberculosis. Urol Clin North Am 2003;30:111–121. 55. Mengistu Z, Engh V, Melby KK, et al. Postmenopausal vaginal bleeding caused by endometrial tuberculosis. Acta Obstet Gynecol Scand 2007;86:631–632. 56. Sabadell J, Castellvi J, Baro F. Tuberculous endometritis presenting as postmenopausal bleeding. Int J Gynaecol Obstet 2007;96:203–204. 57. Subrahmanyam M. Role of surgery and chemotherapy for peripheral lymph node tuberculosis. Br J Surg 1993;80:1547–1548. 58. Ammari FF, Bani Hani AH, Ghariebeh KI. Tuberculosis of the lymph glands of the neck: A limited role for surgery. Otolaryngol Head Neck Surg 2003;128:576–580. 59. Schoch OD, Rieder P, Tueller C, et al. Diagnostic yield of sputum, induced sputum, and bronchoscopy after radiologic tuberculosis screening. Am J Respir Crit Care Med 2007;175:80–86. 60. Cetinkaya E, Yildiz P, Kadakai F, et al. Transbronchial needle aspiration in the diagnosis of intrathoracic lymphadenopathy. Respiration 2002;69:335–338. 61. Langdale LA, Meissner M, Nolan C, et al. Tuberculosis and the surgeon. Am J Surg 1992; 163:505–509. 62. De Montpreville VT, Dulmet EM, Nashashibi N. Frozen section diagnosis and surgical biopsy of lymph nodes, tumors, and pseudotumors of the mediastinum. Eur J Cardiothorac Surg 1998; 13:190–195. 63. Aebert H, Birnbaum DE. Tuberculous pseudoaneurysms of the aortic arch. J Thorac Cardiovasc Surg 2003;125:411–412. 64. Jain AK, Chauhan RS, Dhammi IK, et al. Tubercular pseudoaneurysm of aorta: A rare association with vertebral tuberculosis. Spine J 2007;7:249–253. 65. Suresh K, Kurian VM, Madhu Sankar N, et al. Repair of tuberculous aneurysm of distal aortic arch. Asian Cardiovasc Thorac Ann 2003;11:346–348. 66. Loh YJ, Tay KH, Mathew S, et al. Endovascular stent graft treatment of leaking thoracic aortic tuberculous pseudoaneurysm. Singapore Med J 2007;48:e193–e195. 67. Fatimi SH, Javed MA, Ahmad U, et al. Tuberculous hilar lymph nodes leading to tracheopulmonary artery fistula and pseudoaneurysm of pulmonary artery. Ann Thorac Surg 2006;82:e35–e36. 68. Forbes TL, Harris JR, Nie RG, et al. Tuberculous aneurysm of the supraceliac aorta-a case report. Vasc Endovasc Surg 2004;38:93–97. 69. Lagattolla NR, Baghai M, Biswas S, et al. Tuberculous false aneurysm of the femoral artery managed by endoluminal stent graft insertion. Eur J Vasc Endovasc Surg 2000;19:440–442. 70. Bailey C, Toner A, Nottingham J, et al. Recurrent laryngeal nerve palsy, dysphagia, and aortic fistula. J R Soc Med 2004;97:588–589. 71. de Kruijf EJ, van Rijn AB, Koelma IA, et al. Tuberculous aortitis with an aortoduodenal fistula presenting as recurrent gastrointestinal bleeding. Clin Infect Dis 2000;31:841–842. 72. Hsu RB, Lin FY. Psoas abscess in patients with an infected aortic aneurysm. J Vasc Surg 2007; 46:230–235. 73. Casanova-Roman M, Rios J, Sanchez-Porto A, et al. Deep venous thrombosis associated with pulmonary tuberculosis and transient protein S deficiency. Scand J Infect Dis 2002;34:393–394.
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74. Vaideeswar P, Deshpande JR. Non-atherosclerotic aorto-arterial thrombosis: A study of 30 cases at autopsy. J Postgrad Med 2001;47:8–14. 75. Takeuchi HM, Suzuki M, Unno M, et al. Splenic vein occlusion secondary to tuberculous lymphadenitis of the splenic hilum: report of a case. Surg Today 2000;30:383–385. 76. Cury PM, Linhares MJ, Fiorelli AI, et al. Perioperative myocardial infarction in a patient with tuberculous constrictive pericarditis in the absence of coronary artery disease. J Cardiovasc Surg 2001;42:57–59. 77. Gump WC, Summers LE, Walsh JW. Tuberculosis infection presenting as brain abscess in an immunocompromised host. J La State Med Soc 2006;158:292–295. 78. Yilmazlar S, Bekar A, Taskapilioglu O, et al. Isolated intrasellar tuberculoma mimicking pituitary adenoma. J Clin Neurosci 2007;14:477–481. 79. Sundaram PK, Sayed F. Superior sagittal sinus thrombosis caused by calvarial tuberculosis: Case report. Neurosurgery 2007;60:E776. 80. Terzidis K, Tourli P, Kiapekou E, et al. Thyroid tuberculosis. Hormones (Athens) 2007;6:75–79. 81. Bakaris S, Yuksel M, Ciragil P, et al. Granulomatous mastitis including breast tuberculosis and idiopathic lobular granulomatous mastitis. Can J Surg 2006;49:427–430. 82. Shanbhag V, Kotwal R, Gaitonde A, et al. Total hip replacement infected with Mycobacterium tuberculosis. A case report with review of literature. Acta Orthop Belg 2007;73:268–274. 83. Wang PH, Shih KS, Tsai CC, et al. Pulmonary tuberculosis with delayed tuberculosis infection of total knee arthroplasty. J Formos Med Assoc 2007; 106:82–85. 84. Gopal K, Raj A, Rajesh MR, et al. Sternal tuberculosis after sternotomy for coronary artery bypass surgery: a case report and review of the literature. J Thorac Cardiovasc Surg 2007; 133:1365–1368. 85. Wang TK, Wong CF, Au WK, et al. Mycobacterium tuberculosis sternal wound infection after open heart surgery: a case report and review of the literature. Diagn Microbiol Infect Dis 2007;58:245–249. 86. D’Agata EM, Wise S, Stewart A, Lefkowitz LB Jr. Nosocomial transmission of Mycobacterium tuberculosis from an extrapulmonary site. Infect Control Hosp Epidemiol 2001;22:10–12. 87. Hutton MD, Stead WW, Cauthen GM, et al. Nosocomial transmission of tuberculosis associated with a draining abscess. J Infect Dis 1990;161: 286–295. 88. Tait AR. Occupational transmission of tuberculosis: implications for anesthesiologists. Anesth Analg 1997;85:444–451. 89. Centers for Disease Control and Prevention. Guidelines for preventing transmission of Mycobacterium tuberculosis in health care facilities. MMWR Morb Mortal Wkly Rep 1994;43:1. 90. Hannan MM, Azadian BS, Gazzard BG, et al. Hospital infection control in an era of HIV infection and multi-drug resistant tuberculosis. J Hosp Infect 2000;44:5–11. 91. Shinnick TM, Iademarco MF, Ridderhof JC. Centers for Disease Control and Prevention. National plan for reliable tuberculosis laboratory services using a systems approach. Recommendations from CDC and the Association of Public Health Laboratories Task Force on Tuberculosis Laboratory Services. MMWR Morb Mortal Wkly Rep 2005;54(RR-6):1–12. 92. Centers for Disease Control and Prevention. Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep 2003;52(RR-11):1–77.
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Clinical aspects of tuberculosis in HIV-infected adults Jean B Nachega and Gary Maartens
INTRODUCTION The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pandemic has dramatically changed the epidemiology and natural history of TB. In sub-Saharan Africa, where the HIV prevalence is highest, TB is the most prevalent opportunistic infection and the leading cause of death in HIVinfected individuals.1–5 HIV coinfection is one of the most potent risk factors for TB, increasing the risk of both reactivation of latent infection and progression to active TB following initial exposure to Mycobacterium tuberculosis or reinfection.6–8 Advancing immune suppression as a result of HIV infection is associated with an increasing risk of developing TB and also alters the clinical presentation of TB.9 The sputum smear, which is the cornerstone of diagnosis and often the only diagnostic modality in resource-poor settings, is more often negative in HIV-associated TB. Furthermore, TB progresses more rapidly in HIV-infected individuals and is associated with important changes in clinical and public health considerations. Although effective treatments are available for both HIV infection and TB, co-administration of antiretroviral and antituberculous therapy can result in shared toxicity, drug interactions, and immunopathology, complicating treatment decisions for individuals with both infections. This chapter focuses on clinical rather than global epidemiology, as well as the clinical features, diagnosis, and management of HIVassociated TB.
EPIDEMIOLOGY The global burden of TB is growing, driven largely by the HIVassociated TB epidemic in sub-Saharan Africa, while the incidence of TB is stable or declining in other regions.10 In southern African countries, where the HIV prevalence is highest, more than half of all new TB cases are HIV-infected.10 In rural Malawi the proportion of new smear-positive TB cases attributable to HIV increased from 17% in 1988–1990 to 57% in 2000–2001.11 The global TB burden is covered more fully in Chapter 3. The incidence of active TB in HIV-infected USA patients with latent TB infection (defined by positive tuberculin skin test) is about 10% per year.6,7 Annual incidence rates of about 10% also are described in HIV-infected patients in South Africa regardless of tuberculin skin test status.12 These annual incidence rates are extremely high compared to the estimated 10% lifetime risk of active TB following latent
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TB infection in people without HIV infection. Furthermore, HIVinfected patients have a risk of active TB approaching 40% after recent exposure to M. tuberculosis.8 The risk of TB increases early in HIV infection, doubling within the first year.13 Reactivation from latent TB infection is an important mechanism for the development of adult TB. However, there is accumulating evidence from studies using DNA fingerprinting techniques that a significant proportion of TB cases are recently acquired due to reinfection or new infection, particularly when the HIV prevalence is high. One such study in Malawi found that about two-thirds of cases were clustered, indicating recent transmission, and that HIV infection increased the risk of clustering by about fivefold.14
HIV AND MULTIDRUG-RESISTANT TUBERCULOSIS There is no good evidence that HIV infection is associated with the development of multidrug-resistant (MDR) TB.15 However, institutional outbreaks of MDR-TB have been reported in both developed and developing countries.16,17 The prognosis of MDR-TB is poor in HIV infection due to the diagnostic delay and the weak activity of second-line antituberculous drugs. This was starkly illustrated by the near-universal mortality, mostly before the diagnosis was made, in the outbreak of extensively drug-resistant TB in rural South Africa.17
PROGNOSIS The risk of developing TB increases with clinically advanced HIV disease or with declining CD4+ lymphocyte counts (Fig. 51.1).9,12 In sub-Saharan Africa, TB in HIV-infected individuals occurs across a broad spectrum of CD4+ lymphocyte counts, with about a third of cases occurring with a CD4+ count < 200 cells/mL and a similar proportion among those with CD4+ counts of 200–500 and > 500 cells/mL.18,19 In the United States and other industrialized countries, all forms of HIV-associated TB are regarded as AIDS-defining illnesses, because they generally occur with lower CD4+ counts (median < 200 cells/mL).20 In the current World Health Organization (WHO) staging system, pulmonary TB is stage 3 and extrapulmonary or disseminated TB is stage 4 (equivalent to AIDS).21 In Africa, all forms of TB have a better prognosis than other AIDS-defining illnesses, and the prognosis is similar for extrapulmonary and pulmonary disease.21 The prognosis of TB in communities with high TB incidence and high HIV prevalence can only be reliably assessed in conjunction with the CD4+ count or other clinical features of HIV disease.
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work-up for pulmonary TB should be initiated if cough persists for more than 1 week in patients with HIV, rather than the traditional 3 weeks.28 Because of the protean manifestations of TB, a high index of suspicion should be maintained in the HIVinfected. Tuberculosis is nearly always in the differential diagnosis in HIV-infected patients presenting with intercurrent illnesses in high-incidence settings.
20
15
PTB
TB per 100 py
EPTB
EXTRAPULMONARY TUBERCULOSIS
10
5
0
51
< 50
50 200
200 350
> 350
CD4
Fig. 51.1 The incidence rate per 100 person years (py) of pulmonary TB (PTB) and extrapulmonary TB (EPTB) by CD4+ count in HIV-infected patients in South Africa. Error bars are 95% confidence intervals. Adapted from Holmes CB, Wood R, Badri M. et al.9 CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment. J Acquir Immune Defic Syndr. 2006;42:464–9.
There is evidence from cohort studies suggesting that TB accelerates the course of HIV infection.22,23 The basis for the accelerated HIV disease is thought to be related to prolonged immune activation.24 This topic is explored more fully in Chapter 10.
SYMPTOMS AND SIGNS: OVERVIEW OF THE CLINICAL PRESENTATION OF TUBERCULOSIS IN HIV-INFECTED ADULTS The classical symptoms of TB (fever and weight loss with or without cough) have a wide differential diagnosis in HIV infection. Mycobacterial infections are the most common cause of fever of unknown origin in HIV infection, with TB being overwhelmingly the most common cause in developing countries.25 There are two key factors that affect the clinical presentation of TB in HIV-infected adults: the degree of immune suppression and the rate of disease progression. In HIV-infected individuals with relatively preserved immunity (CD4+ cell count > 200 cells/mL), pulmonary TB generally presents as the typical adult pattern with upper lobe predominance and cavitation. In patients with severe immune suppression (CD4+ cell counts < 200 cells/mL) pulmonary TB presents with noncavitary lower- or mid-zone infiltrates.7,26 However, haemoptysis, which is associated with cavitation, is unusual in HIV-infected patients with severe immune suppression. Disseminated TB also is more common in severely immune-suppressed patients. The second factor affecting clinical presentation is that TB progresses more rapidly in HIV-infected individuals.8,27 A study of ambulant African miners found that TB disease duration was threefold shorter in those with HIV infection.27 As a result, it is important to diagnose TB promptly to reduce the need for hospitalization and mortality in HIV-infected patients. For example, the diagnostic
Extrapulmonary TB is very common in HIV-infected patients, occurring alone or in association with pulmonary disease in 40–60% of cases.29 All forms of extrapulmonary TB occur, but the most frequent forms are lymphadenopathy (peripheral or visceral), pleural effusion, pericardial effusion, intra-abdominal (one or more of peritoneal, intestinal, or lymph node involvement), and meningitis. Musculoskeletal and renal TB occur less commonly in HIV infection (urine mycobacterial cultures are often positive in HIV-associated TB, but this reflects dissemination rather than classic renal TB).30 Lymphadenopathy is the most common form of extrapulmonary TB, either as the major site of extrapulmonary disease or in association with disease elsewhere (usually as a manifestation of disseminated disease). Localized peripheral tuberculous lymphadenitis is often fluctuant because of extensive central caseous necrosis. Occasionally it is mistaken for pyogenic adenitis as the nodes can enlarge rapidly and may be associated with overlying erythema. In disseminated TB the lymphadenopathy is often symmetrical and mistaken for lymphadenopathy due to HIV. In patients with symptoms suggestive of TB, any appreciable lymphadenopathy offers an excellent opportunity to make the diagnosis.31 HIV infection does not change the neurological presentation or cerebrospinal fluid findings of tuberculous meningitis, but is more often associated with TB at other sites.32 Abdominal TB is often accompanied by mesenteric lymphadenopathy and splenomegaly. Disseminated TB may take the form of classic miliary disease, but more commonly presents with disease at two or more noncontiguous sites or with occult dissemination.
INVESTIGATIONS FOR TUBERCULOSIS IN HIV-INFECTED INDIVIDUALS DIAGNOSING LATENT TUBERCULOSIS INFECTION The tuberculin skin test is the standard method of establishing the presence of latent TB infection. In HIV-infected patients the tuberculin skin test is more likely to be negative as the CD4+ lymphocyte count declines.33 The criterion for a positive tuberculin skin test is lower in HIV infection ( 5 mm induration on the Mantoux test), although this has recently been challenged.34 Although false-negative tuberculin skin tests occur more often in HIV-infected patients, particularly in the significantly immunesuppressed, meta-analysis shows that TB preventive therapy is only effective if the skin test is positive.35 The new interferon-g release assays rely on immune responses to antigens that are specific to the M. tuberculosis complex. A recent report indicates that, unlike the tuberculin skin test, these assays are less affected by HIV status.36 However, it remains to be seen whether these new assays predict the risk of TB better than the tuberculin skin test, and thus could replace it as an indication for treatment of latent TB infection.
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IMAGING The chest radiograph has been shown not to be important in excluding TB prior to preventive therapy; symptoms and weight loss are a sufficient screen.37,38 However, chest radiography plays a critical role in the diagnostic work-up of suspected TB in HIV-infected patients, irrespective of whether they have respiratory symptoms. In developing countries chest radiograph is typically delayed until after the sputum smear result, and is omitted if the smear is positive. Several radiographic appearances are highly suggestive of TB, most notably the presence of lymphadenopathy, but none are diagnostic. The differential diagnosis of the key chest radiographic patterns suggestive of TB is covered elsewhere in this book. However, in HIV-infected patients, the degree of immune suppression is a key determinant of the radiographic pattern. In patients with relatively preserved immunity (a CD4+ cell count > 200 cells/mL) pulmonary infiltrates are the typical adult pattern with upper lobe predominance and cavitation. In contrast, in patients with CD4+ cell count < 200 cells/mL, there is a shift towards patterns atypical for adults: mid- or lower-zone infiltrates, and hilar or mediastinal lymphadenopathy (Fig. 51.2). Miliary patterns usually occur with a CD4+ cell count < 200 cells/mL. Normal chest radiographs with pulmonary symptoms and positive sputum culture are not uncommon, particularly with advanced immune suppression.39 Pleural effusions occur with any CD4+ count.7,26,40–42 Depending on the localization of signs and symptoms of TB and the availability of infrastructure and expertise, other imaging modalities may be helpful. Ultrasound scan of the abdomen showing features such as mesenteric lymphadenopathy and splenic microabscesses is strongly suggestive of TB. Cold abscesses and ascites can also be visualized and aspirated. Computed tomography (CT) or magnetic resonance imaging (MRI) scans are particularly helpful with imaging of the central nervous system (see Chapter 24), and with lymphadenopathy, where the central hypodensity due to caseous necrosis is often revealed (Fig. 51.3).
Fig. 51.3 CT scan showing markedly enlarged right supraclavicular lymph node with central hypodense area consistent with caseous necrosis. Wide needle aspiration confirmed TB.
SMEAR AND CULTURE The finding of acid-fast bacilli (AFB) on stained specimens is the cornerstone of the diagnosis of TB. It is the only reliable and affordable rapid diagnostic test, and is often the only diagnostic modality available in developing countries. Mycobacterial cultures have a higher yield than smear and provide a specific diagnosis. As immunity declines, TB becomes more disseminated and there is a reasonably high yield of culture from blood, urine, and bone marrow. The yields of key diagnostic interventions are summarized in Table 51.1. Although there are some contradictory reports, most studies show that the sputum smear is more likely to be negative in patients with HIV infection than in those without HIV.43 Nevertheless, sputum smear remains the most important initial diagnostic test in HIVinfected patients with suspected pulmonary TB and has a reasonably high yield. At least two and preferably three sputa should be sent for smear, and at least one should be an early morning sputum. Sputum induction using an ultrasonic nebulizer and hypertonic saline has been shown to improve the yield of smear and culture in patients with pulmonary TB,44,45 and the use of this technique should be widely promoted. An induced sputum specimen is usually clear, resembling saliva, and the laboratory needs to be informed not to discard the specimen.
INVESTIGATING LYMPHADENOPATHY Lymph node aspiration produces a high rapid diagnostic yield, with macroscopic caseation in about half and smears positive for AFB in a high proportion.46,47 The technique is illustrated in Fig. 51.4. Biopsy, either by excision or by needle core biopsy, should be reserved for cases with negative aspirations.48 The yield of lymph node aspiration and biopsy remains high even in patients with symmetrical lymphadenopathy from disseminated TB.31
MANAGEMENT Fig. 51.2 Chest radiograph of an HIV-infected man with a CD4+ count of
53 cells/mm3 and symptoms suggestive of TB. The radiograph shows asymmetrical hilar and mediastinal lymphadenopathy as well as a non-confluent infiltrate at the left lower zone. Tuberculosis was confirmed on sputum culture.
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ANTITUBERCULOUS THERAPY There have been several studies comparing the outcomes of the standard 6-month rifampicin-based regimens for the treatment of
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Table 51.1 Approximate diagnostic yield by specimen type in HIV-infected adults with tuberculosis Specimen type
Approximate Comment yield (%)
Sputum
Smear
40–70
Induced sputum Lymph node
Culture Smear Culture Smear (aspirate)
75–90 25 75 50–85
Histology or culture (biopsy) Histology Culture Smear Culture
80–95
60–80 60–80 1–10 40–80
Smear Culture Histology Culture Smear Culture
50 100 25–70 40 5 35–75
Liver
Histology
70–80
Blood
Culture
25–40
Pleural biopsy Aspirated pleural, pericardial, or ascitic fluid Pus from cold abscesses Bone marrow Urine
Patients with advanced disease and in-patients have lower yields. Patients with pulmonary cavities have higher yields. In patients with smearnegative sputum. Wide needle (19-G) aspiration. Macroscopic caseation visible in about half. Needle core or open biopsy. High yield with experienced operators. Higher yield with bedside inoculation into liquid mycobacterial culture media.
Higher yield with advanced disease. Classic renal TB is uncommon, positive cultures generally indicate disseminated TB. Less invasive tests generally preferred. Higher yield with advanced disease.
Results for specimen yield were from a variety of sources.30,31,45–51
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pulmonary TB in patients with and without HIV infection. All of the studies reported comparable early clinical response to therapy, time required for sputum culture conversion from positive to negative, and rates of treatment failure. Recurrence rates have varied among studies, with most reporting rates of 5% or less.52–56 Different designs and outcome definitions make cross-study comparisons difficult, and so the optimal treatment duration of antituberculous therapy among HIV-infected individuals is still contentious. It is clear that regimens with rifampicin only in the initial 2 or 3 months are inferior, since they show much higher recurrence rates.57 A recent analytical review reported that the incidence of recurrence in HIV infection was related to the duration of rifampicin therapy: rifampicin durations of 2–3, 5–6, and 7 months were associated with recurrence rates of 4, 2, and 1.4 cases per 100 person years respectively. In most studies it is unclear whether the higher recurrence rates were due to relapse or reinfection. Relapse is defined as recurrent TB with the same M. tuberculosis strain as the first episode. The USA (ATS/CDC/IDSA) recommendations for the treatment of TB in HIV-infected adults are, with a few exceptions, the same as those for HIV-uninfected adults: standard 6-month rifampicin-based therapy. The optional continuation phase regimen of isoniazid plus rifapentine once weekly is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins.58 The development of acquired rifampicin resistance has also been noted among HIV-infected patients with advanced immune suppression treated with twice-weekly rifampicin- or rifabutin-based regimens. Consequently, patients with CD4+ cell counts < 100 cells/mL should receive daily or three times weekly treatment. Directly Observed Therapy (DOT) and other adherence-promoting strategies are especially important for patients with HIV-related TB. For highly TB/HIV-endemic, low-income countries, WHO and the International Union against Tuberculosis and Lung Diseases (IUATLD) recommend a standardized rifampicin-based treatment regimen of 6–8 months (the longer regimen is for retreatment cases) for at least all confirmed sputum smear-positive cases, with DOT for at least the first 2 months. The IUATLD recommends an 8-month regimen with ethambutol rather than rifampicin in the continuation
Fig. 51.4 (A) Aspiration of a cervical lymph node using a wide needle. (B) Macroscopic caseation in the aspirate. This is virtually diagnostic of TB.
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phase for smear-negative HIV-infected patients, but this regimen is associated with high recurrence rates.57 Despite the fact that this regimen is inferior, it remains widely used in Africa.57 The basic principles that underlie the treatment of pulmonary TB also apply to extrapulmonary forms of the disease. Although relatively few studies have examined the treatment of extrapulmonary TB, a 6-month course of therapy is recommended for treating TB involving any site with the exception of the central nervous system, for which a 9- to 12-month regimen is recommended. Prolongation of therapy should also be considered for patients with TB in any site slow to respond. The treatment of MDR-TB is covered elsewhere in this book.
EMPIRICAL ANTITUBERCULOUS THERAPY The relatively rapid disease progression of HIV-associated TB and the high proportion of sputum smear-negative cases often results in the initiation of empirical antituberculous therapy. In areas where mycobacterial culture is available, empirical therapy will often be initiated pending culture results and, if cultures are negative, continued if there has been a response. In settings where mycobacterial culture is not available, case definitions and clinical diagnoses are frequently used to commence antituberculous therapy. A variety of case definitions and clinical algorithms for pulmonary TB have been tested in low-resource settings, with mixed results.39 Three negative sputum smears, no response to a trial of antibiotics, and a compatible chest radiograph is the usual case definition for smear-negative pulmonary TB used in resource-poor settings. The WHO has recently modified this definition to include consideration of acutely ill patients (notably with Pneumocystis pneumonia), but this algorithm is not yet validated. Little work has been done on case definitions for extrapulmonary TB. A recent South African study found high positive predictive value for case definitions for extrapulmonary TB and a modified case definition for smear-negative pulmonary TB.45 Importantly, the study also assessed the response to empirical antituberculous therapy: improvement in C-reactive protein, Karnosky performance score, and symptoms were very sensitive, but improvements in weight and haemoglobin were not very sensitive. A response to therapy occurred in most by 2 weeks and in all by 8 weeks. International agencies and national TB control programmes strongly discourage trials of antituberculous therapy in developing countries, but this dogmatic view needs to be challenged in the HIV era. Case definitions can never be 100% specific. Patients who are not responding to empirical therapy need to be investigated for alternative diagnoses and have their antituberculous therapy discontinued.
ANTIRETROVIRAL THERAPY In sub-Saharan Africa, more than half of new adult cases of TB are coinfected with HIV, and this is often their first presentation with HIV. HIV-associated TB is associated with a high mortality in settings where antiretroviral therapy is unavailable.1,59,60 A significant proportion of patients with TB have relatively advanced HIV disease and thus antiretroviral therapy is indicated. However, there are three problems that arise when antituberculous and antiretroviral drugs are co-administered: shared toxicity, drug interactions arising from the induction of metabolism (cytochrome P450 enzymes) and efflux pumps by rifampicin, and the immune reconstitution inflammatory syndrome (IRIS). The available data suggest that there is an increased risk of adverse drug reactions, particularly hepatitis, in patients co-administered
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antiretroviral and antituberculous therapy. However, the studies are retrospective and do not allow accurate attribution of the risks conferred by HIV infection, antiretroviral therapy, or other concomitant medications.61 Rifamycins induce the activity of cytochrome P450 enzymes located primarily in the intestinal wall and liver. Two key antiretroviral drug classes, protease inhibitors and non-nucleoside reverse transcriptase inhibitors, are substrates of cytochrome P450 enzymes. Protease inhibitors are also substrates of P-glycoprotein, which is also induced by rifamycins. The available rifamycins differ in potency as P450 enzyme inducers, with rifampicin being the most potent and rifabutin the least.62 Co-administration with rifampicin reduces the concentrations of non-nucleoside reverse transcriptase inhibitors to a moderate extent, but dramatically reduces the concentrations of protease inhibitors.63 Rifabutin does not significantly affect the concentrations of ritonavir-boosted protease inhibitors and is recommended when protease inhibitors must be used.63 However, the use of rifabutin in low-resource settings is currently limited due to its very high cost and the widespread use of fixed dose combination antituberculous drugs that include rifampicin. Drug interactions are discussed in further detail in Chapter 60. Between 25% and 40% of patients commencing antiretroviral therapy while being treated for TB develop paradoxical deterioration of TB, the so-called immune reconstitution inflammatory syndrome (IRIS).64 Paradoxical deterioration was well known in the pre-HIV era, but occurs much more frequently in HIVinfected patients starting antiretroviral therapy. The pathogenesis of this immunopathological reaction is not completely understood. The most common manifestation of TB IRIS is enlarging lymphadenopathy with caseous necrosis. It typically occurs within a month of initiation of antiretroviral therapy. Factors associated with an increased risk of IRIS include shorter intervals between initiation of antiretroviral and antituberculous therapy, lower CD4+ counts and rapidly decreasing viral loads.64 New or worsening clinical features should be attributed to IRIS only after a thorough evaluation has excluded other possible causes, notably poor adherence to antituberculous therapy, MDR-TB, new opportunistic diseases, and systemic drug hypersensitivity reactions. The role of adjunctive corticosteroids in the management of patients with IRIS is currently unclear. IRIS is discussed further in Chapter 67. Despite these complications, antiretroviral therapy should not be withheld simply because the patient is being treated for TB. The optimal timing of initiation of antiretroviral therapy in relation to initiation of antituberculous treatment is unclear. Treatment for TB should always be initiated first, and it is prudent to wait at least until it is clear that the patient is improving and tolerating the antituberculous therapy before beginning antiretroviral therapy. While awaiting the results of ongoing controlled trials, a WHO expert opinion panel has suggested that the CD4+ lymphocyte count should determine the initiation of antiretroviral therapy, unless there is other serious HIV morbidity.65 WHO guidelines state that patients with CD4+ counts < 200 cells/mL should initiate antiretroviral therapy after 2–8 weeks of antituberculous therapy, those with CD4+ counts 200–350 cells/mL after 8 weeks, and antiretroviral therapy is not indicated if the CD4+ count is > 350 cells/mL. Until there have been controlled studies evaluating the optimal time for starting antiretroviral therapy in patients with HIV infection and TB, this decision should be individualized, based on the patient’s initial response to treatment for TB, occurrence of side effects, and availability of antiretroviral therapy. For patients who are already receiving an antiretroviral regimen, treatment should
CHAPTER
Clinical aspects of tuberculosis in HIV-infected adults
generally be continued, although the regimen may need to be modified on the basis of the risk of drug–drug interactions, as described in Chapter 60.
COTRIMOXAZOLE Prophylactic cotrimoxazole dramatically reduced morbidity and mortality in a randomized controlled trial in HIV-infected patients with TB in Cote d’Ivoire irrespective of their CD4+ count.66 The generalizability of this result has been questioned, as there was a lower rate of resistance to cotrimoxazole among common community-acquired bacteria in Cote d’Ivoire than in many other areas. But two southern African cohort studies found a similar benefit.67,68 Prophylactic cotrimoxazole is therefore indicated for all HIV-infected patients with TB.
ADJUNCTIVE GLUCOCORTICOIDS Adjunctive glucocorticoids are frequently advocated with antituberculous therapy to reduce inflammation in TB, but the evidence base for this practice is often lacking, particularly in HIV infection. Only a few small randomized controlled trials have been conducted in HIV-infected patients. Mortality was reduced in a small trial of patients given prednisolone for tuberculous pericarditis.51 Adjunctive dexamethasone reduced mortality in a large Vietnamese study of adults with tuberculous meningitis.69 The HIV-infected subgroup appeared to gain a similar benefit, but this failed to achieve statistical significance. A Ugandan study of adjunctive prednisolone in HIV-infected patients with pleural TB found faster resolution with prednisolone, but no mortality benefit.70 Of great concern, however, was their finding of excess cases of Kaposi’s sarcoma in the prednisolone arm. This sobering result is a reminder that the additive immunosuppressant effect of glucocorticoids can have severe consequences in HIV infection. Adjunctive glucocorticoids should only be used in HIV-infected patients when there is likely to be a mortality benefit, which may be the case for tuberculous meningitis and pericarditis, but there is a need for larger studies in both conditions.
OTHER ADJUVANT IMMUNOTHERAPY There are two key hypotheses underlying adjuvant immunotherapy for TB: to reduce the harmful effects of inflammation, as in tuberculous meningitis, and to improve the effect of antituberculous therapy by disrupting granulomatous inflammation that may sequester mycobacteria.71 A plethora of therapies have been evaluated as adjuvant immunotherapy, mostly in small pilot studies.
REFERENCES 1. Mukadi YD, Maher D, Harries A. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001;15(2): 143–152. 2. Holmes CB, Losina E, Walensky RP, et al. Review of human immunodeficiency virus type 1-related opportunistic infections in subSaharan Africa. Clin Infect Dis 2003;36(5): 652–662. 3. Harries AD, Hargreaves NJ, Kemp J, et al. Deaths from tuberculosis in sub-Saharan African countries with a high prevalence of HIV-1. Lancet 2001;357(9267):1519–1523.
51
Immunization with killed Mycobacterium vaccae was shown to modify immune responses to TB, but subsequent clinical trials, including one in HIV infection, failed to show benefit.72 A wide variety of herbal extracts are marketed as ‘immune boosters’, particularly in sub-Saharan Africa, not only by traditional healers, but numerous commercial products are also marketed in pharmacies. Although plant sterilins do have some modest in vitro immune modulatory activity, there is very little clinical evidence of benefit and minimal data on safety. There is a risk of adverse drug interactions when these complementary medicines are used together with antiretroviral therapy.73
MICRONUTRIENTS Concentrations of micronutrients are often reduced in TB patients. A recent randomized controlled trial found that multivitamin and zinc supplementation reduced mortality in HIV-infected patients with TB.74 However, their findings should be viewed with caution because not all of the patients in their study were HIV-infected, and the confidence intervals were wide. Nevertheless it is an affordable intervention that is safe, provided that the doses are not too high.
PREVENTION Two interventions effectively reduce the risk of TB in HIV infection: the treatment of latent TB infection and antiretroviral therapy. Treatment of latent TB infection reduces the risk of TB by about 60% in individuals with positive tuberculin skin tests, but is not effective in anergic individuals.35 A variety of regimens have been shown to be effective, but the best-tolerated and best-studied regimen is isoniazid for 6 months. The available studies have not been adequately powered to assess the duration of benefit, but it appears to be relatively short-lived. Further details of treating latent TB infection are given in Chapter 76. Combination antiretroviral therapy reduces the incidence of TB by about 80%.75 However, a model of interventions to reduce TB incidence in areas with a high HIV and TB burden demonstrated that neither treatment of latent TB infection nor combination antiretroviral therapy had a significant impact on community TB incidence in the model.76 The most effective measures were reduced HIV incidence and improved TB case finding and cure rates.76 Nevertheless antiretroviral therapy and treatment of latent TB infection are important interventions for individuals and may impact on TB incidence in the community in combination with other control measures.
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33. Markowitz N, Hansen NI, Wilcosky TC, et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Ann Intern Med 1993;119(3):185–193. 34. Cobelens FG, Egwaga SM, van Ginkel T, et al. Tuberculin skin testing in patients with HIV infection: limited benefit of reduced cutoff values. Clin Infect Dis 2006;43(5):634–639. 35. Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004, Issue 1. Art. CD000171. 36. Rangaka MX, Wilkinson KA, Seldon R, et al. The effect of HIV-1 infection on T cell based and skin test detection of tuberculosis infection. Am J Respir Crit Care Med 2007;175(5):514–520. 37. Mosimaneotsile B, Talbot EA, Moeti TL, et al. Value of chest radiography in a tuberculosis prevention programme for HIV-infected people, Botswana. Lancet 2003;362(9395):1551–1552. 38. Mohammed A, Ehrlich R, Wood R, et al. Screening for tuberculosis in adults with advanced HIV infection prior to preventive therapy. Int J Tuberc Lung Dis 2004;8(6):792–795. 39. Siddiqi K, Lambert ML, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in lowincome countries: the current evidence. Lancet Infect Dis 2003;3(5):288–296. 40. Long R, Scalcini M, Manfreda J, et al. Impact of human immunodeficiency virus type 1 on tuberculosis in rural Haiti. Am Rev Respir Dis 1991;143(1):69–73. 41. Perlman DC, El-Sadr W, Nelson ET, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1997;25(2):242–246. 42. Wendel KA, Sterling TR. Tuberculosis and HIV. AIDS Clin Care 2002;14(2):9–15. 43. Colebunders R, Bastian I. A review of the diagnosis and treatment of smear-negative pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4(2): 97–107. 44. Parry CM, Kamoto O, Harries AD, et al. The use of sputum induction for establishing a diagnosis in patients with suspected pulmonary tuberculosis in Malawi. Tuber Lung Dis 1995;76(1):72–76. 45. Wilson D, Nachega J, Morroni C, et al. Diagnosing smear-negative tuberculosis using case definitions and treatment response in HIV-infected adults. Int J Tuberc Lung Dis 2006;10(1):31–38. 46. Bem C, Patil PS, Elliott AM, et al. The value of wide-needle aspiration in the diagnosis of tuberculous lymphadenitis in Africa. AIDS 1993;7(9):1221–1225. 47. Pithie AD, Chicksen B. Fine-needle extrathoracic lymph-node aspiration in HIV-associated sputumnegative tuberculosis. Lancet 1992;340(8834-8835): 1504–1505. 48. Wilson D, Nachega J, Chaisson R, et al. Diagnostic yield of peripheral lymph node needle-core biopsies in HIV infected adults with suspected smear negative tuberculosis. Int J Tuberc Lung Dis 2005;9(2):220–222. 49. Luzze H, Elliott AM, Joloba ML, et al. Evaluation of suspected tuberculous pleurisy: clinical and diagnostic findings in HIV-1-positive and HIV-negative adults in Uganda. Int J Tuberc Lung Dis 2001;5:746–753. 50. Karstaedt AS, Pantanowitz L, Omar T, et al. The utility of bone-marrow examination in HIV-infected adults in South Africa. QJM 2001;94:101–105. 51. Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183–188. 52. Kassim S, Sassan-Morokro M, Ackah A, et al. Two year follow-up of persons with HIV-1-associated and HIV-2-associated pulmonary tuberculosis treated with short-course chemotherapy in West Africa. AIDS 1995;9(10):1185–1191. 53. Chaisson RE, Clermont HC, Holt E, et al. Sixmonth supervised intermittent tuberculosis therapy in
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Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996;154(4 Pt 1):1034–1038. El-Sadr WM, Perlman DC, Matts JP, et al. Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1998; 26(5):1148–1158. Connolly C, Reid A, Davies G, et al. Relapse and mortality among HIV-infected and uninfected patients with tuberculosis successfully treated with twice weekly directly observed therapy in rural South Africa. AIDS 1999;13(12):1543–1547. Sterling TR, Alwood K, Gachuhi R, et al. Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons. AIDS 1999;13(14):1899–1904. Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: An analytical review. Clin Infect Dis 2003;37(1):101–112. Vernon A, Burman W, Benator D, et al. Acquired rifamycin monoresistance in patients with HIVrelated tuberculosis treated with once-weekly rifapentine and izoniazid. Lancet 1999;353(9167): 1843–1847. Olalla J, Pulido F, Rubio R, et al. Paradoxical responses in a cohort of HIV-1-infected patients with mycobacterial disease. Int J Tuberc Lung Dis 2002; 6(1):71–75. Santoro-Lopes G, de Pinho AM, Harrison LH, et al. Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clin Infect Dis 2002;34(4):543–546. McIlleron H, Meintjes G, Burman W, et al. Complications of antiretroviral therapy in patients with tuberculosis—drug interactions, toxicity and immune reconstitution inflammatory syndrome. J Infect Dis 2007;196(Suppl 1):S63–75. Li AP, Reith MK, Rasmussen A, et al. Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Chem Biol Interact 1997;107(1–2):17–30. Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2000;49(9):185–189. Lawn SD, Bekker L-G, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5(6):361–373. World Health Organisation. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendation for a public health approach. Geneva: World Health Organization, 2006. Wiktor SZ, Sassan-Morokro M, Grant AD, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a randomised controlled trial. Lancet 1999;353(9163):1469–1475. Mwaungulu FB, Floyd S, Crampin AC, et al. Cotrimoxazole prophylaxis reduces mortality in human immunodeficiency virus-positive tuberculosis patients in Karonga district, Malawi. Bull WHO 2004;82(5):354–363. Badri M, Maartens G, Wood R, et al. Cotrimoxazole in HIV-1 infection. Lancet 1999; 354(9175):334–335. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351(17):1741–1751. Elliott AM, Luzze H, Quigley MA, et al. A randomized, double-blind, placebo-controlled trial
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Clinical aspects of tuberculosis in HIV-infected adults of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis 2004;190(5):869–878. 71. Wallis RS. Reconsidering adjuvant immunotherapy for tuberculosis. Clin Infect Dis 2005;41(2):201–208. 72. Mwinga A, Nunn A, Ngwira B, et al. Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis:
a randomised placebo-controlled trial. Lancet 2002;360(9339):1050–1055. 73. Lee LS, Andrade AS, Flexner C. Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects. Clin Infect Dis 2006;43(8):1052–1059. 74. Range N, Changalucha J, Krarup H, et al. The effect of multi-vitamin/mineral supplementation on mortality during treatment of pulmonary tuberculosis:
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a randomised two-by-two factorial trial in Mwanza, Tanzania. Br J Nutr 2006;95(4):762–770. 75. Corbett EL, Marston B, Churchyard GJ, et al. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet 2006;367(9514):926–937. 76. Currie CS, Williams BG, Cheng RC, et al. Tuberculosis epidemics driven by HIV: is prevention better than cure? AIDS 2003;17(17):2501–2508.
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52
Multidrug-resistant tuberculosis in children Joia Mukherjee and H Simon Schaaf
INTRODUCTION Despite aggressive international efforts, TB remains a leading infectious cause of death, with an estimated 8.8 million incident cases per year.1 In 2000, an estimated 884,000 (10.7%) of these cases occurred among children 15 years of age.2 While children respond well to TB therapy, because TB is difficult to diagnosis in children, the prevalence of TB and the contribution of TB to child mortality is likely to be underestimated.3 Many of the children who die of respiratory infection, diarrhoeal disease, and malnutrition – among the main causes of paediatric death worldwide – probably have TB which is never detected. For those children diagnosed with TB who fail treatment, complications of drug resistance may be a cause of treatment failure. Global TB control efforts have been threatened by the emergence of multidrug-resistant tuberculosis (MDR-TB), defined as strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampin. MDR-TB is estimated to cause 4% of new TB cases in the developing world.4 Children may be less likely than adults to acquire resistance during the treatment of TB due to lower bacillary load and less frequent cavity formation.5 However, there is no reason to expect that children will evade infection by strains which have already developed resistance; that is new or primary resistance (Table 52.1). Indeed, the acquisition of strains of MDR-TB through primary transmission has been shown to be the same for children as for adults.6 In the USA the resurgence of MDR-TB in the 1990s was higher in children than in adults.7 The diagnosis of TB is more difficult in children. Because of lower bacillary load, less cavity formation by the immature immune system, higher rates of extrapulmonary and miliary forms of TB, and lack of a forceful cough, it is rare to have a positive sputum smear microscopy demonstrating acid-fast bacilli as confirmation of active TB in children.8 As a result, the diagnosis of MDR-TB, which requires positive culture as well as confirmation of resistance by drug susceptibility testing (DST), is often elusive.9 While every effort should be made to confirm TB through the use of culture and to confirm drug resistance through DST to avoid exposing children unnecessarily to toxic drugs, for culture-negative children who are thought to have new resistance, transmitted from a source case with drug-resistant TB, therapy should be guided by the results of DST and the history of antituberculous drugs exposure of the source case.10 Many studies have shown that MDR-TB in children is treatable if appropriate drug regimens are used and children have been shown to tolerate second-line antituberculous drugs well. This
532
chapter will describe the transmission, case detection, and treatment of active MDR-TB in children and the management of children who are household contacts of adults with infectious MDR-TB.
ACQUISITION OF MDR-TB IN CHILDREN NEW (PRIMARY) RESISTANCE Because few children have had previous antituberculous chemotherapy and are less likely to develop resistance while on treatment; when children are diagnosed with MDR-TB, they have probably been infected by transmission of a strain already drug resistant (i.e. new drug resistance).11 A community-based drug resistance survey of children performed in the Western Cape Province of South Africa in 2003–2005 compared with one performed in 1994–1998 documented an increasing rate of both isoniazid resistance and MDR, suggesting increasing primary transmission of resistant strains.12 Delays in the initiation of treatment for MDR-TB in children are often due to failure to ask about contacts that have known or suspected MDR-TB.13 Additionally, even when a household MDR-TB contact is known, the spectre of MDR-TB in children is often not raised programmatically. A study in Lima, Peru, documented 16 children who ultimately were shown to have culture-proven MDR-TB, all were smearnegative at the start of therapy. Eleven of the 16 children had a known household contact with documented MDR-TB.10 If the child has a household contact with confirmed or suspected MDR-TB, new (transmitted) resistance in the child should be suspected, even if the child has received previous treatment.10,12
PREVIOUSLY TREATED (ACQUIRED) RESISTANCE IN CHILDREN While infection with a strain of TB already resistant is a more common cause of MDR-TB in children, there are some children who acquire resistance to antituberculous drugs while on treatment. This can happen in the same manner as in adults as a result of incorrect treatment regimens, poor adherence to therapy, malabsorption, or poor host immunity. Additionally, children infected with strains of TB resistant to isoniazid or poly-resistant but still susceptible to rifampicin may develop MDR-TB by amplification of resistance after treatment with first-line drugs. In the cohort in Lima described in the preceding section, due to programmatic guidelines that forbade the empirical treatment of MDR-TB without DST confirmation, all of the children but one received standard first-line therapy for TB for a mean of
CHAPTER
Multidrug-resistant tuberculosis in children
Table 52.1 Definitions of drug resistance and acquisition of drug-resistant tuberculosis in children Polydrug-resistant TB
Multidrug-resistant TB (MDR-TB) Extensively drugresistant TB (XDR-TB)
Primary drug resistance: Acquired drug resistance New drug resistance
Previously treated drug resistance Transmitted drug resistance
Resistance to isoniazid or rifampicin (not both) with resistance to one or more other first-line drugs. Resistance to isoniazid and rifampicin with or without resistance to other anti-TB drugs. Resistance to isoniazid and rifampicin (MDR-TB) in addition to any fluoroquinolone, and at least one of the three following injectable drugs used in antituberculous treatment: capreomycin, kanamycin or amikacin. No previous TB treatment, implying transmitted resistance. Development of drug resistance in a previously treated patient due to inappropriate treatment. Resistance in cultures from patients who have not previously received TB treatment, or who have received TB treatment for < 1 month. Resistance in cultures from patients previously treated for 1 month with only first-line drugs. Implying that drug resistance is due to infection with an already drug-resistant strain, with or without previous antituberculous treatment.
10 months prior to the initiation of MDR-TB therapy. The use of first-line therapy in these children resulted in the development of severe disease and the acquisition of further drug resistance. In all children with a new diagnosis of TB or a history of failure of TB treatment a careful history of contacts should be taken. The traditional strategy of directly observed therapy, short-course (DOTS), uses diagnosis of active TB through smear microscopy alone and administration of standard, first-line, drug regimens given under direct observation. A common DOTS category I treatment is to give only isoniazid and rifampicin in the last 4 months of therapy. The child with pre-existing isoniazid resistance can acquire MDRTB during this period of what is effectively rifampicin monotherapy. In resource-poor settings, it is not standard to perform mycobacterial culture or DST at initiation or after treatment failure of DOTS; thus pre-exisiting resistance is not detected. Until 2005, the World Health Organization (WHO) recommendations were that patients who failed category I of DOTS (isoniazid, rifampin, pyrazinamide, and ethambutol) were given category II, the same four drugs with the addition of streptomycin, thus adding a single drug to a failing regimen. This repetitive use of first-line medications to treat MDRTB may result in acquiring further resistance in strains transmitted with primary resistance.14–17 Such experiences demonstrate that when a patient fails observed therapy, is known to have a household contact with MDR-TB, or has had multiple previous treatments, it is reasonable to suspect MDR-TB. Based on these data, the 2006 WHO guidelines on the management of drug-resistant TB now suggest a new regimen called category IV, which is used for suspected or confirmed MDR-TB and employs second-line drugs.18 Careful analysis of the child who is failing standard first-line antituberculous therapy should be done. Poor adherence of the child to therapy probably still is the most common reason. However, many children fail standard first-line antituberculous therapy because a detailed history about possible source cases with known drug-resistant TB or
52
suspected drug resistance because of treatment failure was not obtained.12 Additionally, a human immunodeficiency virus (HIV) test should be considered in all children with TB and certainly among those who fail therapy as the presence of HIV has been associated with the relapse of TB in children as well as in adults.
CASE DETECTION OF MDR-TB IN CHILDREN The clinical presentation of MDR-TB in children follows the pattern of the presentation of TB in general. Children can develop protean symptoms including chronic cough, failure to thrive or weight loss, and fever. Pulmonary presentations, such as pneumonia or pleural effusion, are not uncommon. Additionally, MDR-TB may present with extrapulmonary manifestations such as meningitis and abdominal involvement. The clinical diagnosis of TB can be buttressed by radiographic findings, if present, and assisted by less specific analysis such as a high sedimentation rate or a positive tuberculin skin test. No clinical or radiological difference was found between drug-susceptible and drug-resistant cases in children; therefore the diagnosis of drug-resistant TB is primarily a microbiological diagnosis.6 Once the diagnosis of TB is made, MDR-TB should be carefully considered by review of household source cases and the child’s previous treatment history. It is clear that the outcomes of MDR-TB in children depend on a prompt diagnosis and the initiation of appropriate therapy for the drug-resistant strain. Aggressive case detection for MDR-TB is now recommended by the WHO and should be undertaken in the child who has active TB and presents with the following risk factors (Fig. 52.1):18 New childhood TB case Yes
Drug-resistant isolate
DST known
Yes
No
Drug-susceptible isolate
Contact with infectious TB case? Drug-resistant source case
Confirmed or probable DR TB
Treat as DR TB according to DST result of child or source cases isolate. Do culture/DST if DR not confirmed
Source case DST not done and failing 1st-line treatment retreatment case chronic TB case
No source case known or DST not done. Drug-susceptible source case
Suspected DR TB
Possible or confirmed DS TB
Do culture/DST on child & source cases specimens Treat as DS TB Close follow-up essential
Do culture/DST on childs specimens if DS not confirmed. Treat as DS TB
Check DST results. Check response to Rx. If DST shows DR or Failing adherent therapy, treat as DR TB DST = drug susceptibility test; DR = drug-resistant; DS = drug-susceptible Reference to culture and DST implies that facilities are available
Fig. 52.1 Algorithm for the diagnosis of suspected or confirmed drug-resistant TB in children.
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children with bacteriologically proven TB when DST demonstrates drug resistance; a child who is a household contact of an MDR-TB patient; a child who is a contact of a TB patient who died while on treatment and there are reasons to suspect the disease was MDR-TB (i.e. the deceased patient had been a contact of another MDR-TB case, had poor adherence to treatment, or had received more than two courses of antituberculous treatment); and children with bacteriologically proven TB who are not responding to first-line drugs given with direct observation.
CONFIRMATION OF MDR-TB Clinical exam, including assessment for the presence of lymphadenopathy, hepatosplenomegaly, pulmonary findings, and failure to thrive, is important for all children suspected of having TB. However, for the appropriate diagnosis and treatment of MDR-TB in a child, it is critical to have information on the resistance pattern of the infecting strain. Standard case detection methods in children under 5 years of age include obtaining gastric aspirates or induced sputum for microscopy for acid-fast bacilli – these specimens can then be sent for culture and DST.19 Sputum induction may be preferable to gastric aspiration, where this can be performed, since the yield of one sample from sputum induction with chest percussion has been shown to be equivalent to three gastric aspirates.20 Standard drug susceptibility testing, as discussed in Chapter 18, is performed once a culture is obtained.
PRESUMED MDR-TB Because of reasons mentioned earlier in this chapter, it is frequently impossible to obtain bacteriological confirmation of TB and therefore drug susceptibility testing in children. When a child has active TB by clinical criteria and has a known household contact with MDR-TB, it is reasonable to assume that the child’s strain of TB bears the same resistance pattern as the adult source case and to design the child’s MDR-TB regimen accordingly. A programmatic case definition including the following criteria of ‘presumed paediatric MDR-TB’ has been useful in several settings to initiate empirical treatment for MDR-TB without confirmatory DST:21,22 1. clinical and radiographic evidence of active TB infection; AND 2. documented failure of a DOTS regimen containing multiple first-line agents; OR 3. household contact with a patient with confirmed or suspected MDR-TB.
TREATMENT Several studies have documented good treatment outcomes in children with MDR-TB. In both adults and children, MDR-TB is curable when promptly detected and treated with drugs to which the isolate is susceptible. Additionally, host factors – particularly
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factors related to cell-mediated immunity – such as the presence of malnutrition or coinfection with HIV are critical to address concomitant with MDR-TB treatment.
MDR-TB REGIMENS FOR CHILDREN As of 2006, there were no specific WHO recommendations for the treatment of MDR-TB in children. However, there are several programmes in Peru, South Africa, and elsewhere that have treated a larger number of children with MDR-TB and have used treatment regimens that are based on the susceptibility pattern of the infecting strain identified from the child or the known MDR-TB household source case. Treatment regimens for children with MDR-TB generally follow the same principles of regimen design in adults (see Table 52.2 for drug doses): 1. any oral first-line agent to which the isolate was susceptible for the duration of therapy; 2. an injectable agent (aminoglycoside or capreomycin) for a minimum of 6 months; 3. a fluoroquinolone for the duration of therapy; and 4. two to three second-line agents (ethionomide/ prothionamide, para-aminosalicylic acid, or cycloserine/ terizidone) for the duration of therapy. This algorithmic approach – adding drugs to a regimen based on the susceptibility pattern of the child’s or source case’s strain in order of potency – creates a standardized approach that can be easily taught and replicated. No studies have evaluated the number of Table 52.2 Antituberculous drugs and dosages for drug-resistant tuberculosis in children Drug
Daily dose (mg/kg)
Frequency
Maximum daily dose
Pyrazinamide Ethambutol Ethionamide/ Prothionamide Aminoglycosides (injectable) Kanamycin Amikacin Capreomycin (injectable) Fluoroquinolones Ofloxacin
25–35 20–25 15–20
Once Once Once twice
2g 1.2 g 750 mg
15–30 15–22.5 15–30
Once daily Once daily Once daily
1g 1g 1g
15–20
800 mg
Ciprofloxacin
20–40
Levofloxacin Moxifloxacin Gatifloxacin Cycloserine/ terizidoneb Paraaminosalicylic acid (PAS)
7.5–10 7.5–10 7.5–10 10–20
Once or twice daily Once or twice daily Once daily Once daily Once daily Once or twice daily Twice or thrice daily
a
150
daily daily or dailya
2g 750 mg 400 mg 400 mg 1g 12 g
Split dose initially. If no gastrointestinal adverse events, once daily dose is possible. b Terizidone is a similar drug to cycloserine.
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drugs needed to treat MDR-TB in children. Because of the view that children have paucibacillary disease, proposed treatment regimens range from three to five drugs to which the child’s strain is susceptible. Extensive pulmonary TB with or without cavitation, and disseminated disease should be treated aggressively with the best available drugs, as the first treatment is the best and often the only chance for cure. Since many children with MDR-TB already have resistance to all first-line agents, the only bactericidal drugs available are injectable agents and fluoroquinolones. Thus, children with MDR-TB generally receive ethambutol and pyrazinamide if the isolate is susceptible or of unknown susceptibility, a fluoroquinolone, and up to three additional second-line drugs for the duration of therapy (when available). Additionally, children should receive an injectable agent for a minimum of 6 months. The length of therapy for MDR-TB is 18–24 months (or at least 12–18 months after the first negative culture). Because intermittent therapy has not been studied for second-line drugs, and many of them are bacteriostatic, treatment for MDR-TB is generally given daily. Rifampicin resistance is complete; therefore rifampicin has no role in treatment regimens for rifampicin-resistant TB. However, primary isoniazid resistance often is low-level resistance and highdose INH at 15–20 mg/kg/day could possibly still add value in the treatment of children with drug-resistant TB, although it should never replace any other drug in such a regimen.23
SECOND-LINE DRUGS IN CHILDREN There is only limited reported experience with the use of secondline drugs for extended periods in children, but in general adverse effects seem to be less in children than in adults. Careful consideration of the risks and benefits of each drug should be made in designing a regimen. Frank discussion on the importance of adherence to therapy and on possible adverse effects with family members is critical, especially at the outset of therapy. No antituberculous drugs are absolutely contraindicated in children. Since MDRTB is a life-threatening and communicable disease, second-line antituberculous drugs should not be withheld from a child who needs them unless hypersensitivity or an intractable adverse reaction has been documented. Children who have received treatment for drugresistant TB have generally tolerated the second-line drugs well. Adverse effects of second-line drugs are discussed in Appendix A2 of this book and are not significantly different in children. Of note, para-aminosalicylic acid (PAS) and ethionamide, as single drugs and especially in combination, have been associated with hypothyroidism and thyroid-stimulating hormone levels should be monitored every 6 months while a child is receiving these drugs. Although fluoroquinolones have been shown to retard cartilage development in beagle puppies,24–27 experience with the use of fluoroquinolones in humans has not demonstrated similar effects. It is considered that the benefit of fluoroquinolones in treating MDR-TB in children outweighs the risk. Cycloserine (or terizidone) has been used effectively in children and is well tolerated. In adults this drug has been associated with seizures, psychosis, depression, and headache; while these have not been reported in children, it is important to keep these adverse effects in mind during follow-up monitoring. In general, antituberculous drugs should be dosed according to body weight. Monitoring monthly weights is therefore especially important in paediatric cases, with adjustment of doses as the child gains weight. All drugs, including the fluoroquinolones and
52
ethambutol, should be dosed at the higher end of the recommended ranges whenever possible. Ethambutol should be dosed at 25 mg/kg body weight per day. Monitoring for optic neuritis in children under the age of 5 years is difficult, but a recent review showed that children have lower serum concentrations of ethambutol than adults at the same mg/kg body weight dose and that optic neuritis rarely occurs at the recommended dose.28 However, because ethambutol is excreted renally, renal function should be monitored if the child has or is at risk of renal function impairment. The possible role of corticosteroids in the management of TB is discussed in Chapter 61. The use of corticosteroids in children with MDR-TB who have not yet been diagnosed and are only on firstline drugs may cause further progression of disease.
ADHERENCE Adherence is a critical component to successful therapy for TB whether it is drug susceptible or drug resistant. However, regimens for MDR-TB are given for a longer period of time and secondline drugs have more frequent adverse effects. Fortunately, the adverse effects of second-line TB drugs are generally manageable without stopping antituberculous drugs.29 Children who have been treated with second-line drugs have tolerated the medications well and long-term sequelae have not been reported. All patients receiving treatment for MDR-TB should have directly observed therapy, both to minimize missed doses and to observe for adverse effects so that they can be managed promptly. Once- or twicedaily therapy is recommended for the fluoroquinolones as well as for ethionomide and cycloserine. Because of non-availability of child-friendly dosages for these drugs it is often a problem to split the dose in two and, furthermore, observation of drug administration more than once daily is difficult in many areas. For the latter, directly observed therapy is best performed by community-based home visitors rather than in a TB clinic as twice-daily travel to and from clinic is logistically complicated.30 Therapy is often started as twice daily because fractionated dosing reduces side effects, but switched to once daily as soon as the child can tolerate the drug. Para-aminosalicylic acid is given in twice- or three-times daily dosages in acidic base such as yoghurt or orange juice for improved absorption. Home visits are also essential for contact tracing and assessing the socioeconomic status of the family.31 Because children with MDR-TB are usually infected by an adult, these children have often lost parents, older siblings, or other family members to MDR-TB as diagnosis and treatment in developing country settings is scarce.32 Thus, children may be in need of social support. Psychosocial support groups for both adults and children have been successfully run in Peru in conjunction with the MDR-TB or DOTS-Plus programmes.
NUTRITION Malnutrition has been cited as a factor that increases the susceptibility to TB infection and the development of active disease. Although this has not been documented with drug-resistant strains, it is logical to assume that malnutrition is a common underlying factor in children with MDR-TB. Additionally, because of frequent delays in the diagnosis and the initiation of appropriate therapy for MDR-TB, children diagnosed with the disease have been chronically ill with TB, a catabolic disease, for some time. Poverty
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underlies the TB epidemic globally and supplemental nutrition should be considered for children with MDR-TB in whom adequate caloric intake cannot be assured. Additionally, medicines with gastrointestinal adverse effects, specifically ethionamide, are better tolerated when taken with food.
HIV The prevalence of active TB is consistently higher in HIV-infected children due to both higher rates of progression from latent TB to active disease and high rates of reinfection and relapse.33,34 Several studies have documented that in the absence of antiretroviral therapy, HIV-infected children do poorly even with adequate TB treatment.35,36 It is unclear whether the proportion of drug resistance or MDR-TB is higher in HIV-infected than in -uninfected TB patients. Although data collected by the World Health Organization/International Union against Tuberculosis and Lung Disease Global Project on Antituberculosis Drug Resistance suggest that HIV infection is not an independent risk factor for the development of antituberculous drug resistance,4,37,38 other data have shown that HIV-infected patients have an increased rate of resistance to antituberculous drugs.39 In our experience with culture-confirmed childhood TB cases, drug resistance was not significantly different in HIV-infected compared to HIV-uninfected cases.40 Several major outbreaks of MDR-TB have been fueled by the presence of HIV-infected persons in congregate settings such as prisons and hospitals. In these outbreaks, while HIV-infected persons are more susceptible to developing active disease, transmission of MDRTB has been documented to HIV-uninfected individuals as well, including healthcare workers. Outbreaks of MDR-TB among HIV-infected persons have been associated with mortality rates as high as 70–90%.41–44 More aggressive management of MDR-TB has reduced the mortality rate in HIV-infected patients, but recently an outbreak of extensively drug-resistant (XDR)-TB in KwaZuluNatal, South Africa, has caused renewed concern with 84% mortality despite some patients being on antiretroviral therapy.45 XDR-TB is defined as MDR-TB in addition to any fluoroquinolone, and at least one of the second-line injectable drugs used in anti-TB treatment: capreomycin, kanamycin, or amikacin.46 The high mortality rate has been associated with a delay in diagnosis of drug resistance leading to a delay in initiating appropriate therapy. It is difficult to measure the rate of HIV and MDR-TB coinfection because the highest rates of HIV are found in resource-poor settings, which have neither the laboratory facilities needed to detect cases of smear-negative TB by culture nor the capability of performing antituberculous drug susceptibility tests to document the presence of MDR-TB. Lacking such infrastructure for detection of individual cases of MDR-TB, national and regional surveillance of MDR-TB is also limited. Given the prevalence of drug-resistant TB in some congregate settings, when an HIV-infected child has been in a hospital or similar setting, MDR-TB exposure should be considered.
CONTACT TRACING AND CHEMOPROPHYLAXIS Available data indicate that close contacts of MDR-TB patients who develop active TB most commonly have drug-resistant disease.47–51 There are many missed opportunities to halt the spread of resistant mycobacteria to children in households where adults are living with
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MDR-TB. The main reason in developing country settings is that the resistance pattern of the affected adult is unknown due to the lack of access by national treatment programmes to DST or second-line regimens, leaving providers with little reason to look for MDR-TB in the affected adult. Additionally, when a child presents with a positive Mantoux test, there is often a failure to ask parents about close contacts (defined as people living in the same household, or spending multiple hours per day together with the patient in the same indoor living space) who have known or suspected MDR-TB. Symptomatic paediatric household contacts should receive:
an evaluation by a physician, including history and physical examination; tuberculin skin testing with purified protein derivative (PPD); a chest radiograph examination (computed tomography is helpful especially in documenting hilar adenopathy but this is often not available in low-resource areas and is not essential); and sputum smear, culture, and DST: if the child is aged less than 5 years or cannot expectorate sputum, induced sputum or gastric aspiration for smear and culture should be considered.
In a study of children who were contacts of adults with MDRTB, 23% children developed TB, 90% of whom were diagnosed in the first year after infection.50 With this high rate of transmission, it is reasonable to give MDR-TB chemoprophylaxis to children with an exposure to a household contact. The current WHO guidelines on MDR-TB recommend no specific chemoprophylaxis for contacts of MDR-TB patients other than INH for the possibility that infection may be due to contact with a source other than the MDR-TB source case in high TB incidence areas.18 Failure of INH chemoprophylaxis in INH-resistant and MDR-TB contacts has been documented. No randomized controlled trials have been done on the efficacy of the treatment of latent TB in MDR-exposed adults or children. In a Delphi survey published in 1994, a panel of experts agreed that some form of preventive therapy was warranted; however, they could not reach a defined consensus on what regimen should be used, although a regimen of pyrazinamide with ciprofloxacin for 4 months was considered somewhat appropriate.52 Subsequently, and despite the lack of evidence, the Centers for Disease Control and Prevention together with the American Thoracic Society and the Infectious Diseases Society of America recommended a two-drug regimen for people with latent TB infection exposed to MDR-TB: pyrazinamide and ethambutol or pyrazinamide and ofloxacin/levofloxacin.53 A prospective childhood contact study mentioned earlier found individualized tailored chemoprophylaxis with two drugs to which the source cases were susceptible or naı¨ve for 6 months to be effective for preventing active TB in children.50 Further studies are urgently needed to evaluate regimens and duration of chemoprophylaxis for specifically young and immune-compromised patients in contact with MDR-TB source cases. In the mean time, some recommend the use of INH chemoprophylaxis, preferably at high dose (15–20 mg/kg),23 and adding two drugs to which the source case is susceptible or naı¨ve may be considered in high-risk contacts. However, the value of INH even at high dose is debatable in contacts of MDR-TB source cases, and possible use of multidrug regimens (usually two drugs), including drugs such as pyrazinamide, a fluoroquinolone, and ethambutol, depending on the susceptibility of the source case’s isolate could be considered.54 The recommended WHO alternative is careful clinical follow-up, most likely 2–3 times monthly for the first 6 months and thereafter 6-monthly for at least two years.18 If active disease develops, prompt
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initiation of treatment with a regimen designed to treat MDR-TB and using the source case’s DST pattern is recommended. Yet it is feasible to further elaborate this recommendation in several scenarios: 1. Child has a positive TST and a household contact with MDR-TB: such a child should have careful evaluation for disease with clinical exam and chest radiograph and, if disease is not present, be given treatment for latent infection with two drugs to which the contact’s isolate is susceptible. 2. Child has a negative TST and a household contact with MDR-TB: such a child should have the TST repeated every 4–6 weeks until after the source case is cured. If the child converts during this surveillance, they would be treated as above (including exclusion of disease). 3. TST is not available: when TST is not available the child should undergo screening with initial physical exam and chest radiograph, with the physical exam repeated every 4–6 weeks.
REFERENCES 1. World Health Organization. Global tuberculosis control: surveillance, planning, financing. Geneva: World Health Organization, 2005. WHO/HTM/TB/2005.349. 2. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1009–1021. 3. Starke JR. Pediatric tuberculosis: time for a new approach. Tuberculosis 2003;83:208–212. 4. World Health Organization. Anti-tuberculosis drug resistance in the world: Third global report. The WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance, 1999–2002. Geneva: World Health Organization, 2004. WHO/HTM/ TB/2004.343. 5. Swanson DS, Starke JR. Drug-resistant tuberculosis in pediatrics. Pediatr Clin North Am 1995;42:553–581. 6. Schaaf HS, Gie RP, Beyers N, et al. Primary drugresistant tuberculosis in children. Int J Tuberc Lung Dis 2000;4:1149–1155. 7. Bloch AB, Cauthen GM, Onorato IM, et al. Nationwide survey of drug-resistant tuberculosis in the United States. JAMA 1994;271:665–671. 8. Smuts NA, Beyers N, Gie RP, et al. Value of the lateral chest radiograph in tuberculosis in children. Pediatr Radiol 1994;24:478–480. 9. Schluger NW, Lawrence RM, McGuiness G, et al. Multidrug-resistant tuberculosis in children: two cases and a review of the literature. Pediatr Pulm 1996; 21:138–142. 10. Mukherjee JS, Joseph JK, Rich ML, et al. Clinical and programmatic considerations in the treatment of MDR-TB in children: a series of 16 patients from Lima, Peru. Int J Tuberc Lung Dis 2003;7:637–644. 11. Steiner P, Rao M, Mitchell M, et al. Primary drugresistant tuberculosis in children. Emergence of primary drug-resistant strains of M. tuberculosis to rifampin. Am Rev Respir Dis 1986;134:446–448. 12. Schaaf HS, Marais BJ, Hesseling AC, et al. Childhood drug-resistant tuberculosis in the Western Cape Province of South Africa. Acta Paediatrica 2006;95:523–528. 13. Schaaf HS, Shean K, Donald PR. Culture-confirmed multidrug-resistant tuberculosis in children: diagnostic delay, clinical features, response to treatment and outcome. Arch Dis Child 2003;88:1106–1111. 14. Furin JJ, Becerra MC, Shin SS, et al. Effect of administering short-course, standardized regimens in individuals infected with drug-resistant Mycobacterium tuberculosis strains. Eur J Clin Microbiol Infect Dis 2000;19:132–136. 15. Espinal MA, Kim SJ, Suarez PG, et al. Standard shortcourse chemotherapy for drug-resistant tuberculosis:
16.
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CONCLUSION Children are not spared the growing problem of MDR-TB and probably XDR-TB. Those who have active disease with MDRTB usually have been infected by transmission of a strain of M. tuberculosis already resistant to isoniazid and rifampin from an adult household contact. If such contact history is not sought, the delay in diagnosis of MDR-TB is likely to be long owing to the difficulty of obtaining bacteriological confirmation in children. Because delays in the initiation of appropriate therapy may result in morbidity and mortality in infected children, empirical treatment for MDR-TB in children with active TB disease who have a known household contact with MDR-TB is reasonable and could be guided by the drug susceptibility pattern of the adult source case. With good clinical and laboratory monitoring, children have been found to tolerate second-line antituberculous drugs well.
treatment outcomes in 6 countries. JAMA 2000; 283:2537–2545. Manalo F, Tan F, Sbarbaro JA, et al. Communitybased short-course treatment of pulmonary tuberculosis in a developing nation: initial report of an eight-month, largely intermittent regimen in a population with a high prevalence of drug resistance. Am Rev Respir Dis 1990;142:1301–1305. Kimerling ME, Kluge H, Vezhnina N, et al. Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999;3:451–453. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization, 2006. WHO/HTM/TB/2006.361. Engelbrech AL, Marais BJ, Donald PR, et al. A critical look at the diagnostic value of cultureconfirmation in childhood tuberculosis. J Infect 2006;53:364–369. Epub 2006 Feb 7. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005;365:130–34. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children with multidrug resistant tuberculosis. Pediatrics 2006; 117:2022–2029. Nelson LJ, Wells CD. Tuberculosis in children: considerations for children from developing countries. Semin Pediatr Infect Dis 2004;15:150–154. Schaaf HS, Victor TC, Engelke E, et al. The minimal inhibitory concentration of isoniazid-resistant Mycobacterium tuberculosis isolates from children. Eur J Clin Microbiol Infect Dis 2007;26:203–205. Farmer P, Bayona J, Becerra M, et al. The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis 1998;2:869–876. Takizawa T, Hashimoto K, Minami T, et al. The comparative arthropathy of fluoroquinolones in dogs. Hum Exp Toxicol 1999;18:392–399. Warren RW. Rheumatologic aspects of pediatric cystic fibrosis patients treated with fluoroquinolones. Pediatr Infect Dis J 1997;16:118–126. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use—safety report. Pediatr Infect Dis J 1997;16:127–129. World Health Organization. Ethambutol efficacy and toxicity: literature review and recommendations for daily and intermittent dosage in children. Geneva: World Health Organization, 2006. WHO/HTM/ TB/2006.365. Furin JJ, Mitnick CD, Shin SS, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:648–655.
30. Shin S, Furin J, Bayona J, et al. Community-based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med 2004;59: 1529–1539. 31. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999;341:1491–1495. 32. Gupta R, Kim JY, Espinal MA, et al. Public health. Responding to market failures in tuberculosis control. Science 2001;293:1049–1051. 33. Schaaf HS, Krook S, Hollemans DW, et al. Recurrent culture-confirmed tuberculosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2005;24:685–691. 34. Cotton MF, Schaaf HS, Hesseling AC, et al. HIV and childhood tuberculosis—the way forward. Int J Tuberc Lung Dis 2004;8:675–682. 35. Mukadi YD, Wiktor SZ, Coulibaly IM, et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cote d’Ivoire. AIDS 1997;1: 1151–1158. 36. Hesseling AC, Westra AE, Werschkull H, et al. Outcomes in HIV-infected children with cultureconfirmed tuberculosis. Arch Dis Child 2005;90; 1171–1174. 37. Espinal MA, Laserson K, Camacho M, et al. Determinants of drug-resistant tuberculosis: analysis of 11 countries. Int J Tuberc Lung Dis 2001;5: 887–893. 38. Dupon M, Texier-Maugein J, Leroy V, et al. Tuberculosis and HIV infection: a cohort study of incidence and susceptibility to antituberculous drugs, Bordeaux, 1985-1993. AIDS 1995;9:577–583. 39. Gordin FM, Nelson ET, Matts JP, et al. The impact of human immunodeficiency virus infection on drug-resistant tuberculosis. Am J Respir Crit Care Med 1996;15:1478–1483. 40. Schaaf HS, Marais BJ, Whitelaw A, et al. Cultureconfirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases. BMC Infect Dis 2007;7(1):140 [Epub ahead of print]. 41. Dooley SW, Jarvis WR, Martone WJ, et al. Mutlidrug-resistant tuberculosis. Ann Intern Med 1992;117:257–258. 42. Centers for Disease Control. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons—Florida and New York, 1988-1991. MMWR 1990;40:585–591. 43. Herrera D, Cano R, Godoy F, et al. Multidrugresistant outbreak on an HIV ward—Madrid Spain, 1991-1995. MMWR 1996;45:330–333. 44. Moro ML, Gori A, Errante I, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS 1998;12:1095–1102.
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45. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575–1580. 46. World Health Organization. Report of the meeting of the WHO Global Task Force on XDR-TB. Geneva: World Health Organization, 2006. WHO/ HTM/TB/2006.XXX. 47. Kritski AL, Ozorio Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 1996;153:331–335. 48. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of multidrug resistant tuberculosis. Pediatr Infect Dis J 2000;19(8):695–699.
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49. Teixeira L, Perkins MD, Johnson JL, et al. Infection and disease among household contacts of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:321–327. 50. Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young children in contact with adult multidrugresistant pulmonary tuberculosis: a 30-month followup. Pediatrics 2002;109:765–771. 51. Bayona J, Chavez-Pachas AM, Palacios E, et al. Contact investigations as a means of detection and timely treatment of persons with infectious multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2003;7(Suppl 3):S501–S509.
52. Passanante MR, Gallagher CT, Reichman LB. Preventive therapy for contacts of multidrug-resistant tuberculosis. A Delphi survey. Chest 1994;106:431–434. 53. American Thoracic Society, Centers for Disease Control and Prevention and Infectious Disease Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–S247. 54. American Academy of Pediatrics. Tuberculosis. In: Pickering LK, Baker CJ, Long SS, et al. (eds) Red Book: 2006 Report of the Committee on Infectious Diseases, 27th edn. Elk Grove Village, IL: American Academy of Pediatrics, 2006: 678–704.
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Multidrug-resistant tuberculosis in adults Francis Drobniewski and Priya Khanna
OVERVIEW Effective early diagnosis, especially of the infectious smear-positive cases, and cure through combination chemotherapy are the principal tools for the prevention of drug resistance including multidrugresistant TB (MDR-TB) (i.e. resistance to at least isoniazid and rifampicin).1 The targets set up by the World Health Organization (WHO) to detect, by 2005, 70% of new sputum smear-positive cases and to successfully treat 85% of these cases have not been achieved; the global case detection rate (although very variable across different countries), reached 60% in 2005, falling short of the 70% target. Treatment success was 84%, 1% short of the 85% target set for the 2004 cohort.2 Individual and programmatic treatment failures have led to increasing rates of drug resistance globally either due to acquired resistance during therapy or in primary resistance where individuals are infected with resistant bacterial strains. Multidrug resistance is the most problematic form of resistance with the recent added complication of extensive drug resistance (XDRTB), i.e. MDR strains which are also resistant to key second-line drugs (kanamycin, amikacin or capreomycin plus any fluoroquinolone). The global rate of drug-resistant TB is not known with certainty but modelling studies have suggested that there were nearly half a million cases of MDR-TB in 2004 and XDR-TB has been reported widely across the globe.3
EPIDEMIOLOGY The real extent of drug resistance, and particularly MDR-TB, is unknown. In part this uncertainty has been due to methodological problems including the absence of longitudinal studies for detecting trends in many countries, failure to differentiate primary and acquired drug resistance in analyses, the selection bias of many surveys and the absence of high-quality laboratory culture facilities.4 Thus, despite the expansion of drug resistance surveillance for both new and previously treated cases in recent years, data on drug resistance are still not available for > 100 countries including many of the WHO-defined ‘high TB burden countries’.3 Nevertheless, there are clear recommendations for standardizing drug resistance surveillance,5 and the WHO and International Union against Tuberculosis and Lung Disease (IUATLD), underpinned by a global international network of Supranational Reference Laboratories, have been systematically mapping the extent of drug resistance, including MDR-TB. Three key reports have
documented the existence of drug resistance and MDR-TB in every corner of the globe.1,6,7 There remain sizeable gaps in our understanding of the distribution of cases globally, detailed systematic determinations of temporal trends remain limited and our comprehension of the magnitude of the global burden of disease due to MDR-TB is therefore uncertain. These gaps not withstanding, estimates of the global burden have been made; in 2004, an estimated 424,203 (95% confidence interval (CI), 376,019–620,061) MDR-TB cases occurred, or 4.3% (95% CI, 3.8–6.1%) of all new and previously treated TB cases. If one assumes that the duration of the disease is between 2 and 3 years, the global prevalence of MDR-TB would range from 850,000 to 1,300,000.3 Three countries, China, India and the Russian Federation, accounted for 261,362 MDR-TB cases, or 62% of the estimated total global burden.3 National and regional studies have also confirmed that drug resistance, including MDR-TB, has been increasing in recent years but cases of MDR-TB are not evenly distributed across the world.1,2,8 Most North American, and Western and Central European countries do not have a significant problem with drug resistance in newly diagnosed cases, reporting approximately 5–10% isoniazid resistance and 1–2% MDR-TB.1,2,9–11 In contrast, the Eastern European region has accounted for very high rates of MDR-TB (with a prevalence of MDR-TB of 9.9 and 39.9% among new and previously treated cases, respectively3) in particular in the Baltic region and countries of the former Soviet Union including Russia.12–16 Unfortunately, only a limited number of internationally validated drug resistance surveys (DRS) have been conducted within Russia and these demonstrated extremely high rates of MDR-TB of approximately 10–20% in new patients and approximately 40% in re-treatment cases.17–29 However, even in Russia, there is variation, with low MDR-TB rates seen in the Orel region where, for example, no cases were human immunodeficiency virus (HIV) infected, differing from that of other regions of Russia.30 In the third round of the WHO Global project data from 79 countries and geographical settings were included; 66 of these countries or settings provided information on drug resistance in new, previously treated and combined cases. The highest prevalence of MDR-TB was reported from Kazakhstan and Israel followed by Tomsk Oblast (Russia), Karakalpakstan (Uzbekistan), Estonia, Lianong province (China), Lithuania, Latvia and Henan province (China) with a prevalence of multidrug resistance of 7.8%. Trends for resistance were analysed in 20 countries with two data points and in 26 countries that provided three data points since 1994. Significant increases in the
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prevalence of resistance to any drug were noted in Botswana (p < 0.0001), New Zealand ( p ¼ 0.015) and Tomsk Oblast ( p ¼ 0.005), whereas significant decreases were reported in Cuba ( p ¼ 0.017) and Hong Kong (p ¼ 0.023). A significant increase in the prevalence of multidrug resistance in new cases was recorded in Tomsk Oblast (p < 0.0001). Significant decreasing trends in multidrug resistance were reported in Hong Kong (p ¼ 0.01) and the USA ( p ¼ 0.002).31 Countries with a low prevalence of drug resistance including MDR-TB may have ‘hot spots’ of resistance. For example, cities such as New York and London have suffered disproportionately in the incidence and prevalence of drug resistance and particularly MDR-TB cases. New York, in a long campaign, turned the tide against MDR-TB in a successful but costly rejuvenation of the TB control system including improvements in diagnosis, case management, clinic and public health infrastructure and outreach provision, and modifications in public health law to improve patient adherence.32,33 The quality of the drug resistance data from the Global Drug Resistance Project is arguably more reliable than that obtained from routine surveillance (and indeed the MDR-TB figure quoted earlier relies heavily on these surveys). When countries are compared, MDR-TB prevalence rates were more variable in the routinely collected data, and the absolute prevalence rates calculated from the two sources did not agree closely. They were also poorly correlated in general, though there was a clear association between surveys and routine surveillance for European countries. If the routinely collected data are to be used for assessing MDR-TB burden and trends, they must be unbiased, and drug susceptibility testing must follow recommended laboratory procedures. In European countries, culture and drug susceptibility tests (DST) are offered to a large proportion of TB patients, which probably reduces selection bias and explains the relatively strong association between measures of MDR-TB prevalence for countries in the European
Region from the DRS project and surveillance.1 The number of reported TB cases is given in Fig. 53.1, and the global prevalence of MDR-TB in new cases from 1994 until 2002 drawn from the special surveys is shown in Fig. 53.2. There is little systematic data on second-line drug resistance regionally or nationally (most data have been based on studies from a single or a small number of institutions). Data for systematic first- and second-line drug resistance in MDR-TB cases in a study of 17 European countries from 2003 to 2005 (where the ex-Soviet Baltic states of Latvia and Estonia accounted for 66% of reported MDR-TB cases) and Samara, a comparable region of the Russian Federation, are shown in Table 53.1.16 The emergence of XDR-TB strains of Mycobcterium tuberculosis (i.e. MDR-TB strains also resistant to any fluoroquinolone and at least one of the injectable agents: kanamycin, amikacin or capreomycin) has recently been documented in many countries particularly in those of the former Soviet Union in Eastern Europe. Global concern increased when extremely high death rates were seen among patients with XDR-TB coinfected with HIV at a hospital in the South African province of KwaZulu Natal. The injectable agents and fluoroquinolones are some of the most important reserve drugs which, when included in a treatment regimen, significantly improve a patient’s chances of survival.35 All but one of 53 South African patients identified to be infected with XDR strains died with median survival of only 16 months.36 In a survey conducted by the Centers for Disease Control and Prevention (CDC), WHO, the UK Health Protection Agency National Mycobacterium Reference Unit and other international laboratories, data were obtained on XDR-TB cases in general, and specifically for the USA (for 1993–2004), Latvia (2000–2002) and South Korea (2004); among MDR-TB cases, an XDR prevalence of 4%, 19% and 16%, respectively, was shown for these countries;37–39 XDR-TB strains were found in at least 17 countries
< 10,000 10,000 < 50,000 50,000 < 100,000 100,000 < 500,000 500,000
Fig. 53.1 Global reported TB cases notified to World Health Organization. Source: WHO Stop TB Department, Website: www.who.int/tb; accessed on 29th April 2007.
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Prevalence - 0.9% 1.0% 2.9% 3.0% 6.4% 6.0% The designations employed and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area of its authorities, or concerning the delimitation of its frontiers or boundaries. Dashed lines represent approximate border lines for which there may not be full agreement.
Fig. 53.2 Prevalence of MDR among new cases, 1994–2002. Courtesy of WHO/IUALTD, Global project on antituberculous drug surveillance in the world. Report no. 3. Geneva: World Health Organization, 2004(WHO/HTM/TB/2004.343).
Table 53.1 Comparative data on drug resistance from Latvia and Estonia (n ¼ 800), Samara Region, Russia and other countries in Europe (n ¼ 246) Drug
Streptomycin Ethambutol Pyrazinamide Kanamycin Capreomycin Ethionamide PAS Ofloxacin Ciprofloxacin Amikacin Cycloserine Rifabutin Clofazimine Doxycycline
a
Estonia and Latvia
Other countries
Samara, Russia
No. resistant
% resistant
No. resistant
% resistant
No. resistant
773 641 441 425 249 234 172 124 — 34 11 — — —
97% 80% 55% 53% 31% 29% 22% 16% — 4% 1% — — —
142 105 82 26 11 42 55 10 11 25 20 106 — —
58% 43% 33% 11% 4% 17% 22% 4% 4% 10% 8% 43% — —
281 161 23 — — — — — 3/69 5/69 1/69 60/68 2/68 5/68
% resistant 49% 28% 9% — — — — — 5% 8% 2% 88% 3% 8%
a Countries involved include Belgium, Croatia, Cyprus, Czech Republic, Denmark, Finland, Ireland, Israel, Netherlands, Norway, Romania, Slovenia, Spain, Sweden and Switzerland. Adapted from Kru¨u¨ner et al (2001),12 EuroTB (2005),16 Ruddy et al (2005),22 Balabanova et al (2005).34
and almost 10% of all MDR strains were also resistant to secondline agents.35 Extensive drug-resistant TB cases have been reported in many countries as indicated in Chapter 54, Fig. 54.1. These data are likely to underestimate the true extent of the problem and more extensive surveys are needed to determine prevalence and risk factors for XDR-TB.36,40
The emergence of XDR-TB poses a major threat to the successful control of TB especially in countries with high HIV prevalence. Combination of resistance to the main TB drugs makes the disease potentially untreatable and requires the development of novel effective anti-TB agents.41 Improvement of infection control, development and introduction of more rapid and accurate diagnostic tests, wider
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dissemination of second-line DST and strict surveillance are essential for timely diagnosis, monitoring and treatment of resistant cases.37,38 Most importantly, the reasons underlying the presence of MDR-TB and XDR-TB need to be addressed quickly and effectively.
LABORATORY DIAGNOSIS OF RESISTANCE FIRST-LINE DRUGS SUSCEPTIBILITY TESTING Conventional methods Drug susceptibility testing is of undoubted value in the evaluation of therapeutic regimens and planning wide-scale treatment. Accuracy is more important than speed as much harm can be done by prescribing a more toxic yet less effective regimen on the basis of a false report of resistance or by trusting a false report of susceptibility rather than the patient’s failure to respond to a regimen. So DST should be performed by well-equipped, experienced laboratories that participate and perform well in an international DST quality control scheme. As a minimum standard, laboratories supplying DST results to clinicians, government and WHO for surveys or surveillance, should correctly identify resistance to isoniazid and rifampicin in over 90% of quality control samples in two out of the three quality control rounds under the WHO scheme. The WHO Supranational Laboratory Quality Control Network offers the greatest global coverage by assessing participating laboratories in their ability to identify isoniazid, rifampicin, ethambutol and streptomycin resistance correctly.1 Four DST methods have been standardized and are widely used throughout the world to measure the drug resistance of M. tuberculosis:42,43 the absolute concentration method, resistance ratio method, proportion method with variants and the BACTEC 460 radiometric method (and now based on the non-radiometric MGIT 960 system). All the methods give accurate results provided they are carefully quality controlled and standardized.1,42,44 Early speciation of mycobacterial growth into M. tuberculosis complex (principally M. tuberculosis and Mycobacterium bovis) and atypical mycobacteria along with detection of rifampicin resistance should take precedence as rifampicin resistance invalidates standard 6-month short-course chemotherapy. Moreover, rifampicin resistance is usually a useful marker of MDR-TB in many countries. Laboratories should aim to identify isolates as M. tuberculosis complex and perform rifampicin resistance in 90% of isolates within 1–2 working days.45 This is challenging but technologically feasible.46–62 Laboratories should also aim to identify M. tuberculosis and rifampicin resistance in over 90% of cases from smear-positive sputum directly where resources are available for this (this will require an investment in appropriate infrastructure, staffing and the implementation of new methodological techniques). European standards for DST have recently been published.45 The frequency of repeat testing of known MDR-TB cases should be limited. In practice, patients with MDR-TB do not need to have DST repeated more than every 2 months.45 In many resource-poor countries, however, the laboratory diagnosis of drug resistance and MDR-TB is poor. This coupled with an intermittent drug supply or the supply of poor quality first- and second-line drugs compromises the success of individual therapy as well as the TB programme as a whole. Rapid methods Rapid liquid culture systems for DST Rapid non-radiometric automated culture methods (e.g. MGIT 960), used for the rapid culture of mycobacteria, are also being
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used for drug resistance analysis. There are several studies that have used these rapid systems to determine susceptibilities/resistance to first-line drugs.63–72 Since capital costs are high and laboratory containment facilities must be of the highest order, it is to be expected that these assays will be performed in larger reference centres. For such services to be functional, good communication both internally within the laboratory and externally with clinicians is essential. Delays in referring specimens and reporting information can lead to a delay in diagnosis, treatment and infection control. A good example is the results of the study by Yagui et al which showed that the total turnaround time from sputum production to diagnosis of MDR-TB and subsequent modification of treatment took 5 months, almost twice as long as the bacteriological procedures themselves.73
Molecular assays Novel molecular assays offer several potential advantages including faster turnaround times for MDR-TB analysis. Many of the key gene mutations conferring drug resistance have been identified, permitting the development of both in-house and commercial molecular assays.46–59,74–91 Nevertheless, the majority are more costly than the current bacteriological methods; the exact proportion of resistant to susceptible organisms producing resistance clinically is unclear and the presence of common gene mutations is not always associated with drug resistance (i.e. silent mutations). However, for drugs such as rifampicin and isoniazid the mutations associated with resistance are now well known and studies have demonstrated their value in the context of centralized national and regional services.15,50,60,86,92,93 They may be of particular value in countries with high rates of MDR-TB. According to the NICE Guidelines, 2006, the TB service should consider the risk for drug resistance and, if the risk is regarded as significant, urgent molecular tests for rifampicin resistance should be performed on smearpositive material or on positive cultures when they become available.94 It is important to bear in mind that although the choice of drugs for therapy can be partially determined using molecular systems, phenotypic culture-based assays are usually considered to be the ‘gold standard’ and are needed to determine which additional agents should be added. Nevertheless rapid analysis of rifampicin and isoniazid resistance in all sputum specimens, with the same sensitivity and specificity as bacterial culture methods, but within 1–2 working days followed by relatively rapid identification of appropriate second-line drugs using liquid culture-based systems would be an optimal strategy. SECOND-LINE SUSCEPTIBILITY TESTING For patients with proven MDR-TB, second-line drug therapy should be instituted, which will require accurate and ideally rapid determination of susceptibility to second-line drugs.95 Standardized second-line treatment programmes based on surveys or individualized treatment will produce higher treatment cure rates than no therapy or first-line drug therapy alone (although treatment must be prolonged). Although individualized treatment strategies will produce the highest cure rates, this will be dependent on the continuous availability of appropriate drugs and the adherence of the patient to the regimen. It is the responsibility of the laboratory, in consultation with the clinician, to determine the spectrum of drugs to be tested. Measuring resistance to second-line drugs is complex and lacks standardization for many drugs. Commercial companies may be reluctant to facilitate standard measurement by providing the pure
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drug reagents needed, tempting some incorrectly, to use pharmaceutical preparations in drug testing. This is important where different drugs within a class are being used for treatment; e.g. it would be negligent to utilize rifabutin to treat rifampin-resistant strains without accurate DST, and similarly for amikacin in strains resistant to streptomycin. In 2001, WHO published guidelines on second-line DST analysis,95 which were premature as subsequent multicentre analysis showed that results obtained from different second-line DST methods were not comparable.96,97 Kru¨u¨ner et al and RuschGerdes et al in their recent studies showed that there is good correlation for most, but not all, second-line drugs between the solid medium-based methods based on proportion and resistance ratio methods and the MGIT 960 system.72,98 Thus, there is a need to develop international quality assurance programmes for second-line drug resistance analysis.45,99 Other methods that have been explored with some success are the early bactericidal activity (EBA) assays used as surrogates for the above methods.100–102
CLINICAL TREATMENT OF MULTIDRUGRESISTANT TUBERCULOSIS The aims of effective treatment are to cure the patient of TB, to prevent death and morbidity from active TB, to prevent relapse of TB, to prevent transmission to others and to prevent development of acquired drug resistance.
TREATMENT OF DRUG-SUSCEPTIBLE TUBERCULOSIS Treatment of drug-susceptible TB is highly effective and is based on a standardized strategy proved over several decades in international clinical trials. Treatment regimens include a combination of drugs administered for a defined period, usually 6–9 months depending on the form of TB and past history of anti-TB treatment. Modern treatment regimens include four first-line drugs (isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin) for the first 2 months followed by isoniazid and rifampicin for the remaining continuation phase.103–109 Treatment is prolonged where the patient is coinfected with HIV. The early administration of appropriate therapy is essential for both preventing the emergence of MDR-TB and treating it when it occurs.110
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS Multidrug-resistant TB represents a substantial challenge to TB control programmes, since the treatment of such cases is complex, more costly and frequently less successful than non-resistant strains. Ultimately patients are more likely to die (and reported cure rates for MDR-TB cases have ranged from 6% to 59%111) although death from MDR-TB disease is not inevitable (just as death from TB before the advent of chemotherapy was not a certainty). A key observation made over 20 years ago remains valid: ‘the largely forgotten fact that one-third of patients with advanced disease with positive sputum smears recover on their own should be kept in mind when claims are made that an inappropriate drug regimen cured a patient with bacterial resistance.’112 Patients with MDR-TB are generally not cured by standard four-drug short-course chemotherapy, the cornerstone of directly
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observed therapy, short course (DOTS).27,113,114 The standard approach in most industrialized countries today is to treat MDRTB with second-line, or reserve drugs. Treatment of MDR-TB cases should be carried out only in specialized centres with sufficient diagnostic and clinical experience. The management strategy should include designing an optimal treatment regimen, based on individual second-line DST of the isolated bacterium if available (or representative data from drug resistance surveys), direct observation of treatment and a plan for monitoring and managing adverse drug reactions.115 Treatment of infectious MDR-TB cases can be carried out at in-patient facilities; non-infectious patients’ choice between hospitalization and ambulatory treatment should be based on severity of disease and social conditions, availability of hospitals with adequate facilities and appropriate infection control measures. As part of the global policy response to MDR, WHO developed a ‘DOTS-Plus’ strategy for the use of second-line drugs in the management of these patients in 1999, followed by the establishment of the Green Light Committee in 2000 to provide access to preferentially priced second-line drugs while ensuring rational use through mandatory programme review and monitoring. The culmination of these efforts has led to the development of WHO guidelines for the pragmatic management of drug-resistant TB.115 Management of MDR-TB cases is complex; often drugs are changed due to side effects and adverse reactions or poor response to treatment. Ideally, the TB control programme in each country should design a treatment strategy when both the drug resistance survey data and the availability and use of anti-TB drugs in the country have been assessed. Programmes that plan to introduce a treatment strategy for drug-resistant TB should be familiar with the prevalence of drug resistance in new patients as well as in different groups of retreatment cases (failure, relapse, return after default and other cases). Three different but effective programme treatment strategies have been formulated:115
Standardized treatment: Regimens are designed on the basis of representative DST data. However, suspected MDR-TB should always be confirmed by DST results whenever possible. All patients in a defined category receive the same treatment regimen. Empirical treatment: Each treatment is individually designed on the basis of a previous history of antituberculous treatment and with the help of representative DST survey data. Empirical treatment is adjusted in each patient when the DST results become available. Individualized treatment: Each treatment is designed on the basis of previous antituberculous treatment and individual DST results.
The drugs used for treatment are described in Table 53.2 and Table 53.3. Table 53.2 describes the main doses and side effects of second-line drugs. Regardless of type of treatment regimen used (standard, empirical or individualized) the following basic principles should be observed:
A detailed history of anti-TB drugs taken by a patient in the past should be obtained. National data on prevalence and patterns of drug resistance to the first- and second-line agents should also be considered when designing a regimen. Regimens should consist of at least four drugs with either certain or almost certain effectiveness. Susceptibility to each drug should be confirmed by laboratory testing. Treatment should be conducted under direct supervision for at least 6 days a week; an injectable agent (an aminoglycoside
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Table 53.2 Second-line drugs, dosages and side effects a
62,110,116–118
Drug
Route
Daily dose
Major side effects
Notes
Ciprofloxacin
PO
500–1,000 mg (max: 1.500 mg) (2 doses)
Antacids, iron supplements and sucralfate reduce gastrointestinal absorption
Ofloxacin Moxifloxacin
PO PO
600–800 mg 400 mg
Amikacinb
IM IV
15 mg/kg (max: 1 g)
Protionamide
PO
0.5–1 g (in 1–2 doses)
Cycloserine
PO
0.5–1 g (in 1–2 doses)
Capreomycin
IM
15 mg/kg (max: 1 g)
PAS
PO
8–12 g (divided doses)
Clarithromycin
PO IV
500 mg PO (2 doses)
Clofazimine
PO
100–300 mg
GI upset, abdominal cramps, photosensitivity, headache, insomnia, interacts with warfarin and theophylline, hypersensitivity As above GI upset, raised LFT, jaundice, CNS problems, prolonged QT interval, photosensitivity Ototoxicity, renal toxicity, occasional vestibular toxicity, hypokalaemia hypomagnesaemia GI upset, raised hepatic enzymes, metallic taste, hypothyroidism (more likely if PAS given concurrently). Antacids/emetics may help but watch other drugs’ interactions. Rash, psychosis, depression, seizures, headache, increases phenytoin levels. Avoid if underlying CNS problems or depression. Ototoxicity, renal toxicity, vestibular toxicity, hypokalaemia, hypomagnesaemia, eosinophilia. GI upset, increased hepatic enzymes, decreased digoxin levels, increased phenytoin levels, haemolytic anaemia in glucose-6-phosphate dehydrogenase deficiency. GI upset, jaundice, hepatitis, interaction with many drugs including anticoagulants, antiepileptics, digoxin, rifabutin, usually by reducing liver enzyme activity. GI upset, causes skin darkening, abdominal pain, rare organ damage if drug crystal deposits occur.
As above Monitor LFT and renal function
Monitor auditory and renal function, blood chemistry Monitor LFT. Start with 250 mg daily dose and increase as tolerated. Increase to bd quickly. Start with 250 mg daily and increase.
Monitor auditory and renal function. Blood chemistry. Commence 1–2 g tds and increase as tolerated by patient. Tablets create a high sodium load—monitor volume and electrolytes in cardiac and renal patients. Only modest activity against TB, used principally to prevent emergence of drug resistance. Avoid sunlight, dosing at mealtime may be helpful.
CNS, central nervous system; GI, gastrointestinal; IM, intramuscular; IV, intravenous; PAS, para-aminosalicylic acid; PO, per os. Drugs are given daily, orally whenever possible. Treatment of drug-resistant TB should be performed by those experienced in its management. b After bacteriological conversion, aminoglycosides can be given thrice weekly. Adapted from Drobniewski (1998),62,110 British Thoracic Society (1994,1998),116,117World Health Organization.118 a
Table 53.3 Alternative method of grouping antituberculous drugs
115
Grouping
Drugs (abbreviation)
Group 1—First-line oral antituberculous agents Group 2—Injectable antituberculous agents
Isoniazid (H), rifampicin (R); ethambutol (E), pyrazinamide (Z) Streptomycin (S), kanamycin (Km), viomycin (Vi), amikacin (Am), capreomycin (Cm) Ciprofloxacin (Cfx), ofloxacin (Ofx), levofloxacin (Lfx), moxifloxacin (Mfx),a gatifloxacin (Gfx)a Ethionamide (Eto), protionamide (Pto), cycloserine (Cs), terizidone (Trd),a P-aminosalicylic acid (PAS), thiacetazone (Th)b Clofazimine (Cfz), amoxicillin/clavulanate (Amx/Clv), clarithromycin (Clr), linezolid (Lzd)
Group 3—Fluoroquinolones Group 4—Oral bacteriostatic second-line antituberculous Group 5—Antituberculous agents with unclear efficacy (not recommended by WHO for routine treatment of MDR-TB patients) a
The long-term safety and efficacy for MDR-TB treatment have not yet been fully confirmed and therefore use ‘is not yet recommended’ for treatment of MDR-TB. b Thiacetazone should be used only in patients documented to be HIV-uninfected and should usually not be chosen over other drugs listed in Group 4. Taken from: World Health Organization. Guidelines for Programmatic Management of Drug-Resistant tuberculosis. WHO/HTM/TB/2006.361.Geneva:World Health Organization. Available at URL:http//www.who.int/tb/publications/2006/who_htm_tb_2006_361/en/index.html
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or capreomycin) must be used for at least 6 months; after the initial period of daily injections (2–3 months), the injectable agent can be administered intermittently (thrice weekly) especially in cases when it has been used for a prolonged period of time and the risk of toxicity is high. Duration of treatment is at least 18 months after culture conversion and extension to 24 months may be indicated for chronic cases. Reliable DST should be used to guide therapy. Pyrazinamide can be used through the treatment as in many chronic cases the lungs are inflamed, creating acidic environment when pyrazinamide is active.109,115
In 2006, detailed guidelines on the management of drug-resistant cases, and particularly MDR-TB, was published by WHO.115 When effective second-line drugs are used, treatment success in MDR-TB cases varies from 48% to more than 80% in good programmes.119–121 For example in Peru, 75 MDR-TB cases were successfully treated, despite resistance to a median of six drugs.120 Of 66 patients who completed therapy, 55 (83%) had a favourable outcome, five (8%) died, emphasizing the importance of early initiation of an appropriate drug regimen. Death rates varying from 0 to 37% were reported in studies of HIV-uninfected individuals, and up to 89% in HIV-infected populations.119,121,122 Even in high-income countries like the UK with access to individualized therapy, survival has been relatively low with a median survival time overall of 3.78 (3.66–6.89) years.123 Several studies suggest that patients who are in poor clinical condition prior to treatment and who are infected with organisms resistant to a large number of drugs are associated with poor outcomes.119,120,123 This is in keeping with the low survival seen in those with XDR-TB. In industrialized countries, treatment in specialized centres with relatively unlimited resources improves survival.124,125 In a Turkish study, involving 158 consecutive patients with MDR-TB, the overall success rate was 77%, with cure in 49% and probable cure in 39%, despite resistance to a mean of 4.4 drugs. Surgical resection was performed in 36 patients. Of the patients with an unsuccessful outcome, 38% were infected with organisms resistant to more than five drugs. Cultures became negative in 150 patients (98%) after a mean of 1.9 months (range 1–9). In a step-down logistic-regression analysis, successful outcome was associated with younger age ( p ¼ 0.013) and absence of previous treatment with ofloxacin ( p ¼ 0.005). In all cases treatment was continued for a minimum of 18 months after the first negative culture and for minimum of 24 months in the absence of first-line drugs. Treatment strategies for MDR-TB that include a fluoroquinolone offer an advantage over regimens that do not.102,120,127 Chiang et al in their 6-year retrospective study involving 229 MDR-TB patients in Taiwan observed that MDR-TB patients who received ofloxacin as part of the regimen had a lower risk of relapse than those receiving only first-line drugs (Hazard Ratio (HR) 0.16, 95% CI 0.03–0.81) and lower risk of TB-related death than those receiving second-line drugs but not ofloxacin (HR 0.50 and 95% CI 0.31–0.82).115,128 In a study of prognostic factors for surgical resection in patients with MDR-TB, resistance to ofloxacin was one of the poor prognostic factors along with low body mass index, primary resistance and cavitary lesions beyond the range of resection.129 There has been limited data to support the use of one fluoroquinolone over another in terms of clinical outcome, and unfortunately cross-resistance to one agent produces resistance to all in vitro and in murine models.130,131 Follow-up duration and survival analyses in many of these studies are relatively short and many
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of the studies were conducted using a variety of methodologies and have outcomes (of cure, success, failure) defined in different ways, making comparisons between studies difficult. One recent study in 106 patients with MDR-TB demonstrated that levofloxacin was more effective overall than ofloxacin when incorporated into a multidrug regimen but the time to achieve sputum smear or culture conversion and rates of adverse effects were the same.127 No fluoroquinolones should be used without verifying that the bacterium is susceptible, including the newer ones. Fluoroquinolones may also have an important place in the management of drug-susceptible TB. Moxifloxacin, for example, a relatively new fluoroquinolone has shown promise in vitro against drug-susceptible TB using early bactericidal assays in vitro and in murine models.132–135 Nuermberger et al in their study showed that the replacement of isoniazid with moxifloxacin offered the potential of reducing the duration of treatment by reducing the time needed to sterilize bacilli in murine models.135 Any combination that reduces duration of therapy is likely to improve adherence and likely to reduce development of clinical resistance. Moxifloxacin has also shown promise against MDR-TB in vitro, in murine models.136 According to the WHO 2006 guidelines the most potent available fluoroquinolones based on the in vitro activity and animal studies are moxifloxacin ¼ gatifloxacin > levofloxacin > ofloxacin ¼ ciprofloxacin (as noted earlier, these may not translate into differences in clinical cure rates).115 Although individualized treatment based on in vitro drug resistance analysis is probably the gold standard for MDR-TB treatment, the need for reliable but costly laboratory facilities for DST means that the application of standardized second-line drug treatment has been advocated for middle- and low-income countries. Overall, studies using standardized treatment approaches for MDR-TB have shown outcomes worse than those for most studies using individualized treatment regimens in expert hands, but better results than individuals either on no treatment or treatment with first-line drugs alone.137 In the past two years successful treatment of patients using second-line drugs in low-income countries, notably Peru, have been reported.120,137
EXTRAPULMONARY DRUG-RESISTANT TUBERCULOSIS Most attention has been given to understanding and treating pulmonary drug-resistant and MDR-TB cases as these are of greatest public health importance. For most extrapulmonary TB, treatment regimens are similar to those applied for pulmonary TB including drug-resistant TB with the exception of TB meningitis. If there are signs and symptoms of meningeal involvement, the regimen should use drugs that have adequate penetration into the central nervous system. Rifampicin, isoniazid, pyrazinamide, protionamide/ethionamide and cycloserine have good penetration; kanamycin, amikacin and capreomycin penetrate effectively in the presence of meningeal inflammation; PAS and ethambutol have poor penetration. The high mortality associated with extrapulmonary MDR-TB, particularly meningitis, has been clearly demonstrated in the UK and the USA and was strongly predictive of death in a series of 180 Vietnamese adults with MDR-TB-associated meningitis.123,138,139
HIV AND MULTIDRUG-RESISTANT TUBERCULOSIS MDR-TB carries a high mortality in the immunocompromised as described earlier. Three studies in the USA demonstrated an improved outcome with early treatment using at least three drugs to
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which the organism was susceptible on in vitro testing, supporting the concept that early institution of appropriate treatment may extend survival even if individuals are HIV-infected.121,122,140 Drug treatment strategies are similar to those employed for HIV-uninfected patients with antiretroviral therapy considered at an early stage.
THERAPEUTIC ALTERNATIVES: IMMUNOTHERAPY Immunotherapy or immunomodulation has remained largely experimental with a few notable exceptions. Strategies have usually combined a standard chemotherapeutic approach plus: 1. adjunct recombinant immunomodulating cytokines (especially Th-1 and Th-1-like cytokines such as interferon-g (IFN-g), interleukin (IL)-2, IL-12, IL-18 and granulocytemacrophage colony-stimulating factor (GM-CSF)); 2. inhibitors of immunosuppressive cytokines (transforming growth factor (TGF)-b) and some proinflammatory tissuedamaging cytokines (tumour necrosis factor (TNF)-a); and 3. immunomodulatory agents such as dexamethasone, imidazoquinoline, diethyldithiocarbamate, poloxamer, dibenzopyran, galactosylceramide, levamisole, and heat-killed Mycobacterium vaccae.141 Cytokine therapy is possible but not always predictable in its outcome. IFN-g has been the most studied cytokine and its main properties are given in Table 53.4. There is limited data on the clinical use of immunomodulating cytokines in drug-susceptible or resistant TB, unresponsive to standard chemotherapy. Following an early report there has been one small open label study in which five MDR-TB smear- and culturepositive patients were given chemotherapy with aerosolized IFN-g and some symptomatic improvement was seen.144,147 A later 6-month study used aerosolized IFN-g as adjuvant therapy in six patients with refractory MDR-TB. The patients received two million international units of aerosolized IFN-g thrice weekly for 6 months while they continued on identical antituberculous chemotherapy. After IFN-g inhalation therapy, sputum smears remained persistently positive in all patients throughout the study period. Sputum cultures were transiently negative at the fourth month in two patients, but became positive again at the end of 6 months of IFN-g therapy. Five patients had radiological improvement including three patients who showed a decrease in the size of the cavitatory lesions. Resectional surgery could be performed in one patient in whom substantial clinical and radiological improvement was noted.148
Table 53.4 Immunotherapy with cytokines a
Cytokine
Action
IFN-g glycoproteins (40–70 KDa)
a
Major immune activator Induces expression of MHC Class II molecules Primes macrophage to release IL-1 Activates macrophages for phagocytosis Stimulates production of reactive nitrogen species mainly via nitric oxide synthase Augments antigen presentation Increases responsiveness to IL-2
Expensive but complex and potentially dangerous. Adapted from Flynn et al (1993, 1995),142,143 Holland et al (1994),144 Cooper et al (1995),145 Newport et al (1996).146
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Adjunct steroid therapy has been part of general TB therapy, e.g. for TB meningitis, whereas other immunomodulators have been applied usually to refractory mycobacterial disease or MDR-TB. Hopes for M. vaccae have waned. Although smaller trials of M. vaccae as an immunotherapeutic adjunct to chemotherapy in Argentina, Nigeria and Romania showed some benefit; larger trials, notably in Southern Africa, have largely been disappointing with little effect on treatment outcome and mortality. Nevertheless, the authors of a study in Argentina using multiple doses of heatkilled M. vaccae (SRL 172) claimed that immunotherapy could reduce the overall period of chemotherapy. In this study, shortcourse, directly observed chemotherapy in 22 newly diagnosed HIV-uninfected pulmonary TB patients was supplemented with a triple-dose of M. vaccae. Patients receiving immunotherapy showed a faster and more complete clinical improvement, accelerated disappearance of bacilli from sputum, better radiological clearance and a more rapid fall in ESR, than those receiving placebo, with a significantly faster return towards normal values in all the immunological parameters. The results were consistent with a regulatory activity on cellular immunity, reducing the influence of Th-2 and enhancing Th-1 to the benefit of the patients.149 If these results can be reproduced then there may be some benefit in shortening treatment, indirectly improving adherence and reducing the emergence of clinical resistance. An alternative approach has been to improve outcomes by trying to antagonize the effects of ‘over’-production of beneficial cytokines such as TNF-a using thalidomide, with modest clinical improvement.150 In a small study, thalidomide therapy was used on four children with paradoxical enlargement of intracranial tuberculomas and tuberculous brain abscesses despite being on adequate antituberculous treatment. Three of the four patients had progressive neurological deterioration. These lesions are frequently not responsive to standard treatment including steroids. Marked clinical and neuroradiological improvement occurred after thalidomide was added.151 Although immunomodulatory therapy is attractive, there remain serious problems including the high cost, occasionally severe side effects and, in many cases, only modest efficacy in potentiating host defence mechanisms, primarily because of the induction of macrophage-deactivating cytokines during the course of long-term administration of adjunctive agents.
SURGICAL MANAGEMENT Adjuvant surgery for pulmonary TB is of value for selected MDRTB cases if chemotherapy with second-line drugs alone is unable to effect cure. Major indications for surgical treatment of MDR-TB are persistent cavities, destruction of one lobe or lung, failure to convert and previous relapses. In 205 patients treated at one expert centre in the USA (which had previously published a major series on treatment outcome of MDR-TB patients recruited from 1973 to 1983119) who were infected with bacterial strains resistant to a median of six drugs, an initial favourable response defined as at least three consecutive negative sputum cultures over a period of at least 3 months, was seen in 85% patients compared with 65% in the prior cohort.124 More importantly the latest cohort of patients had a greater long-term success rate of 75 versus 56%, and a lower TB death rate of 12 versus 22% previously. At their centre, in the 1973–1983 period, only seven of 171 (4%) patients had undergone resectional surgery; all seven became consistently culture-negative. In contrast, 130 of 205 (63%) of the patients in the 1984–1998 period underwent
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resectional surgery. Fluoroquinolones were used in 80% of the patients, with greater use in the last 10 years than in the first 5 years of the study period. Surgical resection, and to a smaller extent fluoroquinolone therapy, were associated with improved microbiological and clinical outcomes. A second study demonstrated bacteriological cure rates of > 90% after surgery in combination with adequate chemotherapy.152
The spread of MDR-TB, particularly within institutions such as prisons, homeless shelters and hospitals has been well documented internationally throughout the 1990s and is a particular concern when many highly vulnerable individuals, for example those infected with HIV, congregate.153,154 Studies using new cellular IFN-g diagnostic assays have demonstrated high rates of TB infection in healthcare workers in India and in Russia.155,156 At the same time, as countries of the former Soviet Union have very high rates of MDR-TB in active disease, one can assume that when staff and patients are institutionally infected, infection is often with MDR-TB strains. As care is primarily institutionalized in Russian hospitals and prisons, interventions to prevent transmission must be a priority. Falzon et al in their analysis of the pooled data from European countries found that TB patients from the former Soviet Union have a high risk of having drug-resistant TB. Thus, public health workers should be aware of the risk of MDR-TB among patients from the former Soviet Union as well as among any patients previously treated for TB.157 MDR-TB patients are no more infectious than similar patients with drug-susceptible TB; however, the consequences of acquiring infection and subsequent disease are more serious. This is so because of:
prolonged potential to remain infectious in pulmonary disease; the need for stricter infection control; a greater treatment cost with a minimum of £65,000;158 prolonged treatment with potentially toxic second-line drugs; worse cure and survival rates in both HIV-infected and -uninfected individuals;119,124,159 and risk to healthcare workers if they get infected.
Box 53.1 details the general principles of infection control for MDR-TB according to British Thoracic Society Guidelines and NICE Guidelines.94,117 Prevention of nosocomial spread can be achieved through a combination of intervention and adequate training of all staff. Appropriate institutional infrastructure that ensures adequate and appropriate ventilation (e.g. negative pressure isolation rooms, air-filtration ultraviolet germicidal irradiation, biosafety cabinets
REFERENCES 1. WHO/IUALTD. Global Project on Anti-tuberculosis Drug Surveillance in the World. Report no.3: Anti-tuberculosis Drug Resistance in the World. WHO/ HTM/TB/2004.343. Geneva: World Health Organization, 2004. 2. WHO. Global Tuberculosis Control: Surveillance, Planning, Financing. Report. WHO/HTM/TB/ 2006.362. Geneva: World Health Organization, 2006. 3. Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006;194(4):479–485.
Box 53.1 The general principles of infection control for MDR-TB according to the British Thoracic Society Guidelines.
INFECTION CONTROL MEASURES
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All patients with MDR-TB if admitted to a hospital should be in a side room. If none are available then the patient should be transferred to a hospital with such facilities. Care should be carried out in a negative pressure room until the patient is non-infectious and smear/culture-negative. Staff and visitors should wear FFP3 or similar masks during contact with a patient with suspected or known MDR-TB while the patient is considered non-infectious.a Before deciding whether to discharge patients from hospital, secure arrangements for the supervision and administration of all antituberculous therapy should be made and agreed upon with patient and carers. Aerosol-generating procedure must be carried out in appropriately engineered and ventilated areas. The decision to discharge must be discussed with the infection control team, the local microbiologist and consultant in Communicable disease/Public Health Medicine. Potentially infectious patients should not seen in the same outpatient clinic as immunocompromised patients (including those with HIV). Negative pressure rooms used for infection control in MDR-TB should meet the standards of the Interdepartmental Group of Tuberculosis,160 and should be clearly identified for staff with a standard sign. Such labelling should be kept up to date.
a
European standard EN 149:2001; masks should meet the standards of the Health and Safety Executive’s Respiratory Protective Equipment at Work: A Practical Guide HSG53.161
in microbiology laboratories) and personal protection devices, such as masks and respirators, are essential. Excellent guidelines to prevent nosocomial transmission between patients and staff, and in those working in laboratories and pathology services, are widely available in print and electronic form.162–167
CONCLUSION Individually MDR-TB (and particularly XDR-TB) is extremely difficult to treat. Cure and survival are compromised especially if the patient is coinfected with HIV. High rates of MDR-TB (and XDR-TB) within a region or country indicates the existence of significant problems within the TB programme which must be addressed. Similarly failure to cure infectious cases and correct poor institutional cross-infection procedures leads to the spread of highly drugresistant TB.
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90. Hellyer TJ, DesJardin LE, Hehman GL, et al. Quantitative analysis of mRNA as a marker for viability of Mycobacterium tuberculosis. J Clin Microbiol 1999;37(2):290–295. 91. Jacobs WR Jr , Barletta RG, Udani R, et al. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 1993;260(5109):819–822. 92. Hale YM, Pfyffer GE, Salfinger M. Laboratory diagnosis of mycobacterial infections: new tools and lessons learned. Clin Infect Dis 2001;33(6):834–846. 93. Parsons LM, Somosko¨vi A, Urbanczik R, et al. Laboratory diagnostic aspects of drug-resistant tuberculosis. Front Biosci 2004;9:2086–2105. 94. NICE, Clinical guideline N33. Tuberculosis: Clinical Diagnosis and Management of Tuberculosis, and Measures for its Prevention and Control. National Institute for Health and Clinical Excellence, 2006. Available at URL:http://www.nice.org.uk/page.aspx?o=CG033 95. World Health Organization. Guidelines for Drug Susceptibility Testing of Second-Line Drugs for Mycobacterium tuberculosis. Geneva: World Health Organization, 2001. 96. Kim SJ, Espinal SM, Abe C, et al. Is second-line anti-tuberculosis drug susceptibility testing reliable? Int J Tuberc Lung Dis 2004;8(9):1157–1158. 97. Pfyffer GE, Bonato DA, Ebrahimzadeh A, et al. Multicenter laboratory validation of susceptibility testing of Mycobacterium tuberculosis against classical second-line and newer antimicrobial drugs by using the radiometric BACTEC 460 technique and the proportion method with solid media. J Clin Microbiol 1999;37(10):3179–3186. 98. Rusch-Gerdes S, Pfyffer GE, Casal M, et al. Multicenter laboratory validation of the BACTEC MGIT 960 technique for testing susceptibilities of Mycobacterium tuberculosis to classical second-line drugs and newer antimicrobials. J Clin Microbiol 2006;44(3):688–692. 99. Johansen IS, Larsen AR, Sandven P, et al. Drug susceptibility testing of Mycobacterium tuberculosis to fluoroquinolones: first experience with a quality control panel in the Nordic-Baltic collaboration. Int J Tuberc Lung Dis 2003;7(9):899–902. 100. Sirgel FA, Fourie PB, Donald PR, et al. The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis. Am J Respir Crit Care Med 2005;172(1):128–135. 101. Gosling RD, Heifets L, Gillespie SH. A multicentre comparison of a novel surrogate marker for determining the specific potency of anti-tuberculosis drugs. J Antimicrob Chemother 2003;52(3):473–476. 102. Hu Y, Coates AR, Mitchison DA. Sterilizing activities of fluoroquinolones against rifampintolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003;47(2):653–657. 103. Combs DL, O’Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy study trial 21: effectiveness, toxicity, and acceptability. The report of final results. Ann Intern Med 1990;112:397–406. 104. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004; 364(9441):1244–1251. 105. East African/British Medical Research Councils. Controlled clinical trial of short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet 1972;1(7760):1079–1085. 106. British Thoracic and Tuberculosis Association. Controlled trial of short-course chemotherapy in pulmonary tuberculosis. Lancet 1976;2(7995): 1102–1104. 107. World Health Organization. International standards for tuberculosis care (ISTC). Tuberculosis Coalition for Technical Assistance (TBCTA), 2006. 108. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. Geneva: World Health Organization, 2003. 109. American Thoracic Society, Centers for Disease Control, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1–77.
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110. Drobniewski F. Drug-resistant tuberculosis in adults and its treatment. J R Coll Physicians Lond 1998; 32(4):314–318. 111. Dye C, Watt CJ, Bleed DM, et al. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 2005;293(22):2767–2775. 112. Grzybowski S. Tuberculosis and Its Prevention. St. Louis, MO: Warren H Green, 1983. 113. Coninx R, Mathieu C, Debacker M, et al. First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons. Lancet 1999;353:969–973. 114. Migliori GB, Espinal M, Danilova ID, et al. Frequency of recurrence among MDR-tB cases ‘successfully’ treated with standardised short-course chemotherapy. Int J Tuberc Lung Dis 2002;6(10): 858–864. 115. World Health Organization. Guidelines for Programmatic Management of Drug-Resistant Tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization, 2006. Available at URL:http://www.who.int/tb/publications/2006/ who_htm_tb_2006_361/en/index.html 116. British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 1994. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1994;49(12):1193–1200. 117. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998;53:536–548. 118. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. Geneva: World Health Organization, 1997. 119. Goble M, Iseman MD, Madsen LA. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampicin. N Engl J Med 1993; 328:527–532. 120. Mitnick C, Bayona J, Palacios E, et al. Communitybased therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003;348(2):119–128. 121. Park SK, Kim CT, Song SD. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998;2:877–884. 122. Park MM, Davis AL, Schluger NW, et al. Outcome of MDR-TB patients, 1983-1993. Prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996;153:317–324. 123. Drobniewski F, Eltringham I, Graham C, et al. A national study of clinical and laboratory factors affecting the survival of patients with multiple drug-resistant tuberculosis in the UK. Thorax 2002;57(9):810–816. 124. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrugresistant tuberculosis. Am J Respir Crit Care Med 2004;169(10):1103–1109. 125. Hutchison DC, Drobniewski FA, Milburn HJ. Management of multiple drug-resistant tuberculosis. Respir Med 2003;97(1):65–70. 126. Tahaog˘lu K, To¨ru¨n T, Sevim T, et al. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001;345:170–174. 127. Yew WW, Chan CK, Leung CC, et al. Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong. Chest 2003;124(4):1476–1481. 128. Chiang CY, Enarson DA, Yu MC, et al. Outcome of pulmonary multidrug-resistant tuberculosis: a six year follow-up study. Eur Respir J 2006;28(5):980–985. 129. Kim HJ, Kang CH, Kim YT, et al. Prognostic factors for surgical resection in patients with multidrug-resistant tuberculosis. Eur Respir J 2006;28(3):576–580. 130. Kam KM, Yip CW, Cheung TL, et al. Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant Mycobacterium tuberculosis: correlation with ofloxacin susceptibility. Microb Drug Resist 2006;12(1):7–11. 131. Ginsburg AS, Sun R, Calamita H, et al. Emergence of fluoroquinolone resistance in Mycobacterium tuberculosis during continuously dosed moxifloxacin
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Extensively drug-resistant tuberculosis (XDR-TB) Anthony P Moll, Gerald Friedland, Neel R Gandhi, and N Sarita Shah
INTRODUCTION TO EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS The term ‘extensively drug-resistant’ (XDR) TB was first coined by the Center for Disease Control and Prevention (CDC) and the World Health Organization (WHO) in March 2006.1 It represents a progression from multidrug-resistant (MDR)-TB, defined as resistance to rifampicin and isoniazid, to further include resistance to second-line antituberculous drugs, including any fluoroquinolone and at least one of the three second-line injectable agents (kanamycin, amikacin or capreomycin). In the presence of such resistance, treatment options are severely restricted and the mortality rates are extremely high. The emergence of XDR-TB is mainly a manmade phenomenon, being an indicator of failing TB programmes. Confirmation of infection with XDR-TB requires a laboratory diagnosis and is dependent on laboratory services capable of conducting drug susceptibility tests (DST) for key first- and second-line anti-TB drugs. The simultaneous emergence of these highly resistant strains, independently created in many different countries around the world, did not attract sufficient attention, but recently an appropriate widespread concern has emerged with the documentation of a cohort of 53 XDR-TB patients in a high human immunodeficiency (HIV)-prevalent setting in rural KwaZulu-Natal, South Africa, with extremely high mortality (98%).2 This was soon followed by reports of cases from the rest of the province and all other provinces, confirming an XDR-TB crisis of yet unknown proportion in South Africa (with > 300 reported cases by December 1, 2006).3 Because of the airborne transmission of TB, XDR-TB poses a serious public health risk which has led to a sustained media interest. This media interest has spotlighted the inadequacies of TB programmes worldwide and has drawn attention to the responses needed to address this new threat. However, media sensationalism and hype has simultaneously adversely impacted populations by arousing stigma, panic and fear. The challenges related to XDR-TB are multiple and include difficult diagnosis in high-HIV-prevalent settings, delayed diagnosis due to the 6–8 weeks needed for standard DST, severely restricted treatment options, infection control issues to prevent nosocomial or community spread and the protection of healthcare workers. XDR-TB further threatens to undermine the gains made in the past decades in the treatment of both TB and HIV.
DEFINITION OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS The revised WHO definition of XDR-TB is now internationally accepted and takes into account:
the most potent and widely used second-line drugs; susceptibility testing methodologies which are standardized, with technical feasibility and reproducibility within the capability of conventional microbiology laboratories; and treatment outcomes significantly worse than those of MDRTB alone.
Extensively drug-resistant TB is defined as resistance to at least rifampicin and isoniazid, plus any fluoroquinolone, plus one of the three second-line injectable drugs, kanamycin, amikacin or capreomycin.4 This definition distinctly separates MDR-TB from XDR-TB as discrete conditions with different treatment options and outcomes.
DISTRIBUTION OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS WORLDWIDE The detailed incidence and prevalence of XDR-TB globally is not known. WHO estimates that each year there are about 420,000 cases of MDR-TB with 116,000 deaths, and approximately 27,000 cases of XDR-TB with 16,000 deaths.5 A survey conducted by CDC and WHO in March 2006 showed the worldwide existence of XDR-TB.1 Data from 49 countries were collected between 2000 and 2004. Out of a total 17,690 isolates, 3520 (19.8%) were MDR-TB, of which 347 (9.9%) were XDR-TB. Table 54.1 shows that XDR-TB is widely distributed geographically and appears to be more prevalent in areas already having high rates of MDR-TB. As of June 2008 XDR-TB has been identified in all regions of the world in 49 different countries, although it is still considered an uncommon infection (Fig. 54.1).6 Notably there is little information available from China, India and Africa. As two-thirds of the world’s MDR-TB is in just three countries – China, India and the Russian Federation – we would expect the bulk of the XDR-TB problem is likely to reside in those same countries. Thus, existing estimates might severely
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prevalence of XDR-TB. Limited (DST) laboratory capacity and availability in many high-TB-prevalent areas around the world further has an impact on available data.
Table 54.1 XDR-TB among MDR-TB isolates by region from which isolates were submitted to supraregional 1 laboratories, 2000–2004 Geographic region Industrialized nations Latin America Eastern Europe Africa and Middle East Asia (other than Republic of Korea) Republic of Korea Geographical region data unknown Total
Total MDR-TB isolates
XDR-TB n (%)
821 543 406 156 274
ORIGIN OF TUBERCULOSIS DRUG RESISTANCE
53 (6) 32 (6) 55 (14) 1 (< 1) 4 (1)
1298 22
200 (15) 2
3520
347 (10)
Tuberculosis drug resistance can be either primary (transmission of already resistant organisms, also called new drug resistance) or secondary (resistance acquired in the host related to inadequate treatment, also called previously treated drug resistance).7 There are three broad categories of mechanisms of acquired resistance to drugs by Mycobacterium tuberculosis: 1. the creation of a lipid-rich cell wall that can reduce the permeability of drugs (and arrest phagosome maturation); 2. the production of enzymes that degrade or modify compounds, rendering them useless; and 3. spontaneous chromosomal mutations of key drug targets.8
Emergence of Mycobacterium tuberculosis with extensive resistance to second line drugs – World wide 2000–2004. Morbidity and Mortality Weekly Report. March 24,2006. Vol. 55 No.11:301–305
Among these, the third mechanism is considered to be the most important. Tuberculosis is an obligate aerobe with a replication time of 15 to 20 hours between divisions, which is relatively slow compared with other microorganisms. Random genetic mutations occur with low but predictable frequencies in the range of one mutation per 106 to 109 replications. The frequency of mutations conferring resistance to particular agents varies from the range of 103 for many second-line drugs (thiacetazone, ethionamide, capreomycin, cycloserine and viomycin) to an intermediate level (around 106) for some first- and second-line drugs (isoniazid, streptomycin,
underestimate the actual number of XDR-TB cases worldwide. Further, the survey included no information about HIV coinfection. Well-studied hotspots for XDR-TB have been Eastern Europe (Latvia, Estonia), Asia (Philippines, Korea) and Latin America (Peru). Whereas many of these countries have a low prevalence of HIV, the emergence of XDR-TB in high-HIV-prevalentcountries heralds a threat of a more significant nature. The lack of standardized data collection globally for second-line DST is a major limitation in systematically assessing the global burden and
18
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Argentina Armenia Bangladesh Brazil Canada Chile China, Hong Kong SAR Czech Republic Ecuador France Georgia Germany Islamic Republic of Iran Italy Japan Latvia Mexico Norway Peru Portugal Republic of Korea Russian Federation South Africa Spain Sweden Thailand UK USA
27
5
10 20 24
28
25
22
16 12 8 11 14
17
2
21
13 3
15
7 26
9 4
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6
1
23
Based on information provided to WHO Stop TB Department, March 2007
Fig. 54.1 Countries with XDR-TB. Confirmed cases to date (from WHO)6. Available from URL: http://www.who.int/tb/challenges/xdr/xdr_map_june08.pdf. Data from Urgent issues in the developing world .Transmission of XDR-TB in South Africa: Discussion of the global implications. Presentation. Paul Nunn. 14th conference on Retroviruses and opportunistic infections. Accessible at http://www.who.int/tb/features_archive/croi_feb07.pdf
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ethambutol, kanamycin and para-aminosalicylic acid) to the lowest levels for rifampicin, on the order of 108 to 1010. When large populations of M. tuberculosis are formed in a host and selective pressure is placed by a chemotherapeutic agent, the small population of M. tuberculosis that has evolved resistance to the agent will continue to multiply while the susceptible bacilli are suppressed. This enables the drug-resistant organism to become the dominant organism in the host. In order to prevent this scenario from occurring, the central strategies in therapy are to: 1. administer at least four chemotherapeutic agents, such that if there are organisms resistant to one or two agents, they will be killed by the other agents; and 2. provide therapy for an adequate duration in order to ensure eradication of populations of M. tuberculosis, which evades both host immune response and drug actions by a number of intricate cellular mechanisms.9 Resistance to monotherapy arises quickly. The time period of acquired resistance under monotherapy varies between agents and has been well characterized for many of the initial antituberculous agents; in a study of isoniazid monotherapy, 11%, 52% and 71% of patients developed resistant strains after 1, 2 and 3 months, respectively.10 In many instances a mutation conferring resistance to one drug can also confer resistance to other drugs of the same class. There exists, then, considerable cross-resistance and class-resistance to antituberculous agents (see treatment options). Genetic mutations that confer resistance occur spontaneously and the isolated resistant bacilli are present in normal bacterial populations that have never been exposed to TB drugs (wild strains). Thus drug-resistant mutants will be present before treatment starts, especially in lesions that harbour large numbers of TB bacilli, for instance primary cavities of untreated patients. Second-line drugs such as ciprofloxacin and amikacin are often used to treat other infections, such as community-acquired pneumonia. If there is underlying undiagnosed TB present this may effectively be monotherapy and could elicit rapidly developing resistance. Not surprisingly, the most common ways in which M. tuberculosis drug resistance evolves or amplifies in the host involve the violation of basic therapeutic principles. The causes of these violations range widely, from the actions of the individuals, by non-adherence, to those of the health provider, by improper regimen selection or suboptimal dosing, to the failure of TB control programmes to provide a consistent support or supply of necessary agents.8 The understanding of these causes has evolved considerably over the past two decades, tending towards increasing recognition of the impact of the social, economic and political environments in which therapy takes place upon the likelihood that patients will be exposed to the proper treatment for an adequate duration.11,12 Further, numerous host factors have been implicated in the facilitation of acquired drug resistance, including the development of local environments recalcitrant to antibiotic penetration or activity and the failure of the immune system to potentiate antibiotic activity.9 Compromise of the host immune response, such as that caused by infection with HIV, may be a significant risk factor for the evolution of drug resistance. Finally, the ‘amplifier effect’ occurs after completion of a course of antituberculous treatment, where small numbers of naturally occurring mutant organisms with residual resistance are amplified. This is due to the elimination of susceptible organisms and the emergence and establishment of remaining drug-resistant ones. Mathematical models have suggested that MDR-TB hotspots could evolve in areas even with successful programmes due to this amplifier effect.13
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TRANSMISSION OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS Transmission of XDR-TB as with other forms of TB is by airborne spread of bacilli in droplet nuclei usually coughed out by a patient with active disease and inhaled by an uninfected person. This can lead to latent XDR-TB infection without progression to active disease in most individuals. However, a small percentage will progress to active XDR-TB disease. It is likely that as with susceptible TB the chance of XDR-TB infection leading to active disease is approximately 10% over a lifetime in HIV-uninfected patients and 10% per year in HIV-infected patients. The factors that influence the progression to active disease are described elsewhere. The XDR-TB strains do not seem to be more virulent than susceptible or MDR-TB strains, but limited information indicates that some strains may be more transmissible.14 Sporadic outbreaks of primary highly resistant TB have been well documented, mostly in the context of HIV infection and associated with very high mortality. Molecular genotyping in such outbreaks have confirmed the presence of one particular strain with nosocomial spread to HIV-infected patients and healthcare workers. In the 1990s such a localized cluster outbreak was due to ‘Strain W’ in New York and cost an estimated US$1 billion to contain.15 Subsequent nosocomial and institutional outbreaks in Italy, Spain, Russia and Argentina made it clear that MDR-TB ranked among the most serious public health issues facing the world.16–19 A unique strain, the KZN strain, initially described in 1994, has been well documented to be associated with XDR-TB in South Africa.2 The spread of XDR-TB from one country to another is considered a serious public health threat. However, from the little evidence that we have, the global existence of XDR-TB suggests that this is not so much spread of resistant strains internationally, but rather the creation of similar strains around the world. This is because the drugs used are more or less the same everywhere, and unfortunately so are the defects in the performance of TB control programmes.5 Whether or not drug-resistant TB is less fit or transmissible, cases of X/MDR-TB are likely to generate more secondary cases due to the prolonged infectious period associated with delayed identification, inadequate treatment, longer time to culture conversion once second-line drugs are instituted and lower cure rates.
INFECTION CONTROL AND EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS Extensively drug-resistant TB infection control encompasses all aspects of airborne transmission. At facility level traditionally this includes the following: 1. Administrative control to reduce risk of exposure, infection and disease through policy and practice: examples include scheduling clinic times to minimize the mixing of highly vulnerable HIV patients with contagious TB patients, isolating MDR- and XDR TB patients and implementing cough hygiene practices; 2. Environmental controls to reduce concentration of infectious bacilli in air in areas where contamination is likely: this is achieved by ensuring adequate ventilation by maximizing natural ventilation, augmenting with mechanical ventilation and using UV lights and air filters; 3. Personal respiratory protection (N95 masks) to protect personnel who work in environments with contaminated air.
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It is difficult to quantify the effect of individual interventions on overall nosocomial transmission; however, recent mathematical modelling indicates that even in resource-limited settings, close to 50% of new XDR-TB cases could be averted over a 5-year period with the proper application of combinations of these strategies.20
CLINICAL PRESENTATION AND DIAGNOSIS OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS Extensively drug-resistant TB, when causing active disease, can present with signs and symptoms consistent with pulmonary or extrapulmonary drug-susceptible TB. The full spectrum of TB symptomatology, from the classical presentation of TB (weight loss, chronic cough, chest pain, blood-stained sputum, night sweats, loss of appetite and loss of energy) to the less typical presentations characteristic of TB in immunocompromised hosts can be encountered with XDR-TB. It is not possible to distinguish between susceptible TB, MDR-TB and XDR-TB at the bedside solely on clinical grounds. Often XDR-TB can be suspected when taking into account the history of the patient, previous TB treatment or apparent failure to respond to second-line TB treatment, especially in high HIV and MDR-TB prevalent settings. The definitive diagnosis is only made when TB bacilli are cultured from
a body sample (usually sputum) and a DST confirms XDR-TB. As conventional DST takes up to 6–8 weeks, this delays the appropriate treatment initiation and separation of patients into the respective susceptible TB, MDR-TB and XDR-TB categories. In this interim period there is an increased risk of nosocomial spread (or community spread) especially in congregate settings in high HIVprevalent regions. In many resource-limited settings, where DST is unavailable, with a consequent inability to diagnose drug resistance, individual patients experience treatment failure with continued transmission to others. The long-term goal is that, ultimately, all patients with known or suspected TB should have access to timely, quality-assured TB laboratory services, including smear microscopy, culture and DST.4 Various new molecular tests for the rapid identification of the rifampicin resistance mutant genes directly from sputum samples from adult patients are becoming available, with results known within 48 hours or less. Since isoniazid resistance almost always accompanies rifampin resistance, this will provide clinicians with at least an MDR-TB diagnosis and an opportunity to intervene much earlier, while the standard DST results are still pending. An algorithm for the initial management of patients at risk of drug-resistant TB and HIV infection has been developed by the WHO Working Group for assessing HIV patients resistant to rifampicin using the rapid test (Fig. 54.2).4
IDENTIFY PATIENT WITH RISK OF DRUG-RESISTANT TB
1. Infection control precautions until diagnosis established 2. AFB smears ¥3 3. HIV test (or confirm previous HIV test result)
SMEAR NEGATIVE EXTRAPULMONARY
SMEAR POSITIVE
Management based on smear-negative/ extrapulmonary guidelines (forthcoming) HIV+, ambulatory HIV+, severely ill HIV+, close contact of MDR- or XDRTB: go to liquid culture and DST HIV
Rapid test for RIF resistance (nucleic acid amplification, phage) HIV test positive Rapid RIF resistance test positive or close contact of known MDR/XDR-TB case or previous treatment failure 1. Perform full rapid 1st and 2nd line DST in liquidmedia rapid transport of specimen or isolate to referral lab if full DST not yet available 2. Start treatment with four or more 2nd-line drugs that are certain (or nearly certain) to be effective based on representative drug resistance profiles of specific patient groups (lab/epidemiological survey) 3. Include 3rd-line drugs or investigational new drugs under compassionate use protocols 4. Adjust treatment according to DST results and continue further management based on WHO guidelines on drug-resistant TB (2006) 5. Start antiretroviral treatment as soon as possible in case not previously started 6. Continue enhanced infection control precautions for drug-resistant TB and HIV-infected persons 7. Initiate investigation among close contacts
HIV test negative Rapid RIF resistance test positive
1. Perform full rapid 1st and 2nd line DST in liquidmedia, rapid transport of specimen or isolate to referral lab if full DST not yet available 2. Start treatment with four or more 2nd-line drugs that are certain (or nearly certain) to be effective based on representative drug resistance profiles of specific patient groups (lab/epidemiological survey) 3. Adjust treatment according to DST results and continue further management based on WHO guidelines on drug-resistant TB (2006) 4. Continue enhanced infection control precautions for drug-resistant TB 5. Initiate contact investigation among close contacts
HIV test positive Rapid RIF resistance test negative
1. Perform 1st line DST in liquidmedia rapid transport of specimen or isolate to referral lab if DST not yet available 2. Begin standardized short course chemotherapy with INH, RIF, PZA, EMB per WHO guidelines for national TB programs (2003 rev) 3. If drug-resistant TB identified by DST, follow WHO guidelines on drug-resistant TB (2006) 4. Initiate antiretroviral treatment as soon as indicated 5. Infection control precautions for HIV-infected persons
HIV test negative Rapid RIF resistance test negative
1. Begin standardized short course chemotherapy with INH, RIF, PZA, EMB per WHO guidelines for national TB programmes (2003 rev) 2. Routine infection control precautions for TB
Fig. 54.2 Algorithm for initial management of patients at risk of drug-resistant TB and HIV infection. Report of the Meeting of the WHO Global Task Force on XDR-TB 2006, Annex 3.4
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Extensively drug-resistant tuberculosis (XDR-TB)
CLINICAL PREDICTORS OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS To date, there are no reliable clinical algorithms for accurately predicting drug-resistant TB.21 In several case-control studies assessing risk factors for drug-resistant TB, the increased risk associated with previous TB treatment ranges from two- to more than tenfold.22 However, little data from Africa or high-HIV-prevalent settings are available. Patients receiving TB therapy who remain or become sputum-positive after 2 months, have persistent fevers or have worsening clinical or radiological parameters should provoke a high suspicion for drug resistance. Studies looking at an expanded array of possible clinical predictors which might provide clinicians with selected weighted risk factors enabling the identification of patients with a high probability of having MDR- or XDR-TB are being conducted.
HIV AND TUBERCULOSIS Diagnosis of any form of TB, including XDR-TB, is more challenging in the presence of HIV disease, in that sputum smear and radiographic findings are less sensitive and smear-negative and extrapulmonary disease are more common as the CD4 count decreases.23–28 The incidence, clinical presentation and diagnosis of extrapulmonary XDR-TB is still largely undescribed. Extrapulmonary XDR-TB diagnosis requires culture and DST from extrapulmonary samples such as lymph node aspirates, pleural effusion, cerebrospinal fluid and bone marrow aspirates to name some. The simultaneous presence of pulmonary and extrapulmonary XDR-TB in the same patient is possible. Regardless of whether HIV is an independent risk factor for the development of XDR- or MDR-TB at the individual level, the increased pool of susceptible patients who serve as both hosts and vectors for all forms of TB, including XDR- and MDR-TB, is certain to increase the absolute burden of XDR- and MDR-TB at a population level. Moreover, at a programmatic level, the HIV epidemic, particularly in Africa, has overwhelmed and disrupted the established TB control programmes, causing rising treatment failure rates and increasing the opportunity for drug-resistant TB to emerge and spread.23–28 Certain second-line drugs are more toxic in patients infected with HIV, while the use of antiretrovirals concomitantly with second-line drugs may result in problematic drug–drug interactions.8
TREATMENT OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS The principles guiding the selection of a drug regimen for XDR-TB are similar to that for MDR-TB, except that treatment options are further restricted because of extended resistance patterns including potent second-line drugs. Individualized regimens are ideally better suited to addressing XDR-TB than standardized regimens. However, this is not practical in areas where laboratory capacity is limited, as one needs the susceptibilities on a wide range of first- and secondline drugs to design individualized regimens effectively. Standardized regimes for XDR-TB are commonly used and often include more than five drugs in order to cover the most probable resistance patterns anticipated. If there is a strong suspicion that a patient has XDR-TB,
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an empirical regimen taking into account the patient’s anti-TB treatment history and representative DST results derived from local surveys may be designed. This is done to avoid clinical deterioration and prevent transmission to further contacts while DST results are pending. Once the patient’s DST results are available, adjustments to the regimen are made accordingly. Should a patient be currently on first- or second-line treatment when an XDR-TB DST result becomes available then the regimen is adjusted as needed. In a patient with chronic disease treated several times with second-line drugs, waiting for DST results may be prudent as long as the patient is stable and appropriate infection control measures are in place. As the duration of treatment of XDR-TB is lengthy, involving complex drug regimens with significant adverse effect and toxicity profiles, the need for patient support, provision of drug literacy and TB education are essential. This involves a multidisciplinary approach and the implementation of a sound, well-organized, patient-friendly programme in a caring environment. Regular follow-up, underpinning of information and the inclusion of a treatment buddy or DOT supporter auger patient retention and treatment adherence. The DOT-plus programme encompasses these concepts.
DRUGS USED IN EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS TREATMENT REGIMENS To facilitate a logical approach when selecting drugs for an XDRTB treatment regimen the use of the five groups of anti-TB drugs proposed by WHO in 2006 is useful (Table 54.2, which is based on efficacy, experience of use and drug class29).
The basic principles used in formulating an extensively drug-resistant tuberculosis treatment regimen29 1. Use at least four drugs where efficacy is certain or highly likely. These are called core drugs. Five or more drugs should be chosen if the susceptibility patterns are less certain or there is extensive bilateral widespread disease. 2. Drugs are given at least 6 days a week. Intermittent (2 or 3 days a week) regimens are not recommended. Once-a-day dosing of pyrazinamide and ethambutol achieve high effective serum levels. Twice a day dosing for ethionamide, cycloserine and PAS improve patient tolerance. 3. Doses are given according to body weight. 4. Do not use drugs for which there is cross-resistance: all rifamycins have high levels of cross-resistance.29,30 Fluoroquinolones have considerable cross-resistance, but in vitro data suggest that higher generation fluoroquinolones may be effective when resistance to lower generation fluoroquinolones is present (cross-resistance between lower generation quinolones, such as ciprofloxacin and ofloxacin, is very high).29,30 Kanamycin and amikacin have almost 100% cross-resistance.29,30 Streptomycin is believed to have low levels of cross-resistance with kanamycin and amikacin.30,31 5. If an injectable can be included (an aminoglycoside or capreomycin), it is administered for a minimum of 6 months and constitutes the intensive phase of treatment. 6. Treatment includes the 6-month intensive phase and continues further for a minimum of 18 months beyond culture or smear conversion. 7. Each dose is given by DOT throughout the treatment where possible.
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Table 54.2 Antituberculous drugs by group and class with XDR-TB treatment options TB drugs by group and class
8
First-line TB> Group 1 < drugs First-line oral > : anti-TB drugs 8 Group 2
> > > > > > > > Injectable anti-TB > > > drugs > > > > > Group 3 Second-line > < TB drugs
TB drugs
Third-line drugs
Aminoglycosides
Rifampicin (R) Isoniazid (H) Ethambutol (E) Pyrazinamide (Z) Streptomycin (S) Amikacin (Am) Kanamycin (Km) Capreomycin (Cm)
Polypeptides Fluoroquinolones
Fluoroquinolones
> > > > > Group 4 > > > > > > Oral > > > bacteriostatic > > > : second-line anti-
Thioamides Serine analogues PAS
( Group 5 Anti-TB drugs with unclear efficacy (not recommended in the routine use on MDR-TB patients)
9
Ciprofloxacin (Cfx) > = Ofloxacin (Ofx) Levofloxacin (Lfx) Moxifloxacin (Mfx) > ; Gatifloxacin (Gfx) Ethionamide (Eto) Prothionamide (Pto) Cycloserine (Cs) Terizidone (Trd) Thiacetazone (Th) Para-aminosalicylic acid (PAS) Clofazimine (Cfz) Amox/Clav (Amx/Clv) Clarithromycin (Clr) Linezolid (Lzd)
8. DST together with the patient’s treatment history guides the choice of drugs. DST does not predict the effectiveness or ineffectiveness of a drug with complete certainty. (For example: a patient is taking rifampicin, isoniazid, ethambutol and pyrazinamide for 3 months before a DST result showing resistance to rifampicin, isoniazid, pyrazinamide, kanamycin and ciprofloxacin becomes available. As the patient was effectively taking ethambutol monotherapy for 3 months, it is likely that an acquired ethambutol resistance has emerged. Ethambutol may not be effective now and should not be chosen as one of the four core drugs.) 9. Drug selection takes into consideration adverse effects, toxicities and cost. Ideally the most potent and effective drugs with the safest and most tolerable profiles are chosen.
Guidelines for selecting the four core drugs for an extensively drug-resistant tuberculosis regimen The rationale of drug selection starts with the choice of at least four core drugs most certain to be effective, and taking into account the extended resistance patterns encountered with XDR-TB. The five drug groups listed in Table 54.2 are used to build a regimen for XDR-TB in the following way: 1. Select all first-line drugs left over which are certain to be, or highly likely to be effective. Pyrazinamide and ethambutol, which are very potent and well-tolerated drugs, are considered. According to susceptibility then, one, both or neither of these two are selected. 2. If possible add one injectable out of (a) kanamycin/amikacin or (b) capreomycin. Again by XDR-TB definition at least one of (a) or (b) cannot be used due to resistance. The use of streptomycin as a core drug in the treatment of XDR-TB is questionable
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XDR-TB definition
29
XDR-TB treatment
Resistance to R and H plus
All sensitive first-line drugs
Resistance to any one of these injectables plus
Add any drug with susceptibility from here
Resistance to any fluoroquinolone
Adding up to one from each subgroup from here to bring the total to five or six drugs (avoid thiacetazone in HIVþ patients)
Only use if five drugs not found above
where streptomycin resistance is prevalent. There is almost 100% cross-resistance between kanamycin and amikacin. 3. By XDR-TB definition there is confirmed resistance to at least one of the fluoroquinolones. As the fluoroquinolones have variable cross-resistance one cannot include any of them as a core drug as there is no certainty of effectiveness. 4. Group 4 drugs are added on the basis of estimated or confirmed susceptibility, drug history, efficacy, adverse effects and cost. It is possible to add a maximum of three drugs from this group by choosing one drug from each of the following subgroups: a. ethionamide, prothionamide; b. cycloserine, terizidone, thiacetazone; and c. PAS. If one drug is needed from group 4 the first drug chosen here is usually ethionamide/prothionamide with one of the serine analogs as an alternative, i.e. cycloserine. Some centres use enteric-coated PAS (the enteric coated PAS is better tolerated than previous PAS formulations). If two drugs are needed, cycloserine with PAS or ethionamide/ prothionamide work well. However, PAS and ethionamide/ prothionamide together are badly tolerated with a high incidence of gastrointestinal side effects.29 When drug choices or severely restricted, three drugs may be needed from group 4, i.e. ethionamide, cycloserine and PAS. Terizidone contains two molecules of cycloserine and can be used instead of cycloserine because of an assumed similar efficacy. Thiacetazone is contraindicated in HIV-coinfected patients as there is a high incidence of Stevens-Johnson syndrome and death. Thiacetazone is considered a relatively weak antituberculous agent; furthermore, thiacetazone has cross-resistance with ethionamide/prothionamide.29
CHAPTER
Extensively drug-resistant tuberculosis (XDR-TB)
5. Group 5 drugs are only used under compassionate protocols in cases where it is impossible to form an adequate regimen using Groups 1 to 4. There are insufficient data verifying their contribution in multidrug regimens at present. The use of group 5 drugs is not advocated in some literature.
TREATMENT DURATION Treatment duration is guided by smear and culture conversion. The minimum period is 24 months (6 months intensive phase plus 18 months continuation phase). The injectable agent (intensive phase) should be administered for at least 6 months or at least 4 months after the patient first becomes smear- or culture-negative. The continuation phase should continue for at least 18 months after culture conversion and this should be extended to 24 months with patients defined as chronic cases or with extensive pulmonary damage.
EXTRAPULMONARY AND CENTRAL NERVOUS SYSTEM EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS The same strategy applies for pulmonary and extrapulmonary XDR-TB. When there is central nervous system involvement, rifampicin, isoniazid, pyrazinamide, ethionamide, prothionamide and cycloserine have good penetration across the blood–brain barrier. Kanamycin, amikacin and capreomycin penetrate only effectively in the presence of meningeal inflammation. PAS and ethambutol have no or poor penetration.
SURGICAL OPTIONS FOR EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS Surgical resection can be successful if timed properly. It should ideally be done earlier in the course of disease when the patient’s risk of morbidity and mortality is lower and when the disease is still localized to one lung or one lung lobe.29
CONCOMITANT TREATMENT OF EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS AND HIV For patients coinfected with XDR-TB and HIV a successful therapeutic outcome will require treatment of both diseases. The optimal timing of institution of HIV therapy once XDRTB diagnosis is made is not known, but the high mortality dictates as early an institution as possible. For those already on antiretroviral therapy when the diagnosis of XDR-TB is made, continuation of HIV therapy is necessary. Treatment of both diseases will add additional pill burden, potentially additive toxicities and possibility of drug–drug interactions. Potential overlap toxicities include neuropsychiatric symptoms with efavirenz and cycloserine, renal impairment with aminoglycosides and tenofovir, gastrointestinal intolerance with didanosine, AZT, ethionamide and PAS, peripheral neuropathy with didanosine, stavudine and aminoglycosides. Since rifampicin is not used, the pharmacokinetic drug interactions of greatest concern are removed. Although there has been no formal study of interactions between HIV medications and second-line antituberculous drugs, most of the latter are renally excreted and not expected to interact with the non-nucleoside reverse transcriptase inhibitors (efavirenz or nevirapine) or the protease inhibitors. Studies to confirm this untested hypothesis are of highest priority.
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HOSPITALIZATION OF EXTENSIVELY DRUGRESISTANT TUBERCULOSIS PATIENTS: ENFORCED HOSPITALIZATION AND TREATMENT DISCUSSION The hospitalization of XDR-TB patients requires availability of adequate isolation facilities with appropriate airborne infection control measures to prevent nosocomial spread while also ensuring a safe environment for healthcare workers and visitors. Potentially long admission periods may be implied, depending on local policy and support systems. Patients may be admitted for the full intensive phase for daily injections, or preferably be kept until not contagious as proven by culture conversion. For a few individuals this could be indefinite or till death in cases of treatment failure. Although most well-informed patients will be agreeable for admission and isolation, the problem arises when a patient refuses admission while infectious, therefore becoming a public health risk. This brings into direct conflict the rights of the individual (freedom, self determination, human dignity, equality, privacy, confidentiality, etc.) versus the public health legislature in place to protect communities against the dangers and consequences of infectious diseases. Classical public health interventions for infectious diseases aim to contain infection, often through quarantine or detention of affected individuals. However, protection of public health always comes at a cost to individual rights.32 Singh et al have recommended, as a last resort, restriction of mobility to prevent the spread of disease in patients who refuse hospitalization whilst they are infectious.3 This has provoked much debate and fortunately is rarely necessary. If instituted it must be transparent, humane, home-based and accompanied by an outreach programme which includes communication and education efforts. In a careful analysis of this issue, taking into account both individual human rights and public health concerns, it does not favour confinement as major intervention. For the vast majority of patients, involuntary detention is not necessary. Patients accept isolation and long-term in-patient stays as a means of decreasing transmission, monitoring side effects and overall increasing chances of survival. Key to this approach is the education of the patient and the patient’s family to improve cooperation and decrease defaulting. Though confinement may be necessary for the occasional patient, in general this approach is unwarranted and only serves to stigmatize patients with drug-resistant TB at a time when clinicians hope that TB suspects will seek care as early as possible. Indeed, a compassionate and humane approach should be required for these patients, most of whom have primary infection and poor survival. Furthermore, a recent model of infection control measures suggests that involuntary detention as a lone intervention, without provision of adequate isolation facilities, would serve to actually increase the number of cases of XDR TB by 3% over the next 5 years due to promotion of nosocomial spread.20 Enforced treatment of XDR-TB patients, even under quarantine conditions, represents a most severe invasion of an individual’s right to freedom and security of the person. Given the toxicity of XDR-TB treatment, potentially severe drug side effects, a low success rate of treatment and the reduced life expectancy of XDR-TB patients, there is not sufficiently strong legal justification for coerced treatment.32
CURE RATES FOR EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS Cure rates of 50–60% were achieved in Latvia amongst predominantly HIV-uninfected patients in a well-equipped soundly managed TB programme.4 Similar XDR-TB treatment success rates between 48% and 60% are reported among HIV-uninfected patients in Tomsk33, South Korea34 and Peru35. In Tugela Ferry, South Africa,
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a survival rate of 16% among XDR-TB patients coinfected with HIV has been reported where treatment options were severely restricted.
GLOBAL STRATEGIC RESPONSE TO EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS 4 To prevent drug-resistant TB, the WHO Task Force on XDR-TB underlined, as its first priority, the need for immediate strengthening of TB control in countries, as detailed in the new Stop TB Strategy and the Global Plan to Stop TB, 2006– 2015. This should be done together with scaling up universal access to HIV treatment and care. The following strategies are recommended by WHO: 1. early rapid diagnosis of resistant TB especially in HIV-infected patients and in high-HIV-prevalent settings; 2. rapid identification of rifampicin resistance to facilitate early diagnosis and treatment; 3. standardized treatment approach to XDR-TB suspects: empirical treatment with a regimen comprising the likely most effective second-line antituberculous drugs available should be given to all known or suspected cases of XDR-TB who are HIV-infected (Fig. 54.2); 4. rapid initiation of treatment; 5. infection control: guidelines on TB infection control are available and should be seen as a priority. Groups for enforcing good infection control procedures with national monitoring and evaluation of infection control practice at country level should be formed.4 Updated infection control guidelines for facility level are available; 6. universal access to HIV treatment and care; and 7. integration of HIV and TB services: the XDR-TB problem in many parts of the world cannot be solved unless HIV is properly considered and appropriately included in the evolving responses.
REFERENCES 1. Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs – worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep 2006;55(11):301–305. 2. Gandhi NR, Moll AP, Sturm W, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575–1580. 3. Singh JA, Upshur R, Padayatchi N. XDR-TB in South Africa: no time for denial or complacency. PLoS Med 2007;4(e50):19–25. 4. World Health Organization. Report of the meeting of the WHO Global Task Force on XDR-TB, Geneva, Switzerland, 9–10 October 2006. WHO/HTM/TB/ 2007.374. Available at the URL: http://www.who. int/tb/challenges/xdr/globaltaskforcereport_oct06. pdf 5. Nunn P. Urgent issues in the developing world. Transmission of XDR-TB in South Africa: discussion of the global implications. Presented at the CROI 2007 14th Conference on Retroviruses and Opportunistic Infections.
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FUTURE RESEARCH AND DEVELOPMENT RELATING TO EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS The following is needed:
Surveillance to determine the geographical distribution and extent of XDR-TB, its association with HIV, its genetic origins and trends over time. HIV testing wherever possible should be included with TB resistance surveys; Scale-up of laboratory services to improve the access and availability of DST for second-line drugs; Further research of molecular testing to develop new diagnostic tools for TB diagnosis, drug resistance determination and fingerprinting in terms of cost, usability in resource-poor areas and turnaround time. Rapid rifampicin resistance tests should be explored to expand the scope of drug resistance surveillance; Systems to be enhanced for the collection and coordination of information on second-line drug resistance; The characterization of clinical predictors for XDR-TB and association with HIV; Launch of microscopically observed drug susceptibility (MODS) which does not require highly skilled personnel, is inexpensive, has been tested in the developing world and has a turnaround time of about 7 days, giving resistance results for rifampicin and isoniazid. Expansion of the MODS capability to include second-line drugs needs to be explored; Interaction of second-line drugs and antiretroviral treatment needs to be studied; Improvement of infection control strategies and implementation; and Development of new TB drugs.
6. Extensively Drug-Resistant Tuberculosis (DR-TB): The Facts. Available at URL: http://www.stoptb.org/ events/world_tb_day/2007/assets/documents/5.5% 20XDR%20TB.pdf 7. Laserson KF, Thorpe LE, Leimane V, et al. Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2005;9:640–645. 8. Rich ML. Diagnosis and treatment of multidrugresistant tuberculosis. In: Raviglione M, ed. Reichman and Hershfields Tuberculosis: A Comprehensive International Approach. New York: Informa Healthcare, 2006: 417–458. 9. Warner DF, Mizrahi V. Tuberculosis chemotherapy: the influence of bacillary stress and damage response pathways on drug efficacy. Clin Microbiol Rev 2006;19:558–570. 10. Medical Research Council. Treatment of pulmonary tuberculosis with isoniazid; an interim report to the Medical Research Council by their Tuberculosis Chemotherapy Trials Committee. Br Med J 1952;2:735–746. 11. Farmer P, Robin S, Ramilus SL, et al. Tuberculosis, poverty, and ‘compliance’: lessons from rural Haiti. Semin Respir Infect 1991;6:254–260. 12. Farmer P. Social scientists and the new tuberculosis. Soc Sci Med 1997;44:347–358.
13. Blower SM, Chou T. Modeling the emergence of the ‘hot zones’: tuberculosis and the amplification dynamics of drug resistance. Nat Med 2004; 10:1111–1116. Epub 2004 Sep 19. 14. Personal communication with AW Sturm, Head of Microbiology, Nelson Mandela School of Medicine, University of KwaZulu-Natal, South Africa. 15. Frieden TR, Fujiwara PI, Washko RM, et al. Tuberculosis in New York City – turning the tide. N Engl J Med 1995;333:229–233. 16. Moro ML, Gori A, Errante I, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. AIDS 1998;12:1095–1102. 17. Centers for Disease Control and Prevention. Multidrug-resistant tuberculosis outbreak on an HIV ward – Madrid, Spain, 1991–1995. MMWR Morb Mortal Wkly Rep 1996;45:330–333. 18. Centers for Disease Control and Prevention. From the Centers for Disease Control and Prevention. Tuberculosis treatment interruptions – Ivanovo Oblast, Russian Federation, 1999. JAMA 2001;285:1953–1954. 19. Ritacco V, Di Lonardo M, Reniero A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997;176:637–642.
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Extensively drug-resistant tuberculosis (XDR-TB) 20. Basu S, Andrews J, Poolman E, et al. Impact of preventing nosocomial transmission of extensively drug-resistant (XDR) tuberculosis in rural South African District Hospitals. Lancet 2007; 370:1500–1507. 21. Friedland GH. Tuberculosis, drug resistance and HIV/AIDS: a triple threat. Clin Infect Dis Rep 2007; 9:252–291. 22. Andrews JR, Gandhi N, Moll AP, et al. Clinical predictors of drug resistance and mortality among tuberculosis patients in a rural South African Hospital: A case control study. Unpublished Thesis. 23. Johnson JL, Vjecha MJ, Okwera A, et al. Impact of human immunodeficiency virus type-1 infection on the initial bacteriologic and radiographic manifestations of pulmonary tuberculosis in Uganda. Makerere University–Case Western Reserve University Research Collaboration. Int J Tuberc Lung Dis 1998; 2:397–404. 24. Elliott AM, Namaambo K, Allen BW, et al. Negative sputum smear results in HIV-positive patients with pulmonary tuberculosis in Lusaka, Zambia. Tuber Lung Dis 1993;74:191–194. 25. Greenberg SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994;193:115–119.
SUGGESTED FURTHER READING/RESOURCES 1. World Health Organization. Guidelines for the Prevention of Tuberculosis in Health Care Facilities in Resource-Limited Settings. WHO/CDS/TB/99.269. Geneva: World Health Organization, 1999.
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26. Palmieri F, Girardi E, Pellicelli AM, et al. Pulmonary tuberculosis in HIV-infected patients presenting with normal chest radiograph and negative sputum smear. Infection 2002;30:68–74. 27. Perlman DC, el-Sadr WM, Nelson ET, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1997;25:242–246. 28. Post FA, Wood R, Pillay GP. Pulmonary tuberculosis in HIV infection: radiographic appearance is related to CD4þ T-lymphocyte count. Tuber Lung Dis 1995;76:518–521. 29. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization, 2006. 30. Rich ML, ed. The Partners in Health Guide to the Medical Management of Multidrug-Resistant Tuberculosis. Boston: Partners in Health, 2003. 31. Meier A, Sander P, Schaper KJ, et al. Correlation of molecular resistance mechanisms and phenotypic resistance levels in streptomycin-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 1996;40:2452–2454.
32. Detention of patients with extensively drug resistant tuberculosis (XDR-TB). Position Statement by the South African Medical Research Council (SAMRC) 2007 January. Available at URL: http://www.mrc.ac.za/pressreleases/2007/ 1pres2007.htm 32. Detention of patients with extensively drug resistant tuberculosis (XDR-TB). Position Statement by the South African Medical Research Council (SAMRC) 2007 January. Available at URL: http://www.mrc.ac.za/pressreleases/2007/ 1pres2007.htm 33. Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet. Published Online August 25, 2008. DOI:10.1016/S0140-6736(08)61204-0 34. Kim H, Hwang SS, Kim HJ, et al. Impact of Extensive Drug Resistance on Treatment Outcomes in Non-HIV infected Patients with MultidrugResistant Tuberculosis. Clin Infect Dis 2007; 45:1290–1295. 35. Mitnick, CD, Shin SS, Seung KJ, et al. Comprehensive Treatment of Extensively DrugResistant Tuberculosis. N Engl J Med 2008; 359:563–574.
2. Tuberculosis Infection Control in the Era of Expanding HIV Care and Treatment. Addendum to World Health Organization, Guidelines for the Prevention of Tuberculosis in Health Care Facilities in Resource-Limited Settings, 1999. Available at URL: http://www.cdc.gov/nchstp/od/gap/ docs/program_areas/TB%20Infection%20Control% 20Document%20Final%2010%2025%2006.pdf 3. World Health Organization. Good Practice in Legislation and Regulations for TB Control: An Indicator of Political Will. WHO/CDS/TB/2001.290. Geneva: World Health
Organization, 2001. Available at URL:http://whqlibdoc. who.int/hq/2001/WHO_CDS_TB_2001.290.pdf 4. Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care (ISTC). The Patients’ Charter for Tuberculosis Care: Patients’ Rights and Responsibilities. The Hague: Tuberculosis Coalition for Technical Assistance, 2006. Availabe at URL: http://www.who.int/tb/publications/2006/ istc_charter.pdf
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Tuberculosis in non-HIV immunosuppressed patients Rodney Dawson and Eric D Bateman
Patients who are immunosuppressed have increased susceptibility to tuberculosis infection and disease. Other causes of impaired host defence and immunosuppression have also been shown to place patients at increased risk of infection/disease (Box 55.1). The risk associated with each varies, but is most profound with iatrogenic immunosuppression in the management of malignancy and organ transplantation, and is milder in diabetes mellitus. In some diseases, for example in systemic lupus erythematosus, the risk represents the dual effects of susceptibility conferred by the disease state and its treatment (for example, systemic corticosteroids). Not only the risk, but also the presentation, investigation and approach to management varies according to the cause. For this reason these conditions will be considered separately.
Sex Male diabetics are generally considered to be at greater risk of TB than females. The reason for this is not apparent.5
DISEASE-ASSOCIATED SUSCEPTIBILITY TO TUBERCULOSIS
The rates of diabetes in patients with TB vary widely in different populations, probably reflecting the varying prevalence of diabetes in different communities. These range from 9.8% in Serbia to 27% in Saudi Arabia, but in most countries, between 10% and 15% of patients treated for TB have concomitant diabetes.1,8 Active TB may also be associated with impaired glucose tolerance that improves/resolves after successful TB chemotherapy.9 In a large Tanzanian TB cohort, glucose intolerance (16.2%) was twice that of controls drawn from the same population.10 This impairment may be transient; thus, patients diagnosed with diabetes while on TB treatment should be reviewed once treatment has been completed.
DIABETES MELLITUS EPIDEMIOLOGY Patients with diabetes mellitus are at increased risk of developing active TB, but this risk, which may be fivefold or more,1 varies according to the background prevalence of TB and various host factors, including the patient’s age and sex, body mass, duration of diabetes and, most importantly, adequacy of glycaemic control. Additionally, TB may result in impaired glucose tolerance that improves/resolves after successful TB treatment. With the rising incidence of obesity-related diabetes in many countries, including those with high TB prevalence, this disease interaction may assume greater significance in the future.
FACTORS INFLUENCING SUSCEPTIBILITY TO TUBERCULOSIS IN DIABETIC PATIENTS Age and duration of diabetes Diabetics over the age of 40 are at increased risk of developing TB,2,3 and a longer duration of diabetic disease predisposes to TB in all age groups. A higher frequency of smear-positive disease has been reported in diabetics aged 60 years and older.4
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Glycaemic control Perhaps the most important determinant of developing TB is the level of diabetic control that patients maintain. Increased risk of smear-positive disease has been demonstrated at HbA1C levels of 9% or more.6 Body mass Low body mass in patients (including younger ones) has been demonstrated to be an independent risk factor for TB in both developed and developing countries.1,3,7 DIABETES MELLITUS IN PATIENTS WITH TUBERCULOSIS
CLINICAL FEATURES OF TUBERCULOSIS IN DIABETES PATIENTS Symptoms and signs The clinical features and presentation of TB in most patients with diabetes are similar to those without, but unusual presentations have been described. The latter includes a higher incidence of extrapulmonary disease. Diabetes might predispose to certain rarer manifestations such as laryngeal TB.11 However, since patients with diabetes frequently have target organ damage with associated symptoms, early symptoms of TB may be missed or attributed to other diseases. A comprehensive history should be obtained on all new TB–diabetes mellitus cases as outlined in Box 55.2. Physical examination The focus of physical examination should be directed towards detecting complications of diabetes including condition of insulin injection
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Box 55.1 Conditions associated with an increased risk of tuberculosis infection/disease Disease states Human immunodeficiency virus infection. Diabetes mellitus. Silicosis. Collagen vascular disease (systemic lupus erythematosus). End-stage renal disease. Malignancy. Malnutrition. Advanced age. Iatrogenic causes Systemic corticosteroid. Immunosuppression after organ transplantation and during anticancer treatment. Gastrectomy and ileojejunostomy. Targeted immune modulation e.g. anti-tumour necrosis factor therapy.
Box 55.2 History and evaluation of the tuberculosis–diabetes mellitus patient Diabetes history Type and onset of diabetes. Diabetic treatment history and drug administration and supply. Level of prior diabetes education. Dietary history and current eating plan. Monitoring and glycaemic control. Episodes and symptoms of hypoglycaemia. Evidence of target organ damage: ○ Microvascular: renal, ocular, neuropathy. ○ Macrovascular: cardiac, arterial disease, stroke. ○ Other: gastroparesis, impotence. Tuberculosis history Duration and symptoms. Presence of extrapulmonary disease. Presence of complications of disease. Smoking history and prior lung disease.
sites, complications of pulmonary TB (pleural and laryngeal involvement) and evidence of extrapulmonary and disseminated disease (for example, meningitis, lymphadenopathy, organomegaly, peritonitis and joint disease). Examination for macro- and microvascular complications of diabetes should be carried out, and so should monitoring of visual acuity during treatment after ascertaining a normal baseline level, alongside colour perception.
Investigations Sputum examination Sputum smear positivity may be seen more frequently than in nondiabetics as the pre-treatment pulmonary bacillary load may be high. The incidence of cavitary disease is also reportedly higher than in non-diabetic patients.12 Chest radiography The pattern of disease is typical in the majority of cases, but atypical presentations have been described. Nissapatorn et al found no differences in the radiological presentations among 1,651 patients with diabetes.13 A preponderance of cavitary and lower-zone disease have, however, been found in another study in diabetes.14 Ikezoe et al, using computed tomography (CT) scan assessment,
55
reported 44% small cavities within tuberculous lesions in diabetics.15 With increasing patient age, basal distribution of disease and other atypical presentations may increase.16
Other investigations Other suggested investigations are shown in Box 55.3. DIFFERENTIAL DIAGNOSIS Table 55.1 lists conditions in diabetics mimicking TB that should be considered. Conversely, because some of the symptoms of TB are similar to those of poorly controlled diabetes and its comorbidities, the diagnosis of TB may be overlooked or delayed.
MANAGEMENT The standard goals and methods of treatment of diabetes apply during tuberculous chemotherapy. More careful monitoring of clinical improvement and sputum conversion is required, especially where glycaemic control is suboptimal or poor. Longer individualized regimens for TB in patients with poor glycaemic control and cavitary disease should only be considered on a case by case basis, given the lack of prospective evidence for prolonged treatment regimens in diabetic patients. Since the development of tuberculous disease may be accompanied by loss of diabetic control, a temporary increase in treatment, on occasions involving a switch to insulin injections in those on oral anti-diabetic drugs, may be indicated. A further reason for Box 55.3 Suggested laboratory investigations in newly diagnosed tuberculosis–diabetes mellitus
Sputum smear and culture. Chest radiography. Urine test for microalbuminuria. Serum creatinine and calculated glomerular filtration rate. Thyroid stimulating hormone. Liver function tests.
Table 55.1 Conditions in diabetic patients that share symptoms with tuberculosis Symptom
Condition
Cough
Angiotensin converting enzyme inhibitor-induced cough. Beta blocker-induced cough. Gastro-oesophageal reflux disease. Cigarette smoking. Congestive cardiac failure. Autonomic neuropathy. Phaeochromocytoma and polyglandular autoimmune disease. Nicotinic acid therapy. Undiagnosed type I disease. Poor diabetic control. Excessive insulin administration. Poor diabetic control. Obstructive sleep apnoea. Congestive cardiac failure. Renal failure Anaemia. Diabetic amyotrophy. Uncontrolled diabetes.
Night sweats
Weight loss Tiredness
Weakness
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the need to increase the doses of oral hypoglycaemic agents is their increased metabolism resulting from the induction of the cytochrome P-450 enzyme system by rifamycins. The use of gatifloxacin in TB as a third-line agent has recently been associated with impairment of glucose homeostasis and the development of hyperglycaemia in non-diabetics.17 Guler et al reported a higher rate of persistence of sputum smear and culture positivity after 2 months of treatment, independent of the extent of pulmonary disease,18 and Restrepo et al noted that patients with TB and diabetes were more likely to be smear-positive at diagnosis, and remain positive at the end of 1 and 2 months of treatment.19 This finding may be attributed to the greater tendency of cavitary disease in diabetics. In contrast to these reports, others have described better patient compliance and treatment success rates in diabetics.13 However, relapse rates might also be higher.20 The above findings might also be attributable to differences in the bioavailability of rifampicin in diabetic patients. In a study from Indonesia, exposure to rifampicin was reduced by as much as 50% in patients with diabetes, compared with non-diabetic controls, and the authors suggested that doses should be increased in patients with higher body mass index (BMI).21
PROGNOSIS The presence of diabetes does not appear to influence the outcome of TB treatment,12 and the 10-year risk of death from TB is the same as in non-diabetics,12 confirming that if correctly and carefully managed, the outcome for diabetic patients with TB should be similar to that of other patients with TB.
SILICOSIS
of defence against mycobacteria and are also required to phagocytose and assist in the clearance of silica particles. The physicochemical properties of crystalline quartz result in damage to cell membranes through a variety of processes, leading to death, lysis and release of dust particles together with potentially tissue-damaging enzymes and other substances.
CLINICAL FEATURES AND INVESTIGATION The onset of symptoms may be insidious, and general symptoms (fever, night sweats, muscle pain and fatigue) predominate. The presence of haemoptysis and increasing respiratory symptoms should alert to the possibility of TB. The presence of silicosis makes chest radiographic changes more difficult to interpret. Careful scrutiny for new changes, particularly the development of cavitation, poorly defined ‘fluffy’ infiltrates surrounding previous tuberculous lesions and the appearance of new crops of poorly defined nodules should be performed. Sputum examination is mandatory and should be repeated in high-risk cases. Chest CT scans may help to define potential new areas of involvement, and serve as a guide to bronchoscopic examination and sampling. A high index of suspicion must be maintained in all silica-exposed and silicotic patients as TB is a frequent finding in postmortem examinations.
PROGNOSIS Although persons exposed to silica are at lifetime risk, results of treatment of TB appear to be satisfactory and similar to those without such exposure.25,26 Treatment regimens of 8–9 months as well as longer duration of PZA therapy have been considered but these decisions should be addressed on a case by case basis with expert advice.
BACKGROUND AND EPIDEMIOLOGY The link between silicosis and the development of TB has been known for more than 400 years, but quantification of this risk whether alone or occurring with other risk factors like HIV infection and tobacco smoking remains a topic of considerable interest. The risk associated with silica exposure, which although less than those with silicosis, is significant.22 Silica exposure imposes a lifetime risk and is not limited to the period of exposure, but manifests in later decades in persons who have retired from industry. Together, silica exposure and the immunosuppression associated with HIV infection is multiplicative and responsible for record high incidence of TB among current and ex-miners.23 The risk associated with silicosis has been described in several industries in different countries,24 but perhaps none better than in the gold miners in South Africa.22,25 Silicotic workers have an approximately threefold greater risk of developing TB and a three- to fivefold greater risk of dying from TB than the general population,24 and 20% to 25% develop TB at some time in their working career or retirement. The association is dose-dependent, increasing with greater profusion of silicosis on chest radiograph,25 although the size of nodules and presence of progressive massive fibrosis might be more significant in determining the risk of TB.
PATHOLOGY AND PATHOPHYSIOLOGY Mechanisms underlying these associations are complex and not fully understood. However, alveolar macrophages are the first line
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TUBERCULOSIS IN PATIENTS WITH RENAL FAILURE EPIDEMIOLOGY The incidence of TB is increased in end-stage renal disease, and estimates of the increased risk of infection/disease vary from two- to 25-fold.27 However, these estimates are not populationbased and have not controlled for other risk factors such as concomitant steroid therapy or diabetes mellitus. In a recent retrospective analysis of 272,024 patients in the US Renal Data System initiated on dialysis therapy over a period of 57 months, the cumulative annual incidence of TB in patients undergoing peritoneal dialysis or hemodialysis was 1.2% and 1.6%, respectively.28 A majority of cases of TB develop within the first year of commencement of dialysis, presumably reflecting the profound effects of uraemia upon immune function.29
TRANSPLANTATION Tuberculosis is also more common in renal transplant recipients, and has been positively associated with duration of haemodialysis before transplantation and the number of episodes of rejection following transplantation, again reflecting immunosuppression, either due to renal failure or iatrogenic. In an Iranian study of renal transplant patients which compared 120 subjects with post-transplant TB with 440 controls,30 and in a retrospective review of Medicare
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Tuberculosis in non-HIV immunosuppressed patients
records in the USA,28 a past history of TB did not appear to be a risk factor for TB after transplantation. In the latter study only systemic lupus erythematosus (SLE) emerged as an independent risk factor for TB in hospitalized post-transplant renal patients.31
Table 55.2 Suggested laboratory investigations in cases of suspected tuberculosis in end-stage renal failure (ESRF)
CLINICAL FEATURES Symptoms and signs The diagnosis of TB in patients with renal failure is often delayed and may be masked by either the underlying disease or by the symptoms of renal failure. Extrapulmonary presentations are common. Fang et al reported a 51.6% incidence of extrapulmonary TB, with the peritoneal and pleural involvement being the most common sites.32 Tuberculosis should be suspected in end-stage renal failure patients with fever of unknown origin (T > 38.3 C on several occasions) and unexplained loss of weight, especially when attempts to obtain a clinical diagnosis fail despite an extensive laboratory and diagnostic work-up. Clinical examination All lymph node groups should be carefully palpated as axillary and inguinal adenopathy can be overlooked. Cardiovascular examination should identify clinical signs of pericardial effusion. Respiratory examination may identify the presence of pleural effusion. The presence of ascites should be noted and the macroscopic appearance of peritoneal dialysate should be checked for a cloudy appearance. Abdominal adenopathy and renal enlargement associated with obstructive uropathy as well as bladder enlargement related to urinary obstruction should be identified. Investigations Sputum examination Sputum may need to be collected by induction procedures to enhance bacillary yield. Chest radiography Nearly half of patients with end-stage renal failure and TB have radiological evidence of pulmonary TB.32 However, the pattern may be atypical (lower zone disease, miliary involvement, adenopathy and/or pleural effusion). An enlarged cardiac shadow may indicate the presence of pericardial effusion.
General ESRF patients with TB may pose an infective risk to immunocompromised renal transplant cases and other patients in dialysis units. Infection control measures and contact tracing should be applied. In patients with ESRF on TB treatment, the same general principles for management of patients with renal failure apply. A thorough drug chart review should be performed prior to prescribing TB medication to identify potential drug interactions especially in transplant patients on cyclosporine and mycophenolate mofetil. The selection and doses of TB drugs should preferably be decided in consultation with a specialist renal physician. Box 55.4 shows the antituberculous drugs that significantly dependent on renal clearance. Tuberculosis drug therapy in renal failure The presence of renal failure affects the selection and dosing of drugs used for the treatment of TB. The American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America makes the following recommendations (Table 55.3):33
Ultrasound Ultrasound examination of the abdomen is useful for confirming abdominal sites of TB including the presence of ascites, adenopathy, and splenic and renal TB.
Other investigations Other suggested laboratory investigations are shown in Table 55.2.
Sputum examination and culture. Chest radiography with lateral projection. Full blood count. Transaminase levels and serum calcium. Serum creatinine and calculated glomerular filtration rate. C-reactive protein. Urine microscopy and culture. Abdominal ultrasound.
MANAGEMENT
Blood results Hypercalcaemia has been described as a feature of TB in patients with end-stage renal failure but this association requires confirmation in larger controlled clinical trials.
Diagnostic samples Biopsy and culture of needle aspirates from extrapulmonary and pulmonary sites of pathology are often required: the pleura (preferably biopsy), bronchial lavage and transbronchial biopsies, peritoneal aspirates, lymph nodes (aspirate or biopsy), liver (biopsy) and joints (aspirate or biopsy). Dialysate from peritoneal lavage should always be sent for culture as acid-fast bacilli (AFB) staining alone on lavage fluid has a low diagnostic yield. Great caution in patients with end-stage renal failure (ESRF) must be exercised for contemplating these procedures because of associated coagulopathy.
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Decreasing the dose for selected drugs is generally not recommended as this may result in lower serum levels of active drug and reduced concentration-dependent antituberculous activity. Increasing the dosing interval is recommended for drugs dependent on renal clearance in patients with creatinine clearance of less than 30 mL/minute (see Table 55.3). Drug absorption may be unpredictable in patients with renal failure due to nausea and vomiting resulting from uraemia, and patients should be questioned regularly about these symptoms.
Box 55.4 Antituberculous drugs that significantly dependent on renal clearance
Ethambutol. Levofloxacin. Cycloserine. Streptomycin. Kanamycin. Capreomycin. Amikacin.
(Metabolites of pyrazinamide may accumulate.)
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Table 55.3 Dosing recommendations for adult patients with reduced renal function and for adult patients receiving haemodialysis Drug
Change in frequency
Recommended dose and frequency for patients with creatinine clearance < 30 mL/min or for patients receiving haemodialysis
Isoniazid
No change
Rifampin
No change
Pyrazinamide
Yes
Ethambutol
Yes
Levofloxacin
Yes
Cycloserine
Yes
Ethionamide p-Aminosalicylic acid Streptomycin
No change No change Yes
Capreomycin
Yes
Kanamycin
Yes
Amikacin
Yes
300 mg once daily or 900 mg thrice weekly 600 mg once daily or 600 mg thrice weekly 25–35 mg/kg per dose thrice weekly (not daily) 15–25 mg/kg per dose thrice weekly (not daily) 750–1,000 mg per dose thrice weekly (not daily) 250 mg once daily or 500 mg/dose thrice weeklya 500–750 mg/dose daily 4 g/dose twice daily 12–15 mg/kg per dose twice or thrice weekly (not daily) 12–15 mg/kg per dose twice or thrice weekly (not daily) 12–15 mg/kg per dose twice or thrice weekly (not daily) 12–15 mg/kg per dose twice or thrice weekly (not daily)
It should be noted that Standard doses are given unless there is intolerance; Medication should be given after haemodialysis on the day of haemodialysis; Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption, without excessive accumulation, and to assist in avoiding toxicity; and Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving haemodialysis and verify adequacy of dosing using serum concentration monitoring. a The appropriateness of 250 mg daily doses has not been established. There should be careful follow-up for evidence of neurotoxicity. Reproduced from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167(4): 603–662.33
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Creatinine clearance should be measured in all patients with renal disease prior to treatment. The timing of drug administration is important. Drugs should generally be administered after haemodialysis to prevent loss of drug during dialysis. This is especially relevant for pyrazinamide (PZA), which is efficiently removed by haemodialysis. The injectable agents – streptomycin, kanamycin, capreomycin and amikacin – are also partially removed and should be given after haemodialysis. Of the standard TB drugs, rifampicin is not removed by haemodialysis due to its wide volume of distribution and high degree of protein binding. Isoniazid and ethambutol are removed by haemodialysis but to a lesser extent than PZA.
TUBERCULOSIS IN PATIENTS WITH NEOPLASIA EPIDEMIOLOGY An increased incidence of TB has been associated with many malignancies, but the assessment of relative risk with different forms of malignancy is confounded by the functional state of patients (weight loss, cachexia and extent of spread) and the level of immunosuppression caused by different modalities of treatment, particularly chemotherapy. In general, however, the risk is greater in haematological malignancy than with solid tumours, and greater with chemotherapy regimens that result in bone marrow and immune suppression. In one review of TB in patients with malignancy, in 30% of cases TB was observed at the time of diagnosis of the malignancy, and in half TB developed during 18 months of therapy. Other surveys have reported that patients with active pulmonary TB are at increased risk of dying of cancer.34 However, from a diagnostic perspective, cancer and TB are often confused, and both must be considered in patients with unusual presentations of either. Patients with haematological malignancies such as Hodgkin’s disease, adult T-cell leukaemia and other lymphoproliferative disease receiving high doses of corticosteroids and fludarabine or who are haematopoietic stem cell recipients have been considered to be at a threefold higher risk than those with other haematological malignancies of developing TB. In their series, Silva et al reported a prevalence of 2.6% of TB in patients with haematological malignancies, with the highest rates (6.9%) in patients with chronic lymphocytic leukaemia (CLL).35
CLINICAL PRESENTATION AND DIAGNOSIS OF TUBERCULOSIS IN PATIENTS WITH MALIGNANCIES The diagnosis of TB in patients with malignancies is often delayed for several reasons. Symptoms in haematological malignancies are often attributed to tumour progression, general loss of functional status and nutrition or anaemia and other side effects of aggressive chemotherapy. Diagnostic confusion and the risk of delayed diagnosis is greatest in patients with bronchial malignancy where these conditions may coexist. On the other hand, Tunell et al have reported delayed diagnosis of malignancy of more than 16 weeks in patients first diagnosed with TB, a five-times longer delay than in a control group.36 However, this delay is probably even greater in TB control programmes that rely solely on sputum examination for management decisions, since these require treatment failure (either bacteriological or clinical) before chest radiographs are reviewed, and the majority of cases of malignancy diagnosed in this way are in an advanced stage. Treatment algorithms in such programmes should therefore include signs and symptoms that prompt review for the presence of bronchial malignancy. These are listed in Box 55.5.
Box 55.5 History and clinical signs suggesting bronchial malignancy in patients with tuberculosis
A history of smoking and previous bronchial or upper respiratory tract malignancy. Failure to gain weight on therapy especially in patients with drugsusceptible M. tuberculosis on initial cultures. The presence of persistent chest pain. Ongoing or new haemoptysis while on TB treatment. Hoarseness of new onset. Persistence of radiological infiltrates or appearance of new ones.
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In patients with TB and suspected malignancy, repeated sputum cytology has been shown to improve the diagnostic yield but this is not feasible when haemoptysis is present and or when patients are unable to expectorate.37 The latter can be overcome in some by use of sputum-inducing methods, but fine needle aspiration under radiographic guidance (preferably using a CT scan) or bronchoscopy has the highest success rate in confirming the diagnosis.
has been reported, this too may be attributable to concurrent diseases and has not been confirmed in all studies. Elderly patients have decreased lymphocyte function and impaired cell-mediated immunological response which manifests as a lower rate of tuberculin skin test (TST) positivity. This has been confirmed in a review of 12 studies comparing TST reaction in the elderly with that in other age groups and in a study of new admissions to nursing homes in Arkansas.41,42
TREATMENT AND PROGNOSIS
CLINICAL PRESENTATION
Tuberculosis occurring in malignancy is treated along standard lines, but attention must be paid to potential drug interactions and side effects in patients who are debilitated by cancer or on aggressive chemotherapy or radiotherapy. Where surgery for cancer is planned, it is advisable to delay this for at least some weeks until TB chemotherapy has been started. Where possible, a longer delay and even completion of TB treatment is advised in patients scheduled to receive chemotherapy and bone marrow transplantation. However, this must be weighed against the impact of such delays upon prognosis of the malignancy. Study of the influence of TB on the prognosis of patients with lung cancer has provided conflicting results.35,38,39
The clinical presentation of TB in the elderly is similar to that in other age groups. The presence of fever, sweating and haemoptysis are less pronounced, but dyspnoea is more common. Comorbidity is common, and symptoms like cough and dyspnoea are frequently overlooked or attributed to other diseases, resulting in delayed diagnosis.
COMPLICATIONS Clinicians prescribing TB medication and following up patients with comorbid disease should be attentive to:
potential drug interactions between TB drugs and multiple chemotherapeutic agents; the effects of nausea and vomiting on drug absorption; the effects of general debility and impaired mobility on drug collection and treatment compliance; the risk of transmission of TB from these to other susceptible patients in clinic and hospital facilities serving patients with cancer and haematological diseases; and the development of other cancer and treatment-related lung disease including: ○ opportunistic lung infection such as fungal pneumonia; ○ drug-induced lung disease; ○ radiation lung injury; and ○ pulmonary thromboembolic disease.
INVESTIGATIONS Sputum examination Elderly patients suspected of having TB may have difficulty expectorating sputum. Collecting three induced sputum samples has shown a better diagnostic yield than serial gastric lavage or fibreoptic bronchoscopy.43 TST testing Although the rate of TST positivity is lower in the elderly, the size of positive reactions is similar to that in younger patients.44 Chest radiography A recent analysis of 12 studies has failed to confirm that the elderly have less cavitary and more atypical findings.41 It is advisable to consider TB in all elderly patients with slowly or non-responding pneumonia. Sputum examination for AFB is mandatory. Interferon-gamma release assays (IGRA) There is insufficient evidence at this stage to propose a clear policy for the use of IGRA tests in the diagnosis of latent and active TB in the elderly.45 MANAGEMENT General management principles for TB are the same as for other adult patients. Some special considerations apply:
AGING AND TUBERCULOSIS BACKGROUND AND EPIDEMIOLOGY The increased risk of TB in older patients is evident from comparison of notification rates for different age groups in the same population. For example, in the USA for the period 2000–2004, the rate for the 65 years and older group was significantly higher than that for all ages (8.85 vs 5.33 cases per 100,000 population). In developed countries this is postulated to be a cohort effect resulting from higher infection rates earlier in the last century with reactivation in the face of an aging immune system. However, an increased risk of newly acquired infection has been observed in nursing homes and chronic care hospitals.40 It is not clear from these statistics whether the higher prevalence of comorbidity like diabetes and renal disease contributes to these differences also aside from aging alone. Similarly, although a higher mortality associated with TB in the elderly
Drug interactions are more common as many patients are on treatment for other medical conditions. Attention to anticipate these and to make suitable adjustments to treatment is required. The use of rifamycins in particular poses problems as these enhance the metabolism of drugs such as corticosteroids, calcium channel blockers and theophylline. Additional supervision for visually challenged patients or patients with physical disability may be required. A DOTS partner is of particular value. Supervised therapy is also necessary in those with conditions associated with cognitive or memory impairment. Drug-induced hepatotoxicity has variously been reported to be increased in the elderly. Symptoms such as poor appetite and vomiting may be mistakenly attributed to other causes. Neutropenia due to therapy should be excluded.46
Although multidrug-resistant (MDR) TB is more prevalent in younger patients it should still be considered in old-age patients who fail to respond to treatment.47
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IATROGENIC CAUSES OF INCREASED RISK OF TUBERCULOSIS INFECTION/DISEASE
CORTICOSTEROID USE AND RISK OF TUBERCULOSIS BACKGROUND Corticosteroids may serve both as a treatment and as a risk factor in TB. On one hand, their use may increase the risk of infection, progression to disease and dissemination. On the other hand, their therapeutic use rests on the anti-inflammatory activity in some TB settings such as SLE, glandular involvement in children obstructing airways, pleurisy, pericarditis, peritonitis, meningitis and ocular involvement.48–52 It can also be used for treating the paradoxical response and immune reconstitution syndrome associated with TB treatment, especially in patients on antiretroviral therapy.53
Systemic lupus erythematosus and collagen vascular diseases Collagen vascular diseases are a major category of disease in which corticosteroids are used – either as a long-term remittive agent or for the treatment of flare-ups of acute arthritis in rheumatoid arthritis and SLE. The risk of TB appears to vary by disease, indication and dosing schedule. It is greater in patients with lupus than those with rheumatoid arthritis,54 and is more common in patients with organic brain syndrome, vasculitis and nephritis, and in patients who receive intravenous ‘pulse’ methylprednisolone or high cumulative doses of prednisolone.55 The use of prophylactic isoniazid (INH) does not appear to effectively prevent recurrence of TB in lupus patients in highly endemic areas, and may be associated with an increased risk of lupus flare. Asthma and chronic obstructive pulmonary disease Inhaled corticosteroids are used in patients with asthma, and severe chronic obstructive pulmonary disease (COPD). In addition, short courses of systemic corticosteroids are used for exacerbations of both diseases. In support of earlier studies performed in the UK, Cowie and King were unable to demonstrate an increased risk of TB in a group of asthmatic South African miners receiving regular oral corticosteroids.56 Inhaled corticosteroids are also considered to be safe in children and adults with asthma who are tuberculin-positive and there is no evidence of increased risk of tuberculous infection or disease.57 In a randomized placebo-controlled trial of more than 1000 children aged 5–10 years treated with inhaled low-dose budesonide, no increase in TB or other respiratory infections was observed.58 However, this study employed a low dose of corticosteroid. In a recent large 1-year international trial involving the use of a high-dose inhaled corticosteroid in patients with COPD, although a small excess in respiratory infections was recorded, no cases of TB were reported.59 Use of inhaled corticosteroids in airway diseases appears safe. Diffuse parenchymal lung disease Systemic corticosteroids are the most widely used treatment for diffuse parenchymal diseases like sarcoidosis, idiopathic pulmonary fibrosis, lymphocytic interstitial pneumonitis, cryptogenic organizing pneumonia and non-specific interstitial pneumonia. Studies of the potential risk associated with their use in these diseases are confounded by several factors. Firstly, studies from places with both high and low prevalence of TB have confirmed an increased
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incidence of TB in patients with diffuse parenchymal lung disease unrelated to treatment.60 Secondly, the presence of diffuse radiographic changes and frequent follow-up provided to these patients has an impact, both positive and negative upon the detection and diagnosis of intercurrent TB. Thirdly, for sarcoidosis there is a long-standing debate concerning a possible aetiological role for Mycobacterium tuberculosis, which, if accepted, would alter the interpretation of TB as a complication of treatment.61,62 However, cases of TB developing in patients with sarcoidosis receiving corticosteroids have been reported.63,64
CLINICAL FEATURES AND INVESTIGATIONS Tuberculosis associated with corticosteroid treatment frequently presents in unusual forms, or as extrapulmonary or disseminated disease. A high index of suspicion is required, particularly in high-prevalence countries, and the general approach and selection of investigations is similar to that for other immunocompromised patients. In those with interstitial disease in whom detection of new pulmonary lesions, particularly if these are nodular or miliary, is a particular problem. CT scanning is of value, not only for defining new lesions but also for seeking patterns of specific diagnostic value. These include cavitation and new pleural involvement as features of TB, aspergillomas in preformed cavities and sequestra suggesting locally invasive aspergillosis.
TREATMENT AND PROGNOSIS The treatment and outcome of TB patients occurring in association with corticosteroid use is similar to those without such treatment. However, in those with pre-existing lung disease, the combined effects with TB may result in significant long-term loss of pulmonary reserve and/or development of bronchiectasis and susceptibility to infections. Supportive care and even domiciliary oxygen might be necessary.
PREVENTION Recommendations concerning INH prophylaxis in patients on systemic corticosteroids vary and are tentative because of lack of firm evidence on the doses of corticosteroids at which the risk increases, and a similar absence of cost/benefit analyses of chemoprophylaxis in this setting. Any benefits of treatment must be weighed against the risk of side effects, especially hepatotoxicity. The American Thoracic Society Statement notes these facts and suggests that chemoprophylaxis is unnecessary for patients receiving moderate doses of oral prednisolone up to 10 mg per day, as the risk in developing TB is uncertain, even in high-prevalence communities.60,65 According to these guidelines, chemoprophylaxis should be considered for patients receiving doses higher than this. Chemoprophylaxis is not necessary for patients receiving inhaled corticosteroids.
TUBERCULOSIS IN ORGAN TRANSPLANT PATIENTS EPIDEMIOLOGY As for other high-risk patients, the incidence of TB following solid organ transplantation reflects the local prevalence of TB, and may be as high as 15% in areas of high TB endemicity. In low-incidence areas the risk of TB in transplant patients has been estimated to be
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between 36 and 74 times higher than that in the general population.66 In their review, Singh et al identified 511 cases of TB in 109 reports and the incidence of TB amongst heart, liver and lung recipients varied from 1% to 1.4%, 0.9% to 2.3% and 2% to 6.5%, respectively, in these three categories of patients.
CLINICAL PRESENTATION IN ORGAN TRANSPLANT PATIENTS Two patterns of TB are observed in organ transplant patients: (1) localized pulmonary disease and/or (2) disseminated disease. The risk of disseminated disease is higher with regimens containing anti-T-cell antibodies or anti-CD3 monoclonal antibody (OKT3). Presenting symptoms are similar to that of TB developing in other clinical settings and include fever, night sweats, unexplained weight loss and loss of appetite. In patients with disseminated disease additional symptoms include those referable to the systems/organs.
INVESTIGATIONS A wide range of chest radiographic patterns varying from focal infiltrates to miliary and diffuse nodular patterns have been observed. Comparison should be made with pre-transplant radiographs, with particular attention to abnormalities that might suggest previous TB. For patients with radiological infiltrates the first approach is sputum examination and culture, but in those with high fever and in periods of profound immunosuppression the yield from blood cultures is also significant and these should be performed. Fibreoptic bronchoscopy under local anaesthesia is often necessary, especially in those with diffuse disease. A combined approach of segmental small-volume lavage, brushing of several affected segments of lung and collection of a post-bronchoscopy sputum sample provides the highest yield. Transbronchial and/or endobronchial biopsies are also advised, especially if alternative diagnoses are being considered, but these increase the risk of haemoptysis, pneumothorax and other complications of the procedure. A less invasive option, suitable for patients with accessible discrete lesions that can be accurately located on CT scanning, is transthoracic fine needle aspiration. Transbronchial needle aspiration is also useful where hilar or mediastinal nodes are observed. In view of the risks of bleeding, particularly in renal transplant recipients, measurement of blood counts including haemoglobin, platelet count and international normalized ratio (INR) as well as bleeding time are necessary. Biopsies and needle aspiration should not be attempted on patients with a INR, low platelet count or prolonged bleeding times, and if other attempts to make the diagnosis fail and, upon review of risks and benefits, these procedures are still considered essential, the abnormality should be corrected using standard measures before they are attempted.67 Depending on the suspected organ involvement of TB, other tests might be required. These include liver function tests, ultrasound examination of the heart, and CT scans of abdomen and chest. Examination of urine, for sterile pyuria, a feature in renal TB, examination of cerebrospinal fluid for suspected meningitis and biopsies of liver, skin lesion, lymph node and less obvious sites like the synovium and vertebra may be required. An aggressive approach is often necessary since the differential diagnosis includes other opportunistic infections such as disseminated aspergillosis that requires specific therapy, and malignancies (lymphomas, Kaposi’s sarcoma and both solid organ and haemopoeitic malignancies) as these are more common in transplant recipients.
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KEY POINTS WITH REGARDS TO SPECIFIC ORGAN TRANSPLANTATIONS Liver transplantation Although rare, TB is one of the most serious infections after liver transplantation. In a high prevalence area Spearman described only three cases among 81 children (age range: 6 months to 14 years), one of whom died of drug-induced liver failure,68 but this complication is rarer in low-prevalence areas. The utility of INH prophylaxis has been questioned for several reasons. Firstly, hepatotoxicity due to INH prophylaxis is more common in liver transplant recipients. Secondly, it is not clear whether patients with previous TB are at greater risk. In a Japanese study of 1116 liver transplant recipients, seven recipients had a previous history of TB (0.63%), but none of the incident cases of TB occurred in this group.69 In this study the median observation period after transplantation was 25.5 months. Thus, isoniazidcontaining regimens, whether for prophylaxis or treatment of TB, require careful and individual evaluation by a liver specialist, and liver biopsies may be required in patients who develop elevated liver enzyme levels on this treatment, to exclude other causes and to guide management. Lung transplantation The incidence of TB in lung transplant recipients is increased. In a large series from Spain, the incidence was 6.41%, or 500 times the national average.70 Of note is that in half of the cases (6/12), diagnosis was determined from the explanted lung, thus suggesting the potential usefulness of using a systematic protocol for diagnosing disease therein to reduce TB after lung transplant. Isoniazid prophylaxis in the recipients also could have a role. ISONIAZID PROPHYLAXIS IN SOLID ORGAN TRANSPLANTATION All transplant patients should receive a tuberculin skin test prior to transplantation. Approximately 70% have negative reactions but those that are positive are at greater risk. The recommendations for INH chemoprophylaxis in renal and heart transplant recipients are described in Box 55.6. These recommendations are based on the fact that these patients do not appear to be at a higher risk of developing isoniazid hepatotoxicity than the general population, that the case fatality rate for transplant recipients is almost 30%, and that in a further similar proportion the allograft is rejected. These dire consequences of untreated dormant disease argue for chemoprophylaxis, at least in low-prevalence areas. Box 55.6 Indications of isoniazid prophylaxis for solid organ transplant recipients 1. Tuberculin reactivity 5 mm before transplantation. 2. Patients with the following characteristics regardless of reactivity: Radiographic evidence of old TB and no prior prophylaxis; History of inadequately treated TB; Close contact with an infectious patient; and Recipient of an allograft from a donor with a history of untreated TB or tuberculin reactivity without adequate prophylaxis. 3. Newly infected persons (recent conversion of tuberculin test to positive).
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TUBERCULOSIS FOLLOWING GASTRECTOMY
At least one report described the development of MDR-TB following Billroth II gastrojejunostomy in a 73-year-old man.75
EPIDEMIOLOGY Reports of patients who developed TB after gastric surgery date back to the early part of the last century, but this association has yet to be confirmed in well-designed prospective studies. More recently a similar risk has been identified in patients undergoing jejunoileostomy bypass surgery for the treatment of obesity. Although these risk factors have in common upper gastrointestinal surgery, the mechanisms responsible for the susceptibility may differ. The former may be related to loss of protective effects of acid gastric secretions upon ingested mycobacteria, while the latter has been linked with the development of malnutrition resulting from malabsorption associated with intestinal bypass surgery. However, malabsorption may also play a role after gastrectomy as symptoms of severe dumping have been reported to be more common in patients who developed TB and most such patients had low BMI.71,72 In one study of TB after gastric surgery only two of 21 patients had a BMI of greater than 22 kg/m2.72 Thorn et al have estimated that post-gastrectomy patients who weighed less than 85% of their ideal body weight were up to 14 times more likely to develop TB than if their weight were normal.73 The incidence of TB following gastrectomy varied from 1.7% to 12.3% in 12 reported studies during 1948 to 1977, but in the three largest series the incidence was only 1.7% to 2.5%.74 In most countries this represents a small fraction of the total reported cases of active TB. However, in a retrospective review from Japan, which has a high incidence of gastrectomy performed for treatment of gastric carcinoma, 9.1% of cases of TB reported over a 3-year period had a history of gastric resection.72
PREOPERATIVE ASSESSMENT AND MANAGEMENT In view of the potential postoperative risk of TB it is advisable, although not based on the results of prospective trials, to obtain a full history of previous TB and Bacillus Calmette-Gue´rin (BCG) vaccination, and to perform a chest radiograph. INH chemoprophylaxis should be considered for untreated patients with radiographic evidence of previous TB and those with a strongly positive TST but surgery need not be delayed unless TB is confirmed. The presence of a low BMI or poor nutritional status strengthens the indication for chemoprophylaxis. Although plausible, there is no current evidence that the risk of TB can be reduced by modifying the surgical approach – for example through pyloric preservation to avoid dumping syndrome, or by pancreatic preservation surgery to reduce the risk of postoperative diabetes mellitus. However, these approaches should be considered in high-risk cases.
TUBERCULOSIS FOLLOWING JEJUNOILEAL BYPASS SURGERY Jejunoileal bypass surgery has been used to effect weight loss in patients refractory to non-surgical methods. There are numerous case reports of patients undergoing this form of surgery developing TB postoperatively, and it is estimated that between 0.3% and 0.4% of patients who have undergone this form of surgery (with most of whom residing in countries with a low incidence of TB) develop TB.76 There are, however, no prospective controlled trials or surveys in estimating the relative risk associated with this procedure. A majority of cases occur in women, but this reflects the sex ratio of subjects undergoing surgery.
CLINICAL PRESENTATION Tuberculosis following jejunoileostomy is usually extrapulmonary: 82% in one series.76 In a small case series of seven cases, the mean interval between surgery and the diagnosis of TB was 16 months.77 Initial symptoms included fever and rapid weight loss. Weight loss is often observed as a second period of decline after stabilization of the initial phase of weight loss resulting from the bypass surgery.76
INVESTIGATION AND TREATMENT Chest radiography and TST should be performed on all patients being considered for bypass surgery.77 Tuberculous chemoprophylaxis is advised for patients with a positive response measuring 10 mm or more prior to surgery, which should be delayed for at least 6 months. As for patients with TB following gastrectomy, therapeutic drug monitoring should be performed because drug absorption in patients following jejunoileal bypass surgery is often unpredictable.
ANTI-TUMOUR NECROSIS FACTOR-a AGENTS INTRODUCTION
POST-SURGICAL SURVEILLANCE
Tumour necrosis factor-a (TNF-a) is a pro-inflammatory cytokine that exists in transmembrane and soluble forms and acts as a ligand that stimulates apoptosis. Through its receptor binding, particularly to receptor TNFR1, it is involved in host defences against intracellular organisms like M. tuberculosis, by enhancing intracellular killing and stimulating granuloma formation, thereby limiting dissemination. However, excessive production of TNF-a can have detrimental effects, including the development of caseous necrosis and excessive wasting in patients with TB.78 The most extensively studied anti-TNF-a agents are infliximab, etanercept and adalimumab.
After gastrectomy, patients require regular follow-up with attention to the presence of complications associated with risk of TB – dumping syndrome, malnutrition, fistula formation and recurrence of tumour within the gastric remnant. Symptoms such as sweating and weight loss may be attributed to dumping, but alertness should be maintained, as these could also be due to TB. A further consideration in patients with malabsorption is whether, when treated for TB, therapeutic drug monitoring is necessary to ensure that adequate levels of mycobactericidal drugs are achieved.
Infliximab Infliximab is a humanized murine chimeric monoclonal antibody with high binding affinity and specificity for TNF-a that forms stable complexes with monomeric and trimeric forms of TNF-a, crosslinking between molecules. It also binds to transmembrane TNF-a. Infliximab is administered as an intravenous infusion at weeks 0 and 2 of therapy followed by an infusion every 8 weeks. Its half-life is 10.5 days. It can be used for treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis and psoriatic arthritis.
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Etanercept Etanercept is a dimeric fusion protein that forms less stable complexes with monomeric and membrane bound TNF, but binds well to trimeric TNF-a and forms stable complexes with TNF-b. It is given twice weekly as a subcutaneous injection and has a shorter half-life of approximately 3 days. EPIDEMIOLOGY OF ANTI-TNF THERAPY AND TUBERCULOSIS The association between anti-TNF treatment and increased risk of TB was first observed in post-approval pharmacovigilance data from patients with rheumatoid arthritis and other autoimmune conditions treated with these agents. This was later confirmed by information gathered by the Spanish Society of Rheumatology. It appears that when used in countries other than the USA, the risk is positively associated with the prevalence of TB in the general population.79 The onset of TB is earlier with infliximab than with etanercept, and dissemination is common. Reactivation of latent TB infection (LTBI) rather than reinfection is often the suspected cause of disease.79 The Food and Drug Administration has estimated that in the USA, the age-adjusted incidence of TB in all patients exposed to anti-TNF-a agents is 8.2 cases per 100,000 patient years of exposure. The British Thoracic Society estimates that the risk of TB in patients with rheumatoid arthritis treated with infliximab is increased fivefold.80 Comparisons of the rates of developing TB with these two agents should be interpreted with caution as these are influenced by the medical indication for which the agent was given, duration of treatment, concurrent therapy and other risk factors for TB. However, it appears that the risk is higher with infliximab than with etanercept given these limitations of interpretation.
ASSESSMENT OF PATIENTS BEING CONSIDERED FOR ANTI-TNF-a TREATMENT Each patient eligible for anti-TNF-a therapy should undergo a risk assessment for TB infection comprising a history, physical examination, chest radiology and tuberculin skin test, with or without IGRA testing. Box 55.7 depicts the high-risk groups for developing TB. Patients should be questioned on their TB history including BCG vaccination, results of previous TST, previous treatment for TB and outcome of treatment. The risk of latent TB is influenced by the age, country of origin, ethnic origin, socioeconomic status, travel history to high-incidence countries and occupation. When anti-TNF-a treatment is commenced, enquiry into symptoms of TB should be made at each visit, and features of TB, including extrathoracic manifestations – nodes, organomegaly and abdominal ascites – which occur in over 50% of cases, should be sought.
Box 55.7 High-risk groups for developing tuberculosis while on anti-TNF-a therapy
Foreign-born individuals. Injection drug users. Healthcare workers. Patients already on immunosuppressive therapy. Medical disorders such as diabetes mellitus or renal disease. Elderly subjects. Silica exposure and presence of silicosis. Malnutrition.
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Chest radiography The chest radiograph is part of the minimum requirement in the work-up of patients for therapy as there is evidence that TST alone, even when steroid therapy is stopped a week prior to skin testing, may not be sufficiently sensitive to identify latent TB in the target group of patients (rheumatoid arthritis, spondyloarthropathies and patients with inflammatory bowel disease).81 However, as the chest radiograph will be normal in most patients with LTBI, it has limited usefulness as a screening test. Three outcomes with the radiographic investigation can potentially be expected. Normal chest radiograph The action in these cases needs to be determined in conjunction with the TST. The utility of the TST in patients on immunosuppression and previous BCG vaccination is discussed below. Abnormal radiograph suggesting active tuberculosis If abnormalities suggest active TB, the patient should be referred for treatment, and use of anti-TNF treatment delayed until it is completed. Abnormal radiograph suggesting previous tuberculosis Previous adequate treatment. If the radiograph is consistent with previous TB and the patient has received adequate treatment for TB as judged by a thoracic physician, they can commence antiTNF treatment but should be monitored clinically every 3 months and chest radiography and sputum cultures performed if respiratory symptoms develop. Previous inadequate or no treatment. The risk of active disease in this group is high and they should be appropriately investigated by a thoracic physician for possible active disease. Even if active disease is excluded there remains a high annual risk of reactivation and the risk–benefit in this group strongly favours tuberculous chemoprophylaxis before anti-TNF is commenced. Tuberculin skin testing Assessment for LTBI is recommended for all patients prior to commencement of anti-TNF agents. The TST is the standard test proposed for this purpose. However, false-positive reactions may be attributable to exposure to non-tuberculous mycobacteria or BCG vaccination in childhood. False-negatives are also not uncommon in the diseases for which anti-TNF is indicated. For example, in one study, anergy was present in 83% of patients with inflammatory bowel disease receiving corticosteroids with or without other immunosuppressive therapy.82 For this reason some recommend that TST not be performed on patients already on immunosuppressive therapy.83 In view of these limitations associated with TST, the potential role of IGRA in identifying patients with LTBI is being actively investigated, but firm recommendations are awaited. TUBERCULOSIS CHEMOPROPHYLAXIS FOR PATIENTS RECEIVING ANTI-TNF-a THERAPY Two regimens have been proposed: 1. isoniazid for 6 months (6H) (although 9 months is recommended in some guidelines, this is associated with an increased risk of hepatotoxicity); and 2. rifampicin plus isoniazid for 3 months (3RH). This approach is thought to be associated with better adherence, but a disadvantage is the higher rate of drug-induced hepatitis in the face of co-administration of other potentially hepatotoxic immunosuppressive drugs.
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Liver function testing (aminotransferases) is recommended at the start of chemoprophylaxis and should be monitored at least every 3 months. If the regimen contains rifampicin, the dose of prednisone (if in use) will need to be doubled. The optimal time for the safe introduction of anti-TNF-a therapy during TB chemoprophylaxis has not been established. In patients with a normal chest radiograph and who are not tuberculin test-assessable (because of concurrent immunosuppressive therapy), it may be started at the same time as chemoprophylaxis.80 However, a pragmatic approach is, when possible, to defer anti-TNF-a treatment until chemoprophylaxis is complete.
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MANAGEMENT OF TUBERCULOSIS IN PATIENTS ON ANTI-TNF-a THERAPY Current evidence suggests that patients who are currently receiving anti-TNF-a therapy should also receive full standard antituberculous chemotherapy. In this situation, where a patient is already on anti-TNF-a therapy and withdrawal might place them at risk of disease deterioration, the patient may continue therapy provided that there is satisfactory evidence of response to TB treatment.
17. Yip C, Lee AJ. Gatifloxacin-induced hyperglycemia: a case report and summary of the current literature. Clin Ther 2006;28(11):1857–1866. 18. Gu¨ler M, Unsal E, Dursun B, et al. Factors influencing sputum smear and culture conversion time among patients with new case pulmonary tuberculosis. Int J Clin Pract 2007;61(2):231–236. 19. Restrepo BI, Fisher-Hoch SP, Crespo JG, et al. Type 2 diabetes and tuberculosis in a dynamic bi-national border population. Epidemiol Infect 2007;13(3): 483–491. 20. Wada M, Yoshiyama T, Ogata H, et al. [Six-months chemotherapy (2HRZS or E/4HRE) of new cases of pulmonary tuberculosis – six year experiences on its effectiveness, toxicity, and acceptability]. Kekkaku 1999;74(4):353–360. [In Japanese.] 21. Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006;43(7):848–854. 22. Hnizdo E, Murray J. Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners. Occup Environ Med 1998; 55(7):496–502. 23. Corbett EL, Churchyard GJ, Clayton TC, et al. HIV infection and silicosis: the impact of two potent risk factors on the incidence of mycobacterial disease in South African miners. AIDS 2000;14(17): 2759–2768. 24. Sherson D, Lander F. Morbidity of pulmonary tuberculosis among silicotic and nonsilicotic foundry workers in Denmark. J Occup Med 1990;32(2): 110–113. 25. Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med 1994;150(5 Pt 1):1460–1462. 26. Cowie RL. Silicotuberculosis: long-term outcome after short-course chemotherapy. Tuber Lung Dis 1995;76(1):39–42. 27. Rom WN, Garay SM, eds. Tuberculosis, 2nd edn. Philadelpia: Lippincott Williams and Wilkins, 2004. 28. Klote MM, Agodoa LY, Abbott KC. Risk factors for Mycobacterium tuberculosis in US chronic dialysis patients. Nephrol Dial Transplant 2006;21(11): 3287–3292. 29. Quantrill SJ, Woodhead MA, Bell CE, et al. Peritoneal tuberculosis in patients receiving continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 2001;16(5):1024–1027. 30. Basiri A, Moghaddam SM, Simforoosh N, et al. Preliminary report of a nationwide case-control study for identifying risk factors of tuberculosis following renal transplantation. Transplant Proc 2005;37(7): 3041–3044. 31. Klote MM, Agodoa LY, Abbott K. Mycobacterium tuberculosis infection incidence in hospitalized renal transplant patients in the United States, 1998–2000. Am J Transplant 2004;4(9):1523–1528. 32. Fang HC, Lee PT, Chen CL, et al. Tuberculosis in patients with end-stage renal disease. Int J Tuberc Lung Dis 2004;8(1):92–97. 33. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167(4):603–662. 34. Aoki K. Excess incidence of lung cancer among pulmonary tuberculosis patients. Jpn J Clin Oncol 1993;23(4):205–220.
35. Silva FA, Matos JO, de Q Mello FC, et al. Risk factors for and attributable mortality from tuberculosis in patients with hematologic malignances. Haematologica 2005;90(8):1110–1115. 36. Tunell WP, Koh YC, Adkins PC. The dilemma of coincident active pulmonary tuberculosis and carcinoma of the lung. J Thorac Cardiovasc Surg 1971;62(4):563–567. 37. Mok CK, Nandi P, Ong GB. Coexistent bronchogenic carcinoma and active pulmonary tuberculosis. J Thorac Cardiovasc Surg 1978;76(4):469–472. 38. Chen YM, Chao JY, Tsai CM, et al. Shortened survival of lung cancer patients initially presenting with pulmonary tuberculosis. Jpn J Clin Oncol 1996; 26(5):322–327. 39. Kim DK, Lee SW, Yoo CG, et al. Clinical characteristics and treatment responses of tuberculosis in patients with malignancy receiving anticancer chemotherapy. Chest 2005;128(4): 2218–2222. 40. Stead WW. Special problems in tuberculosis. Tuberculosis in the elderly and in residents of nursing homes, correctional facilities, long-term care hospitals, mental hospitals, shelters for the homeless, and jails. Clin Chest Med 1989;10(3):397–405. 41. Pe´rez-Guzma´n C, Vargas MH, Torres-Cruz A, et al. Does aging modify pulmonary tuberculosis? A metaanalytical review. Chest 1999;116(4):961–967. 42. Stead WW, To T. The significance of the tuberculin skin test in elderly persons. Ann Intern Med 1987; 107(6):837–842. 43. Brown M, Varia H, Bassett P, et al. Prospective study of sputum induction, gastric washing, and bronchoalveolar lavage for the diagnosis of pulmonary tuberculosis in patients who are unable to expectorate. Clin Infect Dis 2007;44(11):1415–1420. 44. Stead WW. Tuberculosis among elderly persons, as observed among nursing home residents. Int J Tuberc Lung Dis 1998;2(9 Suppl 1):S64–70. 45. Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146(5):340–354. 46. Aisenberg GM, et al. Extrapulmonary tuberculosis active infection misdiagnosed as cancer: Mycobacterium tuberculosis disease in patients at a Comprehensive Cancer Center (2001–2005). Cancer 2005; 104(12):2882–2887. 47. Faustini A, Hall AJ, Perucci CA. Risk factors for multidrug resistant tuberculosis in Europe: a systematic review. Thorax 2006;61(2):158–163. 48. Gie RP, Beyers N, Schaaf HS, et al. The challenge of diagnosing tuberculosis in children: a perspective from a high incidence area. Paediatr Respir Rev 2004; 5(Suppl A):S147–149. 49. Strang JI, Nunn AJ, Johnson DA, et al. Management of tuberculous constrictive pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years follow-up. QJM 2004;97(8):525–535. 50. Wiysonge CS, Ntsekhe M, Gumedze F, et al. Contemporary use of adjunctive corticosteroids in tuberculous pericarditis. Int J Cardiol 2008;124(3): 388–390. 51. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351(17):1741–1751.
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Tuberculosis in non-HIV immunosuppressed patients 52. Simmons CP, Thwaites GE, Quyen NT, et al. The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses. J Immunol 2005;175(1): 579–590. 53. Hammer SM, Saaq MS, Schechter M, et al. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society – USA panel. Top HIV Med 2006;14(3): 827–843. 54. Yun JE, et al. The incidence and clinical characteristics of Mycobacterium tuberculosis infection among systemic lupus erythematosus and rheumatoid arthritis patients in Korea. Clin Exp Rheumatol 2002;20(2):127–132. 55. Mok MY, Lo Y, Chan TM, et al. Tuberculosis in systemic lupus erythematosus in an endemic area and the role of isoniazid prophylaxis during corticosteroid therapy. J Rheumatol 2005;32(4):609–615. 56. Cowie RL, King LM. Pulmonary tuberculosis in corticosteroid-treated asthmatics. S Afr Med J 1987; 72(12):849–850. 57. Bahceciler NN, Nuhoglu Y, Nursoy MA, et al. Inhaled corticosteroid therapy is safe in tuberculinpositive asthmatic children. Pediatr Infect Dis J 2000; 19(3):215–218. 58. Silverman M, Sheffer AL, Dı´az PV, et al. Safety and tolerability of inhaled budesonide in children in the steroid treatment as regular therapy in early asthma (START) trial. Pediatr Allergy Immunol 2006; 17(Suppl 17):14–20. 59. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356(8):775–789. 60. Bateman ED. Is tuberculosis chemoprophylaxis necessary for patients receiving corticosteroids for respiratory disease? Respir Med 1993;87(7): 485–487.
61. Fidler H, Rook GA, Johnson NM, et al. Search for mycobacterial DNA in granulomatous tissues from patients with sarcoidosis using the polymerase chain reaction. Am Rev Respir Dis 1993;147(3): 777–778. 62. Wong CF, Yew WW, Wong PC, et al. A case of concomitant tuberculosis and sarcoidosis with mycobacterial DNA present in the sarcoid lesion. Chest 1998;114(2):626–629. 63. Knox AJ, Wardman AG, Page RL. Tuberculous pleural effusion occurring during corticosteroid treatment of sarcoidosis. Thorax 1986;41(8):651. 64. Baughman RP, Lower EE. Fungal infections as a complication of therapy for sarcoidosis. QJM 2005; 98(6):451–456. 65. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000;49(RR-6):1–51. 66. Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 1998;27(5):1266–1277. 67. British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax 2001;56(Suppl 1): i1–21. 68. Spearman CW, McCulloch M, Millar AJ, et al. Liver transplantation at Red Cross War Memorial Children’s Hospital. S Afr Med J 2006;96(9 Pt 2): 960–963. 69. Nagai S, Fujimoto Y, Taira K, et al. Liver transplantation without isoniazid prophylaxis for recipients with a history of tuberculosis. Clin Transplant 2007;21(2):229–234. 70. Bravo C, Rolda´n J, Roman A, et al. Tuberculosis in lung transplant recipients. Transplantation 2005; 79(1):59–64. 71. Hanngren A, Hedenstedt S, Reizenstein P. Nutritional studies in patients with dumping syndrome. I. Subjects with postcibal symptoms. Am J Dig Dis 1967;12(1):71–80.
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72. Yokoyama T, Sato R, Rikimaru T, et al. Tuberculosis associated with gastrectomy. J Infect Chemother 2004;10(5):299–302. 73. Thorn PA, Brookes VS, Waterhouse JA. Peptic ulcer, partial gastrectomy, and pulmonary tuberculosis. Br Med J 1956;1(4967):603–608. 74. Snider DE Jr. Tuberculosis and gastrectomy. Chest 1985;87(4):414–415. 75. Welsh CH. Drug-resistant tuberculosis after gastrectomy. Double jeopardy? Chest 1991;99(1):245–247. 76. Snider DE Jr. Jejunoileal bypass for obesity: a risk factor for tuberculosis. Chest 1982;81(5):531. 77. Yu VL. Onset of tuberculosis after intestinal bypass surgery for obesity. Guidelines for evaluation, drug prophylaxis, and treatment. Arch Surg 1977;112(10): 1235–1237. 78. Gardam MA, Keystone EC, Menzies R, et al. Antitumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3(3):148–155. 79. Bieber J, Kavanaugh A. Consideration of the risk and treatment of tuberculosis in patients who have rheumatoid arthritis and receive biologic treatments. Rheum Dis Clin North Am 2004;30(2):257–270, v. 80. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-a treatment. Thorax 2005;60(10):800–805. 81. Sichletidis L, Settas L, Spyratos D, et al. Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis. Int J Tuberc Lung Dis 2006;10(10): 1127–1132. 82. Mow WS, Abreu-Martin MT, Papadakis KA, et al. High incidence of anergy in inflammatory bowel disease patients limits the usefulness of PPD screening before infliximab therapy. Clin Gastroenterol Hepatol 2004;2(4):309–313. 83. Provenzano G, Ferrante MC, Simon G. TB screening and anti-TNFa treatment. Thorax 2005;60(7):613.
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Tuberculosis in pregnancy and in the neonate Miriam Adhikari and Prakash M Jeena
INTRODUCTION The term perinatal tuberculosis (TB) encompasses in-utero, intrapartum, and neonatal infection. Perinatal outcomes in relation to pregnancies complicated by TB have been poorly recorded. Most infected neonates born to mothers with TB during pregnancy initially appear relatively well, with disease being apparent in the late neonatal period or early infancy.1,2 Congenital TB is defined by one or more of the following criteria of Cantwell and colleagues: tuberculous lesions evident in the first week of life, primary hepatic complex or caseating hepatic granulomas, evidence of tuberculous infection of the maternal genital tract, and exclusion of the possibility of postnatal transmission of the disease by a thorough investigation of contacts.3 In the clinical setting, it is immaterial whether the disease is acquired congenitally or postnatally as the management of the neonate and the mother is identical. Tuberculosis is primarily a disease of men; in a group of cases reported in 2004 in high-incidence countries, 1.4 million cases were in men and only 775,000 in women. There are a number of possible reasons for this finding, including the poorer access that women have to diagnostic facilities. Pregnancy carries socioeconomic and sociomedical burdens, which include not only the cost of access to antenatal care but also the availability of such care and of trained health professionals to attend deliveries.4 On the other hand it appears from epidemiological evidence that there are real differences between the sexes and this is reflected in the data on exposure to infection and in the susceptibility to develop active disease after infection.5 This genderrelated difference also applies to other forms of pulmonary disease.6 There is also evidence that men are more likely than women to be positive on tuberculin skin testing and to be smear-positive on sputum microscopy.7,8 Women aged 15–24 years have a relatively higher proportion of TB than those in other age groups.9 The mortality of young women increased rapidly in the age range 25–29 in 1999–2000, largely as a consequence of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). The age groups of women with the highest burden of TB and HIV overlap and is particularly striking in developing countries. In addition, the peak mortality for TB and HIV in women corresponds with the prime child-bearing age.10,11 In South Africa, the burden of both TB and HIV is highest in the Province of KwaZulu Natal, and in certain areas of the province the TB rates were 813/100,000,12 and the antenatal HIV-1 seroprevalence rate is 40% or more.13 Tuberculosis and HIV infection are independent risk factors for maternal mortality and in sub-Saharan Africa, 3–4% of HIVinfected mothers die within a year of parturition.14,15
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In the 1990s TB emerged in South Africa as an important chronic infection, predominantly pulmonary, of the newborn.1 This led to studies which highlighted the difficulties in diagnosing TB in mothers and neonates.16 The case load of maternal TB at King Edward VIIIth Hospital, Durban, South Africa, increased from 0.1 to 0.6% over the three years 1996 to 1998 (Fig. 56.1). As much as 72% of these mothers were infected with HIV-1 and the prevalence of TB was 10-fold higher than in mothers not infected with HIV-1. Thus, the relationship between TB and HIV was established in South African and also in other African countries including Zambia where TB was found to be an emerging cause of maternal mortality.15,17
PATHOGENESIS OF PERINATAL TUBERCULOSIS Maternal pulmonary and extrapulmonary TB, including genital infection, exposes the neonate to antenatal, intrapartum, and postpartum risk of infection resulting in TB. Primary TB rather than reactivation of previous disease of the mother is more likely to lead to congenital transmission of Mycobacterium tuberculosis, which occurs by a number of routes (Box 56.1).18 The child may acquire TB inutero through haematogenous spread via the umbilical vessels or aspiration or ingestion of infected amniotic fluid, or during delivery by aspiration or ingestion of infected amniotic fluid or cervicovaginal secretions. Alternatively, infection may be acquired postpartum by inhalation or ingestion of tubercle bacilli from an infectious source case, usually the mother.19 Breastfeeding does not transmit TB. The strain of M. tuberculosis isolated from the neonate is invariably the same as that from the mother, irrespective of whether transmission occurred before or after birth.20 Transmission from mother to foetus or neonate is particularly likely to occur if the mother has miliary or untreated TB, microscopically detectable acid-fast bacilli in sputum smears or when the maternal disease is diagnosed late in pregnancy or post-delivery.18
VERTICAL TRANSMISSION OF TUBERCULOSIS It is difficult to quantify the exposure of the foetus and newborn to maternal TB as little work has been done on vertical transmission of the disease. The lack of a gold standard for the diagnosis of neonatal tuberculous infection as opposed to disease contributes to this.21
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Tuberculosis in pregnancy and in the neonate
microscopy or culture. Negative sputum smears or cultures do not therefore exclude the possibility of transmission of M. tuberculosis to the newborn.23
90 80
Number of women
70
TB/HIV-1 coinfected
CLINICAL FEATURES OF TUBERCULOSIS IN THE NEONATAL PERIOD
60 50 40 30
TB/HIV-1 uninfected
20
TB/HIV-1 status unknown
10 0 1996
1997 Year
1998
Fig. 56.1 Caseload of active TB and TB/HIV coinfection in pregnant women at King Edward VIIIth Hospital Durban, 1996–1998.
Box 56.1 Pathogenesis of tuberculosis in the newborn
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Haematogenous spread through the umbilical cord. In-utero aspiration or ingestion of infected amniotic fluid. Intrapartum aspiration or ingestion of infected amniotic or cervicovaginal secretions. Postpartum inhalation or ingestion from an infected source case, usually the mother.
Although the risk of transmission and progression from infection to disease is highest in the first year of life, the exact extent of this risk is not clear.22 In South Africa, 16 of 107 (15%) mothers with TB transmitted the bacilli to their infants within the first three weeks of life. Tuberculosis in the neonate was diagnosed in the first week of life when maternal TB was diagnosed antenatally and by the third week when maternal TB was diagnosed in the immediate postpartum period. Risk factors associated with the transmission of the mycobacterium included firstly, mothers diagnosed with TB within a month of delivery (relative risk 2.6; 95% CI 1.1– 6.5). This risk was unaffected by HIV status and preterm delivery. As much as 63% of the mothers were diagnosed with TB in the last trimester. Secondly, a lack of prenatal care was associated with a 5.6-fold increase of vertically transmitted TB (95% CI 1.9–16.4) and transmission was affected by the duration of antituberculous therapy before delivery. If a woman is noncompliant or non-adherent to therapy at any stage, transmission may occur. Non-adherence to therapy was confirmed in a few cases where mothers were supposed to have been on an adequate duration of therapy.18 All the mothers had pulmonary involvement as part of their clinical picture of TB. Pleural effusion, generalized lymphadenopathy, or any other extrapulmonary manifestation of TB did not affect the risk of vertical transmission. Genital TB was detected in two cases (one ovarian, one endometrial). Only seven of the 16 mothers who transmitted the TB bacillus were positive on sputum smear
The most important aspect of prevention and detection of TB in the newborn is the maternal history. A high index of suspicion is essential if cases are to be diagnosed and the likelihood of TB is increased in mothers who are infected with HIV.9,24 Critical points in the maternal history include unresolving pneumonia, contact with a household member with TB, whether the mother is on antituberculous treatment, and if so, for how long (Box 56.2). Transmission and outcomes are definitely affected by duration of therapy before delivery. Four months or more of therapy is protective to the foetus,18 but adherence to therapy is important as non-adherence increases the risk of transmission of M. tuberculosis to the foetus or neonate. Symptoms of TB in the neonate are usually non-specific and include lethargy, poor feeding, low birth weight, poor weight gain, and unresolving or recurrent pneumonia. Signs and symptoms may be present at birth but overt expression of the disease more often occurs in the second or third week of life when respiratory problems, hepatosplenomegaly, and lymphadenopathy are present.1,25,26 Other clinical features may include skin lesions, seizures, jaundice, ear discharge, paravertebral abscess, and haematological anomalies. Although the signs may suggest chronic intrauterine infection they may also mimic acute infection, depending on the clinical phase and severity of the disease. The diagnosis may be difficult and therefore missed.19,27 In a setting of poor response to antibiotics and supportive therapy and when microbiological evaluations for acute infections and serological tests for chronic intrauterine infections are negative, TB should be considered, particularly if the mother is known to be infected with HIV.
CRITERIA FOR INVESTIGATION OF THE NEONATE As stated above, a maternal history of TB in the past or during pregnancy is important for the diagnosis of congenital or neonatal TB. In the neonate, clinical and radiologically progressive pneumonia or lymphocytes in the cerebrospinal fluid in the absence of an identifiable acute bacterial pathogen are criteria for investigation of TB. Maternal genital TB, which may result in infection during birth, is a subclinical disease unlikely to be detected clinically unless specifically sought.
Box 56.2 Factors suggesting tuberculosis of the neonate
Maternal unresolving pneumonia. Maternal contact with a member of the household with TB. Mother on treatment for tuberculosis – consider the duration of, and adherence to, treatment. Mother known to be infected with HIV.
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Box 56.3 Investigations for tuberculosis of the neonate
Chest radiograph. Three early morning gastric aspirates/washings. Induced sputum. Endotracheal aspirate (if infant is mechanically ventilated). Cerebrospinal fluid. Liver biopsy. Lymph node biopsy. Cultures of skin lesions or ear discharges. Bronchoalveolar lavage. Polymerase chain reaction (PCR). TB blood culture.
Specimens from the neonate suitable for microscopy and culture include gastric aspirates, induced sputum, tracheal aspirates if the neonate is mechanically ventilated, cerebrospinal fluid, and, if seen on the chest radiograph, pleural fluid (Box 56.3). Early morning gastric aspirates should be taken on three consecutive days before the first feed of the day. The aspirates are placed in tubes containing 1% sodium bicarbonate buffer before being transported to the laboratory. If deemed appropriate, a liver or lymph node biopsy may be undertaken for histology and culture of M. tuberculosis. In the event of death, relevant biopsies (for example, liver, lung, nodes, skin lesions) should be taken, with maternal consent, for histological and microbiological examination. Samples are examined microscopically for acid-fast bacilli and cultured on standard media for 12 weeks.1 Chest radiographs may not initially show the classical features of TB and a radiographic diagnosis may be difficult. If a neonate has skin lesions or an ear discharge, specimens should be taken for microbiological examination.19 Induced sputum is more likely to be positive on microscopy and culture than gastric aspirates (Fig. 56.2).28 Bronchoalveolar lavage (BAL) has been recognized as an important investigation in children and this has been extrapolated to the newborn.29 Detection of M. tuberculosis DNA in BAL fluid by polymerase chain reaction (PCR) has been shown to be of value (Fig. 56.3).30,31
Fig. 56.3 Tuberculosis PCR positive in BAL fluid. Bilateral pneumonic changes, denser areas of consolidation around the hilar regions, and more fine diffuse changes throughout the lung fields.
CLINICAL FEATURES OF TUBERCULOSIS IN PREGNANT WOMEN The presenting features of TB in pregnant women are similar to those in non-pregnant women.32,33 Diagnosis is delayed by the common overlapping symptoms of malaise and fatigue which occur in both pregnancy and TB and, unless specifically sought, the disease may not be identified during routine antenatal care. Pregnant women may be asymptomatic but have abnormal chest radiographs.32 There may be vague signs of TB such as mild cough, fever, and fatigue or, alternatively, there may be more obvious signs such as haemoptosis and gross weight loss.34–36 Pulmonary TB, the commonest form of the disease, includes bronchopneumonia, cavitation, bronchiectasis, interstitial pneumonitis, and pleural effusion. In a study of 82 HIV-infected and 25 HIV-uninfected South Africa women with TB, pleural effusions were significantly more common in the HIV-infected group (27 vs 3, p = 0.05).37 Extrapulmonary manifestations occur in 5–10% of pregnant women who have TB,38,39 and include miliary and meningeal forms which are particular risk factors for congenital TB.40 The disease may be undiagnosed in the mother until the diagnosis is suspected or made in the neonate.23
PROGRESSION OF TUBERCULOSIS IN PREGNANCY
Fig. 56.2 Bacillus cultured from sputum. Chest radiograph shows bilateral pneumonic changes, more marked on the right; note no adenopathy is present.
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During the pre-chemotherapeutic era, the long-term prognosis for TB in pregnancy was regarded as poor, with a 10–50% mortality rate, and in 1975 one study showed a 30–40% mortality rate in pregnant women with advanced TB.41 In another study, pregnancy-related complications such as miscarriage and difficult labours were seen more frequently in women with TB.42 The immune response in pregnancy
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Tuberculosis in pregnancy and in the neonate
shifts the cell-mediated Th1 response towards Th2 antibody help responses which allows for tolerance of non-self antigens of the foetus. As Th1-mediated immune responses are essential to protective cellmediated immunity in TB, and Th2-mediated responses are antagonistic to such protection, pregnancy favours the progression of TB.43,44 This is supported by a greater proportion of pregnant patients with pulmonary TB being sputum smear-positive.35
INVESTIGATIONS OF PREGNANT WOMEN AND MOTHERS WITH TUBERCULOSIS Investigations of pregnant women and mothers suspected of having TB include microscopical examination of sputum smears for acid-fast bacilli, culture of sputum, and other specimens including endometrial samples for M. tuberculosis, histological examination of biopsies from relevant body sites, and chest radiography. Awareness of the clinical picture and radiological features suggestive of TB is essential for correct diagnosis. The tuberculin skin test is unhelpful in adults in high-incidence regions as many will be positive as a result of prior infection. In a study in Malawi, screening by history for pulmonary TB in the antenatal period was found to be acceptable by the women and the nursing staff although there were some concerns. The women were concerned about the stigma of TB and its association with HIV and possible adverse effects of antituberculous drug therapy on the neonate during the breastfeeding period. Members of staff were concerned about the increasing workload.45 If TB is suspected and the chest radiograph is clear, evidence of extrapulmonary TB must be sought, particularly if the mother is known to be infected with HIV. If indicated, endometrial samples should be obtained within 72 hours of delivery. These may be obtained, with the woman’s consent, by using a vaginal speculum to visualize the cervical os, inserting a telescoping catheter inserted and rotated through the os. The sample should be divided between two sterile leak proof containers and transported immediately to the respective laboratories for microbiological and histological examination.16
PREGNANCY OUTCOMES MATERNAL MORTALITY The World Health Organization (WHO) African region has the highest estimated incidence rate of TB in the world, at 356 new cases annually per 100,000 population.46,47 A study in South Africa revealed an overall maternal mortality rate of 200/105 deliveries with TB (14.9%) being the third leading cause of maternal death after sepsis (34%) and hypertensive disorders (25%) of pregnancy.16 In those cases of TB-related deaths where HIV status was known, 75% were infected with HIV-1. The overall hospital-based perinatal mortality for women with TB was 10,270/100,000 and for HIV-1 coinfected the mortality was 12,170/100,000 deliveries. For TB in the absence of HIV-1 the mortality was 3,850/100,000. The relative risk of death in mothers with TB and HIV-1 coinfection versus those without HIV-1 coinfection was 3.2. The mortality rate for women who were HIV-1 uninfected was 145.8/100,000.48 Increases in the incidence of TB-associated deaths in pregnancy have also been reported from Lusaka, Zambia, where perinatal deaths
56
due to TB increased from 0% in the 1970s to 14% by 1997, with 92% of these cases being HIV-1 associated.17 A similar trend of increasing perinatal mortality due to TB has been reported from Zimbabwe.49
OBSTETRIC, PERINATAL, AND NEONATAL OUTCOMES Earlier studies failed to show a striking effect of TB on pregnancy,50 but this picture has changed with more recent data. Likewise, in earlier studies, no significant effect of maternal TB on the neonate was apparent, but more recent studies have shown significant differences in respect to the neonate between women with and without TB during pregnancy. If diagnosed and treated, the effects of TB on pregnancy and the neonate are not so serious but in populations with a low socioeconomic status TB increases the risk of abortions and premature delivery.50 The perinatal outcome of 79 pregnancies complicated by active pulmonary TB was compared with 316 cases matched for age and socioeconomic status.51 Infants born to women with TB were significantly lighter than the controls, there was a twofold increase in prematurity (22.8% vs 11.1%), a small size for gestational age (20.2% vs 7.9%), and a sixfold increase in perinatal deaths (10.1% vs 1.6%). These adverse effects were more pronounced in those cases in which TB was diagnosed late in pregnancy, when adherence to antituberculous treatment was poor, and in those with advanced pulmonary disease. A similar study on 33 pregnant women with extrapulmonary TB showed that disease confined to lymph nodes was not associated with adverse obstetric outcomes but that those with more serious manifestations of disease (intestinal, skeletal, meningeal, renal, and endometrial) suffered similar adverse outcomes as those with pulmonary TB.52 In Mexico, late diagnosis and poor care resulted in a fourfold increase in obstetric morbidity and a ninefold increase in preterm labour.53 In a further study from that country,54 the perinatal outcomes of 35 mothers with TB were compared to those of 105 healthy mothers and revealed that, in the former, the neonates were significantly smaller (2.8 vs 3.1 kg) and that the relative risks of premature delivery and perinatal death were, respectively, 2.1 and 3.1. Poor outcomes were particularly prominent in women with advanced pulmonary TB in late pregnancy. In Durban, South Africa, neonates of women with TB were significantly smaller, with 49% having a birth weight less than 2.5 kg compared to 21.8% for the overall hospital deliveries. Perinatal mortality in those mothers with TB and HIV was 1.6-fold higher than for the King Edward hospital, Durban and the KwaZulu Natal region.22 According to the criteria of Cantwell, the overall mortality for congenital TB is 38% in the untreated and 22% in the treated.3 Pregnancy in women infected with HIV-1 alone tends to result in low birth weight premature babies,55 particularly in those with advanced HIV disease.56 The outcome of pregnancy in those with both HIV disease and TB is worse but it is not entirely clear which disease has the greater bearing on adverse outcomes. In the South African study, follow-up of those infants with TB and HIV infection showed persistent or worsening clinical signs, with death occurring on average by the age of 9 months.26
MANAGEMENT OF THE PREGNANT WOMAN WITH TUBERCULOSIS The physician caring for the pregnant woman with TB is faced with several possible scenarios. The woman may be
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asymptomatic, with TB only being detected after consideration or confirmation of the disease in the newborn. She may develop signs and symptoms either during pregnancy or in the puerperium. She may be either infectious or non-infectious during the pregnancy or in the puerperium. She may have drug-susceptible or drug-resistant TB. If TB is diagnosed, therapy must be commenced as promptly as possible to avoid the serious effects of the disease on the woman, the foetus, and the neonate, and also to render the woman non-infectious.23,53 The WHO recommends that treatment of TB in pregnant women should be similar to that for non-pregnant women, being based on standard shortcourse regimens of 6 months’ duration,57 although treatment may be extended in women infected with HIV. Daily rather than intermittent therapy is preferable. The first-line drugs, isoniazid, rifampicin, ethambutol, and pyrazinamide, are readily absorbed from the gastrointestinal tract and freely cross the placenta.58 Patients should be monitored for adverse drug reactions but in general the side effects of the first-line drugs are similar in pregnant and non-pregnant women. There is, however, limited evidence that the risk of isoniazid-related hepatitis is 2.5 times higher in pregnant than in non-pregnant women.59,60 Treatment of drug-resistant TB in pregnancy poses problems as certain second-line drugs are unsafe and should not be used because of the risk of teratogenicity and a lack of clinical experience. These include para-aminosalicylic acid (PAS), quinolones, ethionamide, terizidone, and cycloserine. Various birth defects have been described with ethionamide and PAS.61 Aminoglycosides including streptomycin are potentially ototoxic to the foetus.51 Whenever possible, therefore, pregnant women with drugor multidrug-resistant TB should be referred to appropriate TB centres for management. The WHO DOTS treatment strategy is being increasingly used in developing countries, with some achieving almost 100% coverage.4,62 In a retrospective analysis of over 12,000 patients with pulmonary or extrapulmonary TB, all 16 who were pregnant were able to complete their therapy. Drug tolerance was good and no adverse pregnancy-related outcomes occurred.63 Women who are considered for investigation for TB in pregnancy should receive counselling and testing for HIV. Appropriate notification of confirmed cases of TB in the mother should be done in order to facilitate investigations of household contacts, the newborn, and other children at risk.
the tests based on the detection of interferon-g produced by T cells (e.g. ELISPOT, see Chapter 22).64
MANAGEMENT OF THE ASYMPTOMATIC INFANT Bacillus Calmette-Gue´rin (BCG) should not be given to neonates exposed to TB while screening for active disease is being conducted. Investigations should be carried out to determine whether the mother is infectious and, if possible, the drug susceptibility pattern of her infecting strain. If the neonate has no evidence of active TB and the mother has drug-susceptible TB, the former should receive prophylaxis based on daily rifampicin (10 mg/kg) and isoniazid (INH) (10 mg/kg) for 3 months (Fig. 56.4). Alternately INH alone may be given for 6 months. At the end of this period the infant should be screened for TB and, if negative, treatment should be stopped and BCG given after 2 weeks. If the mother has infectious TB due to a drug-resistant strain of M. tuberculosis and the infant has no evidence of active disease, the latter should receive prophylaxis based on three drugs selected according to the mother’s drug susceptibility pattern. Isoniazid (10 mg/kg), ethionamide, and quinolones are usually recommended. If the mother is non-infectious then the guidelines recommend that the neonate should receive prophylaxis based on INH monotherapy, or a combination of INH and rifampicin,65 while being screened by radiology, tuberculin skin testing, and other immunological tests (see above),64 and while awaiting culture results. The combination of drugs is preferred in situations where regular drug administration cannot be relied upon and where isoniazid resistance is common. Prophylaxis is stopped at the end of the 3-month period if tests for TB infection or disease are negative and BCG is given 2 weeks later. If the diagnosis of TB can neither be confirmed nor refuted, INH monotherapy should be continued for a
Mother infectious – Screen the family, notify mother’s TB, continue mother’s therapy Infant asymptomatic
Prophylaxis to infant INH & RMP x 3 months Treat for 6 months with anti-TB therapy Review at 3 months
MANAGEMENT OF THE NEONATE EXPOSED TO MATERNAL TUBERCULOSIS Not all foetuses or neonates of women with infectious TB become infected but, if they are, the risk of subsequent progression to active disease is high. The characteristics of the disease in neonates depend on the infectiousness of the disease in the mother and whether her disease is multidrug-resistant. As described earlier, the risk of infection is highest if maternal factors include poor adherence to antituberculous therapy, commencement of such therapy within 3 months of delivery, and sputum smear-positive for acid-fast bacilli during pregnancy or at the time of delivery. The exposed neonate may have infection or disease and, if the latter, may be asymptomatic or symptomatic. In the absence of clinical, radiological, and microbiological features of active disease, infection is determined by tuberculin skin testing or by one of
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Baby symptomatic with signs due to primary progressive TB disease
Mantoux/IGRA/Clinical CXR and clinical Negative
Positive Normal
Mantoux no response Clinical normal CXR (if available) normal
Mantoux reponse Mantoux > 10mm but < 10 mm CXR & clinical CXR & clinical
Stop prophylaxis
If TB treat fully
Nil Stop
Treat for TB
Fig. 56.4 Algorithm for the management of the newborn exposed to TB.
CHAPTER
Tuberculosis in pregnancy and in the neonate
further 3 months or the combination of INH and rifampicin for a further month. The infants are vaccinated with BCG 2 weeks after stopping prophylaxis. If, during the period of prophylaxis, cultures prove positive for M. tuberculosis or the infant develops physical signs suggestive of TB a complete course of antituberculous therapy must be given. Prophylaxis does not offer protection against the subsequent acquisition of TB in high-risk settings, particularly in areas where HIV infection is prevalent.
MANAGEMENT OF THE SYMPTOMATIC INFANT Symptomatic infants may present with congenital TB due to intrauterine infection, usually manifesting as hepatosplenomegaly with jaundice, disseminated TB, including meningeal and miliary forms, or pulmonary TB. A differential diagnosis of HIV disease, syphilis, cytomegalovirus infection, congenital herpes, or atypical pneumonia due, for example, to Mycoplasma pneumoniae infection should be considered.22,27 A complete investigation of mother and neonate should be undertaken. Antituberculous therapy should be commenced on suspicion or while awaiting bacteriological confirmation. Standard WHOrecommended drug regimens, such as a 2-month course of isoniazid 10 mg/kg/day, rifampicin 10 mg/kg/day, and pyrazinamide 25 mg/kg/day, followed by a 4-month course of INH and rifampicin are suitable for all forms of active TB. Response to therapy is indicated by increased appetite, weight gain, and radiological resolution.
´ RIN (BCG) VACCINE BACILLUS CALMETTE-GUE The protective effect of BCG vaccination has remained controversial. A meta-analysis of BCG vaccination trials showed gross geographical variation in protective efficacy but that, on average, the vaccine is 50% effective in preventing pulmonary TB in adults and children. Protection against disseminated and meningeal TB in the first two years of life is somewhat higher, up to 80%.66 Despite BCG vaccination, TB remains a major epidemic in certain regions of the world. The primary strategy for prevention and control of TB in most industrialized countries is to break the cycle of transmission by early identification and treatment of persons with active TB, especially in high-risk groups. Vaccination with BCG in such countries is only indicated for infants and children at high risk of exposure to infectious adults.67 In resource-restricted regions where the burden of TB is high, BCG should be administered to all neonates to protect them from disseminated TB and TB meningitis in the first few years of life.68 A uniform policy of immunizing all newborns with BCG in a standardized manner avoids confusion and missed opportunities for vaccination. The vaccine is extremely safe in the immunocompetent hosts with local reactions and regional suppurative adenitis occurring in only 0.1–1% of those vaccinated. A recent South African study, however, showed a higher rate of local reactions in children infected with HIV.69 In a group of 49 HIV-infected children with TB confirmed by positive culture, BCG vaccine (Danish strain) was the cause in five cases. These children presented with ipsilateral axillary adenitis with or without pulmonary disease.70 As described earlier, BCG vaccination should be deferred in neonates exposed to source cases of TB until active disease has been excluded. If antituberculous therapy is given, either for prophylaxis or treatment of active disease, BCG vaccination should only be
56
administered 2 weeks after therapy has been stopped. WHO now recommends that BCG should not be given to confirmed HIVinfected neonates because of the possibility of disseminated BCG-osis. In areas where the accurate status HIV is unknown, BCG should be given due to the high burden of the disease in infancy.
BREASTFEEDING Under the Revised National Tuberculosis Control Programme in India, breastfeeding is recommended irrespective of the TB status of the mother.4 Breastfeeding by mothers with TB is also recommended by the American Academy of Paediatrics.65,71,72 Separation of mother and child is not an option that can be considered in a resource-restricted setting. As TB is transmitted by the aerogenous route, the mother with open pulmonary TB is still likely to infect the infant if she chooses to formula-feed. The risk of transmission of TB through breast milk is negligible. The first-line antituberculous drugs cross into breast milk in small amounts and have no adverse effects.59 To date, there is no evidence that the transfer of small amounts of antituberculous drugs to the neonate contributes to the development of drug- or multidrug-resistance.
TUBERCULOSIS AND HIV INFECTION A significant increase in the prevalence of TB in pregnant women was shown in Durban, South Africa, between 1996 and 1998 by an increasing caseload from 0.1% to 0.6%.73 Among a group of 146 pregnant women with TB 115 (78.8%; 95%CI 71.2–85.1%) were infected with HIV-1; 26 (17.8%; 95% CI 12–25%) were uninfected and in five the HIV status was not determined. The TB/HIV-1 coinfection rates increased from 36.4% in 1996 to 88.3% in 1998. The TB prevalence rate in pregnant women not infected with HIV-1 at King Edward VIIIth Hospital, Durban, South Africa, was 72.9/100,000 and for those who were infected with HIV-1 it was 774.5/100,000, with a relative risk of TB due to HIV-1 infection of 10.62 (95% CI 6.9–16.3). The attributable fraction of TB related to HIV-1 infection in pregnant women was 71.7%. Most cases of TB were pulmonary, occurring in 78.8% of the patients, and there was no significant statistical difference between HIV status and the proportion of cases of pulmonary TB that were positive on sputum microscopy or culture.
BREASTFEEDING Although, as discussed earlier, breastfeeding by mothers with TB is generally recommended, there are confounding factors in regions with a high prevalence of both TB and HIV. Although breastfeeding does carry a risk for transmission of HIV, some studies indicate that exclusive breastfeeding reduces HIV transmission when compared to mixed feeding.74,75 Also, mixed feeding increases the risk of diarrhoeal and respiratory illnesses.76,77 UNAIDS/UNICEF/WHO recommends that breastfeeding should be supported by adequate voluntary testing for HIV infection and counselling.78 A recent metaanalysis on the effect of breastfeeding on infant mortality due to infectious diseases concluded it is difficult, if not impossible, to provide safe breast milk substitutes to children from under-privileged populations.79 In cases where HIV-infected mothers find that they have no option but to breastfeed, then exclusive breastfeeding seems to be the most reasonable way to increase the safety of feeding. Good lactational management not only encourages proper attachment of
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the infant to the breast with frequent emptying, it also prevents cracked nipples, breast engorgement, and mastitis which may increase the risk of transmission of HIV through breast milk.80 In the Gambia it has been shown that replacing colostrum with pre-lacteal feeds increases the risk of neonatal mortality with an odds ratio of 3.4.81
MANAGEMENT OF TUBERCULOSIS AND HIV INFECTION IN PREGNANCY The suppression of the cell-mediated immune responses resulting from HIV infection increases the risk and severity of TB and, conversely, TB accelerates the progression of HIV disease.82,83 This synergistic effect contributes to the high maternal mortality in coinfected women.16,17 Tuberculosis and HIV in pregnancy may present in several scenarios: firstly, a pregnant women develops TB and then is found to be HIV-infected and may require treatment for both diseases urgently. Secondly, TB is diagnosed in an HIV-infected pregnant woman who does not require antiretroviral therapy (ART) for herself but needs it for the prevention of mother-to-infant transmission of HIV. Thirdly, overt manifestations of TB may appear in HIVinfected pregnant women due to immune reconstitution. In all scenarios, once the diagnosis of TB is confirmed or strongly suspected antituberculous therapy should be commenced immediately to prevent progression of the disease and adverse obstetric events.23,53
MANAGEMENT OF TUBERCULOSIS IN THE HIV-INFECTED PREGNANT WOMAN ON ANTIRETROVIRAL THERAPY Antiretroviral therapy, by reducing the viral load and allowing recovery of CD4 T-cell counts, has changed the prognosis of those infected with HIV.84,85 Large clinical studies have demonstrated that the occurrence of common opportunistic infections is reduced with recovery of CD4 counts to > 200 cells/mm3.2 The National Department of Health recommends ART for all HIV-infected women, whether pregnant or not, if the CD4 counts are < 200 cells/mm3. A non-nucleoside reverse transcriptase inhibitor, nevirapine (200 mg daily for 2 weeks and then 200 mg twice daily), and the nucleoside analogue reverse transcriptase inhibitors, stavudine (40 mg twice daily if the body weight > 60 kg and 30 mg twice daily if < 60 kg body weight) and lamivudine (300 mg daily), are recommended for use in pregnancy. These agents are associated with adverse reactions, drug interactions, and toxicity. A study of 188 patients who were severely immunocompromised (low CD4 counts) at the time of diagnosis of TB and commenced on ART showed that 20% experienced the common AIDS-related complications of peripheral neuropathy, rash, and gastrointestinal upsets during initiation of therapy.86 Nevirapine binds directly to viral reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activity by disrupting the catalytic site of the enzymes. Nevirapine is metabolized in the liver and there is the risk of hepatitis (Table 56.1). As mentioned earlier, a lead-in daily dose is given for 2 weeks followed by twice-daily administration during which time the patient should be regularly monitored for signs of the life-threatening Stevens Johnson syndrome. The incidence of hepatotoxicity with nevirapine is higher in HIV-infected pregnant women with CD4 counts between 200 and 500 cell/mL and careful monitoring is required. Efavirenz, another non-nucleoside reverse transcriptase inhibitor, is teratogenetic and should not be used in pregnancy. Lamivudine is a synthetic nucleoside analogue that is phosphorylated to the active
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Table 56.1 Side effects of antiretroviral and antituberculous drugs Side effect
Antiretroviral drug
Antituberculous drug
Nausea
Pyrazinamide
Hepatitis
Stavudine Lamivudine Nevirapine
Rash Peripheral neuropathy
Nevirapine Stavudine Lamivudine
Isoniazid, rifampicin, pyrazinamide Pyrazinamide Isoniazid
50 triphosphate metabolite which inhibits HIV reverse transcriptase, resulting in inhibition of the formation of viral DNA. The side effects include lactic acidosis, mainly in women, hepatitis, gastrointestinal disturbances, blood dyscrasias, and peripheral neuropathy. Stavudine is a synthetic thymidine nucleoside analogue and is phosphorylated by cellular kinases to stavudine triphosphate which is the active agent. The side effects are similar to those of lamivudine. Nevirapine and rifampicin both increase the risk of hepatitis. Both drugs are metabolized by cytochrome P450 (CYP450) enzymes and, by inducing these enzymes, rifampicin reduces plasma concentrations of nevirapine by 30%.87 The reduced drug concentrations lead to the emergence of drug resistance but increasing the dosage runs the risk of increasing hepatic toxicity. Patients should be monitored by full blood counts and liver function tests twice-weekly initially for 2 months then four times weekly for the remainder of the duration of therapy until they are clinically stable, and CD4 counts and viral loads should be checked every 6 months. Antiretroviral therapy is usually commenced after the fourteenth week of pregnancy to avoid teratogenic effects to the foetus, although it may be commenced earlier in pregnancy if the CD4 count is < 50 cells/mm3 and the woman is critically ill. At all stages adherence to therapy is crucial; 95% adherence results in a virological failure of 21%, whereas if adherence drops to less than 70% the virological failure rate is 82%.88 Whenever possible, antituberculous therapy should be started before commencement of ART in women coinfected with HIV and TB during pregnancy. Antituberculous therapy should be given for at least 2 weeks, and preferably for 2 months, before commencing ART. The burden imposed by the taking of large numbers of pills for ART and antituberculous therapy, together with the risks of drug interactions and toxicity, are good reasons for delaying the commencement of ART therapy until treatment of TB has been completed. Combining ART and antituberculous therapy requires careful consideration of, and monitoring for, drug interactions.
MANAGEMENT OF TUBERCULOSIS IN THE HIV-INFECTED WOMEN WHERE THERE IS A NEED ONLY TO USE ANTIRETROVIRAL THERAPY FOR PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF TUBERCULOSIS Antituberculous therapy should be commenced as soon as the diagnosis of TB is confirmed as the combination of such therapy with the ART regimens used for prevention of mother-to-child transmission of TB has fewer adverse effects, drug interactions, and toxicities than the more aggressive ART regimens used for treating those with symptomatic HIV disease.89
CHAPTER
Tuberculosis in pregnancy and in the neonate
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) In some patients, immune reconstitution results in an inflammatory syndrome occurring days to months after commencing ART. Outcomes of IRIS range from minimal morbidity to death. Antigens associated with ongoing infections or those persisting from past infections elicit this exaggerated immune response. In the management of IRIS, full antituberculous therapy is required with the continuation of ART. Antimicrobial agents, non-steroidal inflammatory agents, and/or steroids may be indicated in the management of IRIS.85 The possibility that IRIS enhances the risk of developing active TB was demonstrated by the development of overt disease in 19 of 110 patients (17%) receiving ART.90 Thirteen of these patients, from communities with high background rates of TB, developed the disease at a median of 41 days after commencing ART (‘early’ group) and the remainder developed it at a median of 358 days after commencing ART (‘late’ group). The early group had lower CD4 counts. Thus, anti-HIV treatment may result in the emergence of active TB and thereby reduce the benefits of ART. IRIS occurs more frequently in patients with advanced HIV disease and is less frequent if ART is commenced in patients with CD4 counts > 200 cells/mm3. Earlier commencement of ART may, by lowering the risk of overt TB, reduce the risk of transmission of M. tuberculosis to the foetus or neonate.
REFERENCES 1. Adhikari M, Pillay T, Pillay DG. Tuberculosis in the newborn: an emerging disease. Paediatr Infect Dis J 1997;16:1108–1112. 2. Pillay T, Khan M, Moodley J, et al. The increasing burden of tuberculosis in pregnant women, newborns and infants under 6 months of age in Durban, Kwazulu Natal. S Afr Med J 2001;91:983–987. 3. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report: Congenital tuberculosis. N Engl J Med 1994;330:1051–1054. 4. Arora VK, Gupta R. Tuberculosis and pregnancy. Ind J Tuberc 2003;50:13–16. 5. Dye C. Global epidemiology of tuberculosis. Lancet 2006;367:938–940. 6. Caracta C. Gender differences in pulmonary disease. Mt Sinai J Med 2003;70:215–224. 7. Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 1998;2:96–104. 8. Boeree MJ, Harries AD, Godschalk P, et al. Gender differences in relation to sputum submission and smear-positive pulmonary tuberculosis in Malawi. Int J Tuberc Lung Dis 2000;4:882–884. 9. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–1021. 10. Connolly M, Nunn P. Women and tuberculosis. World Health Stat Q 1996;49:115–119. 11. Diwan VK, Thorson A. Sex, gender and tuberculosis. Lancet 1999;353:1000–1001. 12. Wilkinson D, Davies GR. The increasing burden of tuberculosis in rural South Africa - the impact of the HIV-1 epidemic. S Afr Med J 1997;87:447–450. 13. Wilkinson D, Connolly C, Rotchford K. Continued explosive rise in HIV-1 prevalence among pregnant women in rural South Africa. AIDS 1999;13:740. 14. Beckerman KP. Mothers, orphans and prevention of paediatric AIDS. Lancet 2002;359:1168–1169. 15. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 1997;349:1269–1276.
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CONCLUSIONS The dual epidemics of TB and HIV/AIDS have spiraled the mortality rates of younger women in the childbearing age. Both diseases are independent risk factors and act synergistically for increased maternal mortality in sub-Saharan Africa. Maternal TB in the pregnant woman exposes the foetus and newborn to the increased risk of TB. It is crucial to detect TB in the pregnant woman and to determine duration of therapy. Equally, a high index of suspicion for the diagnosis of TB is necessary in newborns who presents non-specifically or as chronic intrauterine infection. Adverse pregnancy outcomes, particularly with advanced TB, include an increased risk of abortion, prematurity, and low birth weight for gestational age. According to WHO guidelines the treatment for pregnant and the non-pregnant woman is the same. It is generally recommended that mothers with TB exclusively breastfeed their newborns especially in HIV-endemic areas. Antiretroviral therapy allows immune recovery and reduces the common opportunistic infections associated with HIV and should be instituted in all women with CD4 counts < 200 cells/mm3. Antituberculous therapy should be commenced for at least 2 weeks before commencing ART. Careful monitoring of drug interactions and toxicity are essential. If either or both infections are detected early and managed appropriately the prognosis for mother and baby is vastly improved as compared to late diagnoses, which carry a poor prognosis.
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61. Brost BC, Newman RB. The maternal and fetal effects of tuberculosis therapy. Obstet Gynecol Clin North Am 1997;24:659–673. 62. Sharma SK, Liu JJ. Progress of DOTS in tuberculosis control. Lancet 2006;367:951–952. 63. Arora VK, Sarin R. Revised National Tuberculosis Programme: Indian perspective. Ind J Chest Dis Allied Sci 2000;42:21–26. 64. Jafari C, Ernst M, Kalsdorf B, et al. Rapid diagnosis of smear-negative tuberculosis by bronchoalveolar lavage enzyme linked immunospot. Am J Respir Care Med 2006;174:424–437. 65. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998;53;536–548. 66. Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of Bacillus Calmette-Guerin vaccination of newborn infants in the prevention of tuberculosis: meta-analysis of the published literature. Pediatrics 1995;96:29–35. 67. The role of BCG vaccination in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the elimination of tuberculosis and the Advisory Committee on Immunisation Practices. MMWR Recomm Rep 1996;45(RR-4):1–18. 68. Fine P. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995; 346;1339–1345. 69. Jeena PM, Chhagan MK, Topley J, et al. Safety of the intradermal Copenhagen 1331 BCG vaccine in neonates in Durban, South Africa. Bull World Health Organ 2001;79:337–343. 70. Hesseling AC, Schaaf HS, Hanekom WA, et al. Danish bacille Calmette-Guerin vaccine-induced disease in human immunodeficiency virus-infected children. Clin Infect Dis 2003;37;1226–1233. 71. American Academy of Paediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics1994;93:137–150. 72. Bass JB, Farer LS, Hopewell PC, et al. Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and Centers for Disease Control and Prevention. Am J Respir Crit Care Med 1994;149:1359–1374. 73. Pillay T. The increasing burden of tuberculosis in pregnant women in Durban, South Africa. In: Perinatal Tuberculosis and HIV-1 Co-infection. Doctoral thesis, University of KwaZulu Natal, 2002: 45–52. 74. Coutsoudis A, Pillay K, Spooner E, et al. Influence of infant-feeding patterns on early mother-to-childtransmission of HIV-1 in Durban, South Africa: a prospective cohort study. South African Vitamin A Study Group. Lancet 1999;354:471–476. 75. Taren D, Nahlen B, van Eijk A, et al. Early introduction of mixed feedings and postnatal HIV transmission. Abstract MoPeB2200, XIIIth International AIDS Conference, Durban South Africa July 2000.
76. Perera BJ, Ganesan S, Jayarasa J, et al. The impact of breastfeeding practices on respiratory and diarrhoeal disease in infancy: a study from Sri Lanka. J Trop Pediatr 1999;45:115–118. 77. Cesar JA, Victora CG, Barros FC, et al. Impact of breast feeding on admission for pneumonia during postnatal period in Brazil: nested case control study. BMJ 1999;318:1316–1320. 78. UNAIDS/UNICEF/WHO. HIV and infant feeding: a policy statement developed collaboratively by UNAIDS, UNICEF and WHO. Press statement 5 May 2003. [online]. Available at URL: http://data. unaids.org/Publications/IRC-pub03/infantpol_en. pdf 79. Effect of breast feeding on infant and child mortality due to infectious diseases in less developed countries: a pooled analysis. WHO Collaborative Study Team on the Role of Breast Feeding on the Prevention of Infant Mortality. Lancet 2000;355:451–455. 80. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA 2000;283:1175–1182. 81. Leach A, McArdle TF, Banya WAS, et al. Neonatal mortality in a rural area of the Gambia. Ann Trop Paediatr 1999;19:33–43. 82. Badri M, Ehrlich R, Wood R, et al. Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area. Int J Tuberc Lung Dis 2001;5:225–232. 83. Collins KR, Quinones-Mateu ME, Toossi Z, et al. Impact of tuberculosis on HIV-1 replication, diversity and disease progression. AIDS Rev 2002;4:165–176. 84. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998;352:1725–1730. 85. Hirsch HH, Kaufmann G, Sendi P, et al. Immune reconstitution in HIV-infected patients. Clin Infect Dis 2004;38:1159–1166. 86. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16:75–83. 87. Kwara A, Flanigan TP, Carter EJ. Highly active antiretroviral therapy (HAART) in adults with tuberculosis: current status. Int J Tuberc Lung Dis 2005;9:248–257. 88. Paterson Dl, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Int Med 2000;133:21–30. 89. Harries AD, Chimzizi R, Zachariah R. Safety, effectiveness, and outcomes of concomitant use of highly active antiretroviral therapy with drugs for tuberculosis in resource-poor settings. Lancet 2006;367:944–945. 90. Breen RAM, Smith CJ, Cropley I, et al. Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy? AIDS 2005;19:1201–1206.
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Tuberculosis outbreaks in confined situations Mary C White and Jacqueline P Tulsky
INTRODUCTION Confined locations, with or without overcrowding, have long been recognized as factors in the transmission of Mycobacterium tuberculosis. The probability that a person exposed to M. tuberculosis will become infected depends on a number of factors, including host infectiousness and resulting concentration of infectious droplet nuclei in the air, the duration of exposure, and the proximity of the person with active TB disease to those at risk.1,2 The likelihood of transmission also varies with the size of the space where droplet nuclei are suspended and ventilation – whether mixed with uncontaminated air, diluted using fresh air, filtered or treated, or controlled to change the distribution and movement of the organism between diseased and at-risk persons.3–5 The subsequent probability of disease among those infected is also based on a number of primarily host-related factors. While complex, the transmission of infectious particles from a diseased to a susceptible person is facilitated by certain environmental situations. The physical proximity to those with disease along with time of contact are generally the basis for contact investigation, focusing first on closest, most confined contacts and moving outward to social and then occasional contacts. Some confined spaces, where persons with unrecognized or inadequately treated disease transmit M. tuberculosis to others, have been well studied. Others are emerging as settings important in the clinical and epidemiological considerations of exposure and risk. This chapter will review those confined spaces known to facilitate transmission of TB, as well as new spaces recently recognized as settings for outbreaks or newly identified as places where persons at risk may congregate with infectious persons. Closed spaces provide a single piece of information for clinicians and public health TB controllers that should be added to other information in the identification, management and control, and ultimately prevention of this disease. Information on outbreaks that have occurred and new reports of settings for transmission may assist clinicians by raising their level of awareness of the complex role that the environment plays in this disease and its spread. Most outbreak investigations and follow-up case control or cohort analyses come from high-income countries, but some are available from areas of both few resources and high TB incidence. This review selects from the English language literature to illustrate key points. Although overlapping in both populations at risk and characteristics of outbreaks, confined settings will be divided as follows for this discussion: healthcare settings (hospitals, mental health care hospitals); assisted living situations (nursing homes, long-term care
facilities); forced and other long-term living situations (prisons and jails, military barracks); occasional or temporary living situations (shelters); regular congregate settings (schools, child and adult day care centres); and occasional congregate settings (aeroplanes, trains, pubs, cars). Key points common to these settings as well as new and unresolved issues are presented in Tables 57.1–57.4.
HEALTHCARE SETTINGS Healthcare facilities are probably best understood because of the inherent nature of the setting. There has been long-standing recognition of the risk for disease transmission in a place where persons with illnesses or risk factors that compromise their immune status are concentrated; and where such persons have procedures with the potential to facilitate transmission of microorganisms, in particular respiratory care procedures. The level of risk to others, including other patients, healthcare workers, and visitors in general, is based on the prevalence of TB in the general population and the number of smear-positive patients seen in the facility. For the most part, healthcare-associated transmission of M. tuberculosis has been linked to close contact with persons with undiagnosed and unsuspected TB disease, exposure to the immune-compromised such as human immunodeficiency virus (HIV)-positive persons, and close contact with active cases during procedures done in confined settings within the hospital, such as: aerosol-generating procedures, including bronchoscopy, endotracheal intubation, suctioning, and other respiratory procedures; open abscess irrigation; autopsy; and sputum induction and aerosol treatments that induce coughing.1 There is evidence of a number of factors in transmission, such as delays in suspicion of active disease, delays in isolation, host factors, and failure to initiate prompt or adequate therapy; in addition, characteristics of the confined space of the hospital have contributed to transmission in outbreaks.6,7 A hierarchy of control measures, including administrative, engineering, environmental controls, and personal protection, has been proposed for risk reduction in healthcare settings, in both developed and developing countries.1,8 Yet many healthcare facilities in lowincome countries have limited resources to implement them, while healthcare workers in high-income countries may not have a high level of suspicion for the disease despite availability of resources. The World Health Organization (WHO) has proposed low-cost interventions for settings with limited resources, with a focus on early diagnosis and rapid treatment of active cases rather than environmental controls, guidance that would serve high-income countries as
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Table 57.1 Key findings in outbreaks related to healthcare facilities, including mental health and long-term care facilities (LTCF) Failure to suspect or recognize an active TB case General Misdiagnosis; lack of suspicion or awareness of TB in differential diagnosis; atypical presentation in elderly or immune compromised. Failure to recognize disease in healthcare workers, lack of surveillance for disease, mobility of healthcare workers—from high-TB-incidence countries. Duration of exposure to unrecognized disease. Failure to report to the health authorities. Mental health facilities—few healthcare workers trained in TB recognition; lack of understanding of public health reporting; high-risk population with difficulties in evaluating patients for symptoms or obtaining history and physical exam from patients; therapeutic community may facilitate spread. LTCF—few healthcare workers trained to order diagnostic testing or authority to initiate isolation. High-/low-resource issues In resource-rich countries, continued low index of suspicion for TB despite well-funded healthcare facilities. Few resources for diagnosis in areas with limited resources. Different role of healthcare facility vs community in healthcare worker risk, risk of disease from patients, and risk of disease transmission from workers. Inadequate resources for screening and managing coinfection with HIV. HIV Rapid progression from infection to disease with atypical presentation of active disease. LTCF—joint housing and care facilitating transmission. Failure of infection control procedures General Failure to initiate isolation. Poor or inadequate use of personal protective devices. Engineering failures in negative pressure rooms for isolation. Failure to keep patients in isolation; failure to keep doors shut; misunderstanding of complex nature of negative pressure rooms and role of doors and windows in disrupting flow. Inadequate precautions during high-risk respiratory procedures. Duration of exposure or long duration of hospital stay. Health beliefs of healthcare workers that TB is inevitable. Mental health facilities—some locked and crowded, without access to windows; not set up for isolation. LTCF—lack of facilities, trained staff; mixing of elderly with high-risk patients and staff with HIV. High-/low-resource issues In resource-rich countries, low adherence rates in healthcare workers for screening follow-up and treatment of LTBI. Reliance on engineering controls that may not be effective in resource-rich areas. Crowding and proximity in resource-limited areas. Higher risks to healthcare workers in resource-limited areas. Mobility of healthcare workers between countries; lack of understanding of role of BCG in TB prevention. HIV Housing of HIV-positive persons together, along with failure of infection control measures. Lack of understanding of need to co-manage HIV and TB. HIV-positive healthcare workers both at risk and presenting risk, reluctance to admit status because of stigma. New or unresolved issues Surveillance of healthcare workers for LTBI or disease. Use of interferon-g assays for surveillance of healthcare workers, contact investigation, screening. Non-compliance of healthcare workers and role of work setting and poverty in reluctance to present with symptoms. Consideration of separate housing of MDR- and XDR-TB patients from each other, and from HIV-positive persons and HIV coinfected.
LTBI, latent TB infection.
well, considering that many outbreaks occur because of failure to suspect TB and take rapid action to control it.9 The impact of widespread TB transmission on the healthcare system points to the urgency to address nosocomial transmission in all hospitals, with cost-effective measures that can be used by all.10–12 The emergence of multidrug-resistant TB (MDR-TB) has prompted additional concerns, and extensively drug-resistant TB (XDR-TB) has already been identified in a number of countries with evidence suggesting transmission in hospitals.13
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Poor infection control practices, including lack of adequate isolation, overcrowded hospitals, and the impact of HIV facilitating rapid breakdown from infection to disease, provide the ideal conditions for nosocomial outbreaks, a situation made more urgent because of drug resistance.14,15 Evidence of drug resistance in South Africa, with clear implications for the rest of the world, raises important questions about where patients are triaged and how they are housed in hospitals. Some experts are calling for isolation facilities for patients with MDR- and XDR-TB that are
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Table 57.2 Key findings in outbreaks related to prisons
Table 57.3 Key findings in outbreaks related to shelters
General Inadequate number of public health-focused healthcare workers in the system. Security as a higher priority than health: difficulty in access to records of movement of prisoners; difficulty in healthcare worker access to prisoners for care. Poor adherence to medications for LTBI and active TB. Extensive time of exposure. Poor ventilation. Extreme crowding. No isolation facilities; open cell design, multiple prisoners per cell; frequent movement between cells for issues of safety and violence prevention. High-risk activities within prison facilitating HIV transmission. Frequent transfers between prisons without adequate communication. Failure to communicate with public health officials—either about release or about re-incarceration. Delayed diagnosis of exposed and disease cases in outbreak investigation due to loss to follow-up of released prisoners. High/low resource issues Economic barriers to screening: lack of laboratory facilities or personnel for sputum smear or symptom review at entry or at regular intervals. Extreme crowding, malnutrition in low-resource facilities. HIV Rapid progression from infection to disease with atypical presentation of active disease. Housing of known HIV-positive prisoners together with communal areas. New or unresolved issues Failure of public health system to recognize and establish a role in the care of incarcerated persons. Surveillance of healthcare workers and prison guards for LTBI or disease. Surveillance of incoming prisoners—interferon-g assays, symptom review, chest X-ray; and timing of surveillance. Role of prisons as focal points for MDR- and XDR-TB transmission and ways to interrupt transmission.
General Few healthcare workers in the system; no consistent communication between shelter workers and public health authorities. Facilities not designed for long-term housing of high-risk populations. Crowding. Time of exposure. Poor ventilation. No isolation facilities. Programmes designed for rapid turnover; movement from shelter to shelter, to prison, to boarding houses or other temporary residences. Poor or no records to facilitate outbreak investigations. No or inconsistent screening for TB. High/low resource issues Extreme crowding. Housing for new immigrants or transient workers with no locating information after leaving the shelter. HIV High-risk host factors among the homeless with less access to healthcare. New or unresolved issues Communication between shelters and public health. Privacy concerns balancing public health issues with individual rights. Source of resources for prevention screening and LTBI treatment.
LTBI, latent TB infection; MDR, multidrug-resistant; XDR, extensively drug-resistant.
separate in particular from patients with HIV as well as others, and raise questions about the expense and government commitment to infection control that will prevent transmission.16 Of the reported TB outbreaks in healthcare facilities, several involved transmission of MDR-TB strains in the USA,7,17–20 and in Europe, South America, South Africa, and Russia.21–24 The majority of the patients and certain healthcare workers in these outbreaks were HIV-positive, and progression to TB and MDRTB disease was rapid. Factors contributing to these outbreaks were more related to institutional policy failures than to the characteristics of the institution itself.1 Although most reports of transmission of MDR-TB have been to HIV-positive persons, there have been reports of transmission to HIV-negative persons, such as that reported from Argentina.25 In many cases, outbreaks have been related to an inadequate infection control programme or inadequate application of a programme in place. In one, transmission of MDR-TB in a Chicago hospital to six patients and one healthcare worker, all of whom had acquired immunodeficiency syndrome (AIDS), resulted from insufficient environmental controls and delayed recognition
LTBI, latent TB infection.
of active disease.26 Despite having a N95 respirator fit testing programme, not all healthcare workers reported always wearing a respirator when entering a TB patient’s room. While mandated in US hospitals, respirator use was not found to be an effective measure for preventing transmission in this outbreak; researchers have shown inconsistent use and effectiveness of N95 respirators in a Brazilian hospital and concluded that respirators as a sole control measure is inadequate in any setting – and not cost-effective in resource-limited settings.27 The WHO recommends use of personal respiratory protection as the third line of defence for TB control, when risk cannot be adequately reduced by administrative and engineering controls.9 In settings where respiratory isolation is difficult and climate permits, opening windows and doors to create natural ventilation may be a low-cost measure to reduce transmission.28 A second failure in the Chicago outbreak related to isolation.26 The initial case patient, diagnosed at admission, refused to remain in isolation. And finally, the lack of negative-pressure rooms – resulting in air flow from case patient rooms into the hallway – probably facilitated transmission to a healthcare worker without direct care exposure and a secretary without any patient care responsibilities. Likewise, in MDR-TB outbreak among AIDS patients in New York, both proximity of rooms of exposed and case patients and the lack of negative-pressure ventilation in isolation rooms were associated with transmission.18 Similar outbreaks resulted in transmission to HIV-positives, with brief periods from exposure to disease and high fatality.22,23 Factors contributing to the outbreak included inadequate facilities for respiratory isolation; crowded infectious disease wards; poor patient compliance with isolation procedures, treatment, or mobility limitations; longer duration of stay; delayed recognition of the outbreak; and a high proportion of persons with very low CD4+ counts. Transmission specifically to healthcare workers has been attributed to delay in diagnosis, poor ventilation without negative pressure in
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Table 57.4 Key findings in outbreaks related to other and new congregate settings Worksite Low level of suspicion for worksite outside of healthcare facility. No reporting mechanism; no common healthcare providers for workers. Fear of deportation of undocumented results in limiting cooperation with public health authorities. Schools Delayed diagnosis and low level of suspicion. Few healthcare workers or persons trained in recognition of suspicious symptoms. Inadequate ventilation and overcrowding. Foreign-born students isolated from others and from access to healthcare. Childcare facilities Unlicensed facilities ‘hidden’ from usual public health requirements or oversight. Fear of deportation of undocumented adults limiting cooperation with public health authorities. Bars, pubs Reluctance of persons to name contacts, in particular among alcohol or drug abusers. Relative young age, lowering index of suspicion among providers. Non-adherence to treatment among persons found to have LTBI in countries that screen and treat. Lack of social cohesion in loose social networks that preclude assistance to ill colleagues. Links to HIV-positivity; links between persons with and without high-risk behaviours. Difficulty in distinguishing single space for transmission in bar-hopping. Automobiles ‘Hot boxing’ to enhance inhalation of drugs that facilitates TB transmission. Reluctance of cases to name contacts. Novel methods to observe social interactions to facilitate investigation. Airplanes Risk associated with close proximity to active case—within two rows. Risk associated with long flight duration; overall risk is low. Inherent mobile nature of exposed persons hampering contact investigation and case finding. Inadequate records for investigation. New or unresolved issues Education of healthcare providers to identify non-traditional congregate settings. Education of public to appropriately identify real versus imagined risk of transmission. Evaluation of techniques to map social networks. LTBI, latent TB infection.
isolation rooms or not keeping the doors closed, high levels of air recirculation, and poor precautions during high-risk respiratory procedures such as mechanical ventilation, bronchoscopy, irrigation, or autopsy procedures.21 In low- and middle-income countries, locations such as in-patient TB facilities, laboratory, internal medicine and emergency facilities, and occupational categories such as radiology technicians, patient attendants, nurses, ward attendants, paramedics, and clinical officers had higher risk.29 In outbreaks involving healthcare workers, time of exposure, as well as lapses in infection control practices and inadequate ventilation, was important;19 among those who developed active disease, delayed identification and treatment of the healthcare workers themselves facilitated further transmission.20
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Outside of outbreaks, there is consensus that community exposure is the dominant risk factor among healthcare workers in the USA and in other developed countries.4,21 In resource-limited countries, however, the attributable risk for TB disease among healthcare workers compared to the risk for the general population has been shown to range from 25 to 5,361 per 100,000 per year.29 Healthcare workers, therefore, have been shown both to be at risk and to present risks to others. In settings without regular surveillance of healthcare workers, there have been suggestions of focal outbreaks of staff-to-staff transmission.30 In the USA as in many European countries, non-national (non-native) healthcare workers make up an increasing proportion of the healthcare staff, many from countries with high TB prevalence, and outbreaks have occurred from healthcare workers to patients.31,32 Problems in testing healthcare workers, in particular physicians and trainees who may rotate from one setting to another, and lack of understanding of infection status and treatment recommendations for latent infection, have been identified as barriers, with resulting non-compliance among healthcare workers at all levels of diagnosis and treatment.33 Hospitals for the mentally ill may present additional issues in the management of TB and prevention of outbreaks. In one outbreak in Japan, chest radiographs were not taken regularly for in-patients and because of delayed diagnosis, 18 cases, linked by restriction fragment length polymorphism (RFLP) in eight cases with cultures available, were identified in a 3-year period.34 A further issue was failure of the diagnosing physician to report the case to public health authorities. In another, transmission occurred after a patient developed a productive cough and died with a diagnosis of pneumonia – with TB identified after her death.35 In this outbreak as well, delayed diagnosis and failure to report to public health authorities was cited. In an outbreak in France, culture-positive TB linked by RFLP was found in six of 15 mentally ill patients, with five secondary cases.36 Again, prolonged contagiousness for 3 months due to delay in diagnosis was reported, as was crowded living conditions. Additional problems of isolating the patients effectively may have resulted in further transmission, as the first case was a psychotic patient with whom communication was nearly impossible and medical examination was difficult. Links between mental illness and drug use, homelessness and incarceration make this population at risk for TB but at the same time difficult to evaluate because of the mental illness. Limited numbers of healthcare workers attuned to or trained in physical illness diagnosis may have added to the delay in diagnosis in these outbreaks. Mental health facilities may be locked with limited access to windows for safety reasons, and efforts to make the setting home-like, including mixing of patients and staff as part of the therapeutic community, may further facilitate outbreaks.
ASSISTED LIVING SITUATIONS Living situations in general are considered confined spaces and of primary concern in outbreaks of M. tuberculosis. Although this chapter focuses on confined spaces outside the usual households considered for identification of close contacts to an infectious case, the home should not be omitted from this discussion. MDR-TB, thought to have emerged from human error, spread readily in persons with HIV living in crowded conditions in the New York City epidemic in the 1990s.15 Widespread immigration – for a better life or to escape war or violence – has resulted in persons, coming from
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countries with high endemic rates of TB, living in crowded spaces as they struggle to survive in a new country. And even in the wealthiest nations, inner cities have gang- and drug-related violence that may force residents of poorer neighbourhoods to board windows and prohibit children from playing outside as a safety measure, thus making a confined space where ventilation is limited. The confluence of poverty, drugs, incarceration history, and violence may lead to the household as a tightly locked fortress with the inadvertent side effect of increased risk for TB transmission. Extended care or long-term care facilities (LTCF) have been well recognized as high-risk settings for TB outbreaks, in which the ageadjusted risk of TB doubles, compared to that of community-dwelling persons.37 Factors associated with this increased risk are primarily hostrelated, although the confined space plays a role as well. Residents of an LTCF by nature have multiple chronic diseases and functional impairments that increase their risk of infection or progression to disease, and are more likely to have prior infection coupled with the immunological decline seen in aging.38 Tuberculosis in the elderly may present without typical symptoms and be unrecognized. Moreover, LTCF may house both young and old persons, including HIV-positive persons who may have symptoms attributed not to a new diagnosis of TB but to the HIV/AIDS that brought them to the facility in the first place. LTCF share many of the same risk factors for TB outbreaks found in hospitals. Although LTCF in the USA and many countries have licensure or accreditation similar to that of hospitals, ongoing monitoring of adherence to infection control requirements falls heavily on the individual institution. LTCF may not have clinical personnel trained to suspect TB early and begin diagnostic procedures and isolation. Recommendations in the USA include systematic screening of residents and employees, capacity for early diagnosis of active disease, airborne infection isolation, capacity for prompt initiation of treatment of active TB disease, and treatment of LTBI.37,39 However, many LTCF fail in all categories, in particular the early and rapid diagnosis of disease. There may not be capacity to initiate isolation or adequate ventilation control measures,40 so that the time between development of infectious disease and transfer to an acute hospital may be adequate for transmission to other residents or staff. The aging of populations in many countries, combined with high levels of migration among aging persons from countries with high prevalence of TB to lowprevalence countries and vice versa – and migration of healthcare workers as well – make the likelihood of outbreaks in LTCF more likely over time.41 An outbreak in two LTCF in the USA was recognized because of increase in tuberculin skin test (TST) conversions among employees in annual testing in one facility, a recommended practice in the USA.37,39 This investigation revealed a highly infectious, unrecognized case that resulted in transmission of infection to 40 employees and 24 residents – some of whom moved between the two LTCF – and 14 employees of a nearby hospital, and four active TB cases with many additional suspected cases among residents who died over the period of the outbreak.42 The index case was a 91-year-old woman who developed symptoms (productive cough and weakness) 2 years after admission to the LTCF, and was hospitalized six times in 8 months with a diagnosis of pneumonia, without any diagnostic studies to rule out TB. Cavitary disease on chest X-ray was recognized only after her death, 8 months after onset of cough. Higher risk of TST conversion was found for those with rooms on the same wing as hers. Ventilation examination revealed separate heating and cooling systems for wings of the
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LTCF, positive air pressure in each room with respect to hallways, and a centrally located vent in the hallway that returned air to a heating or cooling unit for recirculation. The return air vent was located immediately outside the room of this presumed index case. Investigators speculated that there may have been more TB cases in this as well as in other LTCF, as staff had employment in more than one facility. The high proportion of TB cases among the elderly and the failure to consider TB in the differential diagnosis of persons with respiratory symptoms probably results in many silent outbreaks in this setting.42 Housing for persons living with HIV/AIDS has been identified as another setting for transmission. An outbreak in an orphanage for children with HIV/AIDS in Jamaica between 2001 and 2002 was described in which four cases of active TB, two of whom died, as well as concurrent outbreaks of varicella and scabies occurred.43 This outbreak of multiple infectious processes was facilitated by the group living situation of children at high risk for infectious diseases – 50% had been receiving antiretroviral therapy – with links to the outside community, as the index case of varicella was a 13-year-old resident who attended a nearby school with HIV-negative children. Likewise, an outbreak in a housing facility for HIV-positive adult males resulted in 12 new diagnoses of active disease, with similar RFLP patterns in all culture-positives.44 In this outbreak persons with HIV/AIDS rapidly progressed to active disease, leading to extensive exposure of others even when TB was identified at the first sign of symptoms. Living situations that congregate persons with similar diseases can be therapeutic and can become centres of excellence for treatment as well as places for sensitive and understanding care; but the inexorable links between TB and HIV make these settings at high risk for outbreaks.
FORCED AND OTHER LONG-TERM LIVING SITUATIONS PRISONS AND JAILS For this discussion, references to prison are meant to include all detention facilities regardless of type unless stated otherwise. In both high- and low-income countries, prisons have been recognized as confined settings where TB rates greatly exceed those of the surrounding community. Moreover, in many countries with declining rates of TB, rates in prisons remain high.45–47 In some resource-limited countries, TB prevalence 5–10 times the national average is not uncommon and can be up to 50 times the reported national rate.48,49 Transmission in prison has been reported in many countries using RFLP, clinical, and epidemiological evidence.50,51 Reports of MDR-TB have come from both the developed and developing world.45,52–55 Prisons are a focal point for acquisition and transmission of TB with rapid progression to disease, in particular among HIV-positive persons. Factors associated with higher rates include characteristics of prisoners: over-representation of injection drug users; persons at high risk for or with HIV; and persons with low socioeconomic status, who may be new immigrants or refugees from countries with high endemic TB rates and who have limited access to healthcare in the community.46,56 HIV testing is inconsistent in prisons; some require testing at entry, others offer testing, but the majority do not test at all. In a review of HIV in 142 low- and middleincome countries, HIV was found to be > 10% in 20 of 75
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countries with data, with evidence of HIV transmission in prison in seven countries where injection drug use was known to occur.57 Characteristics of prisons make them unique settings for transmission. By definition and by design, prisons are confined spaces, which contribute to transmission, and many are overcrowded and have inadequate ventilation. Routine screening for TB at entry and periodically, by TST, symptom screen, or chest radiograph, is not consistently done nor is there agreement on the optimal method. Providing healthcare is not the mission of prison systems and is rarely given priority, the number of trained healthcare staff is small in proportion to the number and severity of illness of the population, and services may be limited. Recidivism is high, and time in the facility has been associated with TB transmission.58 Movement of prisoners into and out of overcrowded and inadequately ventilated facilities, coupled with existing TB-related risk factors and security issues that may not support TB control, complicate the rapid identification and adequate management of TB. In the USA, outbreaks have occurred even in jails, the relatively short-term facilities for detention.59 During a 3-year period, active disease was diagnosed in 38 inmates and five guards, with 79% of culture-positive prisoners and both culture-positive guards having matching DNA fingerprints. Median length of incarceration was associated with TB diagnosis, as was repeat incarcerations, indicating increased exposure time.58 In another outbreak, two prisoners and one guard were diagnosed with active TB, and subsequent investigation revealed a total of 18 cases: three were infectious for a total of 7 months before diagnosis and control measures were undertaken.60 As in other settings, delayed diagnosis and time of exposure were key factors. Movement between jails has also been associated with transmission.61 A homeless man with productive cough and haemoptysis was referred for chest X-ray in a California community but didn’t follow up. He travelled to Kansas where he was detained in three different jails and one state prison for 4 of 6 months with continued symptoms before being diagnosed with pulmonary TB with a cavitary lesion. His presumed diagnosis at various times included bronchial asthma and lung cancer before diagnostic sputa were obtained for evaluation. In the estimated 12 months of infectiousness, 800 possible contacts were identified and 318 evaluated. Two developed active disease with RFLP-linked isolates, and 21% of those with no previously documented TST had a positive test. A number of issues are raised from this outbreak.61 The outbreak most clearly was associated with delayed or misdiagnosis, which not only led to transmission but also to limited ability to determine the extent of the outbreak. Some former prisoners could not be found and others refused follow-up. While not formally evaluated, all three local detention facilities housing the symptomatic inmate had open-cell design with multiple inmates per cell, which is common in the USA and elsewhere. Overcrowding has been correlated with TST conversion in the Maryland prison system,62 and in this outbreak, higher conversions in previous negatives among other prisoners (14%) as compared to employees (5%) support the role of the confined living space as a factor. Transmission within prisons has also led to community cases. From 1995 to 1997, an outbreak occurred in a large urban jail in Tennessee. Subsequent analysis of culture-positive community cases demonstrated that 23% involved a strain indistinguishable from the jail strain, and 12 cases (63%) with that strain had no history of incarceration.59 Likewise, transmission in a Maryland jail resulted in 18 epidemiologically linked cases, 11 exposed in the community and six in the jail.63 TST conversion rates were
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associated with days of exposure to the index case. And in the UK, a prisoner was thought to be an index case for 11 subsequent cases that occurred in a community.64 Factors related to this outbreak included poor adherence in the community and failure of communication between public health and prison healthcare authorities – not that communication was not done, but that private clinicians did not know when the index case was imprisoned, and considered the case lost to follow-up. The authors raised issues about the role of physicians, courts, and prisons in managing infectious diseases, and the balance that must be struck between public health and patient confidentiality.65 Transmission to staff of detention facilities, as well as to other prisoners and community contacts, has been reported, adding to the evidence that the facility can serve as a reservoir for disease.66 An outbreak of drug-susceptible TB occurred in two geographically close facilities in Florida during a 6-month period in 2004.67 The source case was an HIV-positive staff member, a secretary in the medical unit of one facility who had frequent contact with co-workers and correctional officers involved in prisoner transport. The individual had been diagnosed with extrapulmonary TB in 2001, was managed by a private physician, and was reported to be non-adherent to self-administered medication for TB. No investigation occurred in 2001 because the patient was considered to be non-infectious. Pulmonary symptoms developed approximately 6 months before diagnosis of active disease in 2004. An additional five HIV-negative correctional staff members were diagnosed with active disease, all epidemiologically linked and four of five RFLP-matched with the index case. In this setting in a high-income country, failure to monitor adherence to TB medications was a factor. The intersection of HIV with TB, an issue in other confined settings for diagnosis and management of both diseases, is particularly critical in outbreaks in prisons. As some prisons house HIV-positive or persons with AIDS in separate facilities, TB can readily spread within and beyond the confined space of the prison housing area. In 1995 an outbreak in a housing unit for HIV-positive persons resulted in 15 cases with a distinct TB strain.68 A case-control study revealed exposure of 20 or more hours per week in a communal day room as the primary risk factor among prisoners with a CD4+ count of < 100; not having a television in a single-person room was protective, supporting the hypothesis that this communal room was the site where transmission likely occurred. The authors speculated that in this segregated setting for HIV-positive prisoners, ambulatory patients were more likely to go to the communal room and thus be at risk, although this association was modified by CD4+ count – there was no association between time in the communal room and transmission among those with counts of 100 or more. They suggested that those with lower counts were more likely to spend their time in the communal room or in their own singleperson cells; thus prisoners at highest risk were those who were ambulatory enough to be in the communal room but not well enough to spend time in other areas. An outbreak of TB in 1999 was recognized in one of three HIV-dedicated dormitories of a state prison in the USA, resulting in 323 exposed HIV-positive prisoners, 30 additional cases in 4 months, and TST conversions among 71% of prisoners housed on the same side of the dormitory of the case patient.69 The index case had a TST of 15 mm 15 years prior to diagnosis with active TB, but had failed at two LTBI treatment attempts because of gastrointestinal side effects. Six weeks prior to TB diagnosis, he was hospitalized with fever, abdominal pain, and cough; chest X-ray was normal and sputum specimens were not obtained. He was returned to the prison without a definitive diagnosis.
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Information that smear-positive TB was diagnosed in a former prisoner, housed in the same dormitory but released, led to the investigation and identification of the index case. In the subsequent outbreak investigation a medical student who examined the index patient in the hospitalization prior to diagnosis was found to have smear-positive cavitary TB with the same DNA fingerprint pattern; two other inmates developed disease in the next 2 years.70 An important feature of this outbreak was the transfer of prisoners: five were diagnosed after release from prison, before the index case was diagnosed. Also, segregation of HIV-positive prisoners facilitated transmission of undiagnosed disease to hosts who, once infected, rapidly developed disease. Reasons for segregation of HIV-positive prisoners have included reducing transmission of HIV within the prison and improving medical care for HIV-positive persons by housing them near specialized medical facilities.69,70 However, without administrative and environmental controls to screen and quickly manage suspected TB cases, including consideration of TB as a differential diagnosis even in the presence of negative chest X-ray, transmission may be facilitated by segregated housing of persons more likely to develop active and unrecognized disease. Additional barriers in outbreak investigations were changes in housing assignments, difficulty in ascertaining areas where prisoners had been, and access to visitation and housing records that required close cooperation with correctional staff. These outbreaks demonstrate that even with precautions to screen prisoners at entry and regularly – in one, HIV-positive prisoners were medically evaluated every 6 months and those taking highly active antiretroviral therapy (HAART) every 3 months – transmission can readily occur to other prisoners, staff, and the community. Transfers between prisons are common, and poor communication is a barrier to TB management. Transmission of MDR-TB in an outbreak in a New York State prison was associated with HIV, resulting in high mortality.53 The 39 active cases resulting from this outbreak, 38 of whom were HIV-positive, were in 23 of the 68 New York State prisons while infectious; 12 were transferred through 20 prisons while ill. Transfer of prisoners with active TB has also been observed in Thailand prisons, where authors speculated that poor communication between facilities resulted in missed cases and thus the potential for transmission.71 Further, laws in the USA that mandate availability of healthcare for prisoners also allow prisoners to refuse care; in one outbreak the source case, an HIV-positive prisoner with MDR-TB, was transferred to prison while ill with undiagnosed disease, where he refused medical care, lived in the general prison population, and transmitted disease to other prisoners.54 Although some of the same issues face countries with fewer resources, the underlying community prevalence is considerably higher, resulting in extremely high rates of disease within prisons. Evidence from the former Soviet Union illustrates the critical nature of the problem, where the incidence rate for MDR-TB in Russia reached 83 per 100,000 in 2002.72 Many TB cases were thought to originate among prisoners. In one region of Russia, TB incidence among convicted prisoners was 2,190 per 100,000 but lower among pre-trial detention prisoners, 1,890 per 100,000. Both rates were considerably higher than the rate in the general population, 86 per 100,000.24 At the time, the prevalence in the entire Russian penal system was reported to be 2,828 per 100,000.73 Overcrowding, malnutrition, inadequate ventilation, and long periods of incarceration were cited as factors, in addition to HIV coinfection, poor adherence to TB treatment, both in prison and after, and high loss to follow-up. Frequent moves between cells to prevent violence have been thought to facilitate mixing of susceptible and infectious
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prisoners, and economic constraints present barriers to sputum smear microscopy as the standard method for diagnosis.73 In a population-based cross-sectional study including molecular epidemiological analysis, the Beijing family strain was found to predominate, and previous imprisonment was a risk factor for infection with this strain, which caused radiologically more advanced disease and prison isolates were twice as likely to be drug-resistant.24 HIV coinfection was present in 10%, and high rates of concurrent hepatitis B and C infections supported the role of drug abuse in the population infected with this strain, and younger age supported both recent and active transmission as well as the impact of prison as a focal point for transmission. Although this is not a report of an outbreak per se, it reflects a regional epidemic, with prison as a central focus. These reports of drug-resistant TB in prisons resulted in worldwide response with collaboration between governmental organizations and the WHO and increased budgets for TB control measures including directly observed treatment, short-course (DOTS) for prisoners. Although the WHO reported progress in controlling the transmission of TB, prisons remain a problem site for TB in Russia and throughout the world.74
MILITARY INSTALLATIONS Military installations are long-term living situations where crowding can occur. Crews on ships live and work in crowded, enclosed spaces, and outbreaks of M. tuberculosis have been reported.75 An example is an outbreak recognized on a US Navy ship in 2006; the index case was a 32-year-old sailor, born in the Philippines, negative for HIV, who was found to have smear- and culture-positive, pan-susceptible, cavitary TB.76 He was screened and diagnosed with LTBI in 1995 and completed a 6-month course of isoniazid, the standard treatment at the time. The outbreak investigation included 5,000 sailors as well as 1,225 family and friends who boarded the ship in Hawaii and sailed to California, civilian guests who slept in the same quarters as sailors for this 1-week trip. Because annual TSTs are mandatory in the US Navy, baseline results were available for the sailors. Excluding previous positives, 3% acquired infection. Risk factors included being born outside the USA and being housed in the section of the ship with the index case. Sleeping quarters were an open-bay compartment with 120 bunks stacked three high. The index case’s bunk was approximately 18 feet from an air intake that exhausted directly overboard, and investigators speculated that this ventilation prevented additional transmission during the prolonged exposure during the ship’s deployment. Although military recruits are generally screened at enlistment and represent healthy individuals, outbreaks of TB as well as other infectious diseases have occurred in the often-confined spaces for military housing.
OCCASIONAL OR TEMPORARY LIVING SITUATIONS SHELTERS Shelters for the homeless, battered women, refugees, and other groups made vulnerable because of personal, economic, social, or political circumstances share characteristics of other confined settings that can lead to transmission. In particular, shelters for the homeless concentrate those with risk factors for TB and for
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progression from LTBI to active disease: intravenous and nonintravenous drug and alcohol abuse, HIV, poor nutrition, low socioeconomic status, male sex, history of time in jail or prison or other institutional settings, and coming from ethnic minorities or newly immigrated from countries with high TB prevalence.77,78 Personnel in shelters vary in training and professional background, but few have healthcare skills. And the homeless are less likely than many other groups to access or have access to preventive or routine healthcare services, including both TB and HIV testing. Characteristics of many shelters include overcrowding, poor ventilation in particular during winter months when windows and doors are likely to be shut, inconsistent testing or evaluation of residents for symptoms, poor record keeping, and lack of infection control measures. Efforts to investigate and stop outbreaks are complicated by rapid disease progression in persons coinfected with HIV, limited communication between health department jurisdictions, case management failures, and challenges to identifying contacts in a mobile population without a reliable address.79 Because of the way homeless or unstably housed persons access shelters and because of poor records of residents, investigators are less able to measure precisely the time and proximity of contact with an index case. A large outbreak in a Paris, France, shelter for immigrants from North Africa and sub-Saharan Africa illustrates difficulties in both investigation and rapid management of an outbreak.78 This shelter, a five-storey building divided to house migrants separately by region of origin, had rooms about 15 m2 in size, with a single window that was usually closed. Despite ‘official’ bed counts, rooms housing sub-Saharan immigrants were crowded, with beds shared by 2.5–3.5 persons on average each night. During a 1-year period, 56 cases of active disease were diagnosed among 1,360 usual or occasional shelter residents. All cases had recently arrived, and all but one were housed in the subSaharan section of the shelter. Incidence of active disease was estimated to be 4.1%. Similar findings came from North Carolina, involving transmission from a 37-year-old index case.80 Eight additional cases occurred in 8 months, including one who had been in the shelter as well as in a casual labour agency with the index case, but who was diagnosed in prison. The shelter was overcrowded, housing over 350 persons per night in a 92 50 m space, with windows and doors rarely opened. All nine cases were African American males, six coinfected with HIV. Exposure, categorized in intervals (39–76, 77–114, and 115–153 nights), resulted in increasing relative risks of 1.8, 2.7, and 3.5, respectively, of TST conversion compared to those spending 38 or fewer nights at the facility. An additional four cases were identified in the subsequent 8 months with matching RFLP, indicating continued transmission characteristic of outbreaks related to shelters for the homeless. Movement between shelters in a given region complicates outbreak investigations. RFLP typing of isolates from the homeless has led to broader understanding of the epidemiology of TB in this population,81 the relationship between HIV status and strain,82 and differences in infectiousness between primary TB and exogenously reinfected secondary cases.83 In a large study of TB cases in Maryland and Washington, DC, from 1996 to 2000, 78% of 23 cases were linked to another case by RFLP, and half the patients were associated with a single homeless shelter and others were linked by sharing boarding or transitional housing.84 A recent outbreak investigation in Washington State demonstrated the considerable movement of persons between homeless facilities, and the authors speculated that in addition to individual risk factors in this population and characteristics of the setting, the fact that it was not
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confined to a single homeless facility was in itself a factor that facilitated transmission.85
REGULAR CONGREGATE SETTINGS The occupational setting has been reported – in addition to the healthcare facility – as a space where outbreaks have occurred. An outbreak in Maine, initially thought to be related to a boarding house when a 71-year-old resident developed active TB, revealed that another man was the index case, a 32-year-old resident of the same boarding house who had been treated with tetracycline for chronic cough and sore throat, despite chest X-ray consistent with TB.86 After several months of active disease that was not treated by his private medical provider, he was finally adequately diagnosed and treated. Contact investigation, divided into social (friends, fellow boarding house residents, and persons frequenting taverns) and occupational contacts who worked with him at a local shipyard, revealed 21 additional cases, 12 of whom worked in the shipyard. Workstations at the shipyard were enclosed, cramped, and crowded, and 27% of close work contacts and 7% of intermediate contacts had positive TST. All infected workers were US-born, and 53% were younger than 35 years of age. In this middle-class community with low expected TB rates including low expected TST positivity, cases of active TB occurred for more than 3 years after the outbreak was recognized, and low levels of suspicion among private physicians for diagnosing – and inadequate treatment and reporting after recognition – were cited as reasons for the occurrence and length of the outbreak. Schools have been identified as a congregate setting for TB outbreaks, and selected investigations illustrate the primary factors associated with transmission. In the USA, schools are the most common site reported in community-based outbreaks, with contributing factors primarily being delayed diagnosis, sustained contact, inadequate ventilation, and overcrowding.87 In a high school outbreak in the USA, the index case was symptomatic for 6 months, and risks were calculated on the basis of classroom and bus exposure.88 Classroom risk was stratified by the number of classes shared, excluding classes with enhanced ventilation (such as art and gym), and the risk of infection increased with the number of classes shared with the index case. Of 781 classroom contacts sought for screening, 72% completed testing with 10% TST positive. Of 67 who rode the bus to school with the index case in this rural region, 19% were TST-positive, and one subsequently developed active disease. A student with 6 months of symptoms prior to diagnosis and ultimately found to have extensive pulmonary disease was the index case for an outbreak in a Canadian university. From the contact investigation, risk factors were identified as > 35 hours spent with the index case and smaller classroom size, but as little as 3 hours of contact per week resulted in significant infection rates among contacts in this more detailed analysis of hours of risk.89 Among 279 Canadian-born contacts – to control for confounding by Bacillus Calmette-Gue´rin (BCG) or prior sensitization to nontuberculous mycobacteria in the foreign-born – 20% were TST positive, compared to 1.5% in Canadian-born university students of the same age. Three persons identified as family or close social contacts developed active disease, but no active cases resulted from the school contacts. Increased risk of infection in school contacts was observed in rooms mechanically ventilated compared to those naturally ventilated, although whether windows were open or shut was not known for the time of exposure.
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Tuberculosis outbreaks in confined situations
Boarding schools – where students live for school terms – provide additional opportunities not unlike those of military recruits or other live-in settings where residents are young and presumably healthy. An outbreak occurred in a school (grades 9–15) in Israel, where two-thirds were from the former USSR and Ethiopia.90 Although Israel has a declining incidence of TB, this outbreak among foreignborn students from high-incidence countries illustrates the additional complexities when considering the risk in this congregate setting. This particular school had dormitories in which four students from the same country of origin shared crowded living conditions with poor ventilation, thereby increasing the risk from sharing classroom time to living and social contact. Six active cases, all Ethiopian students, were diagnosed over a 1-year period, with confirmed common RFLP pattern in five of the six. Investigators distinguished close contact (being in the same class or dormitory) from remote contact (being in the school), and controlled for BCG vaccination, finding 61% TST-positive. Childcare facilities including nursery schools are well recognized as common sites for disease transmission, but reports of M. tuberculosis outbreaks are rare and transmission to very young children in these settings generally occurs from adolescents or adults. One of the largest reported paediatric TB outbreaks in the USA occurred in a private-home family childcare centre in San Francisco despite licensure requirement requiring annual TB screening for on-site adults.91 During a 2-year period 11 cases (nine among children) were identified in the unlicensed centre, a private apartment in a predominantly Hispanic neighbourhood, in which an adult with active TB, symptomatic for > 1.5 years, resided intermittently. All paediatric cases were US-born Hispanic children of foreign-born parents. Of 67 persons in contact with the index case excluding the active cases, 91% completed testing and 54% were found to have LTBI, including 12% who had documented conversion from prior negative TST. This outbreak pointed out missed opportunities to stop transmission, including delayed identification of the index case as a person who should have been screened early in the epidemic investigation; evaluation of RFLP isolates at different laboratories without data sharing, as well as delays in laboratory DNA fingerprint results from transport time and batch processing; and loss to followup of contacts who had left the country as well as the possibility that one or more adults in the setting may have been undocumented and thus fearful of participating with disease control investigators.
OCCASIONAL CONGREGATE SETTINGS BARS, PUBS, AND RESTAURANTS Many contact investigations involve evaluation of social settings where confined spaces play a role in transmission. Although initial investigations may put these sites as more remote in terms of risk, the nature of the confined space may amplify the exposure. In England an outbreak was associated with a public house in which 16 men and women were found with active TB, none of whom had other risk factors for TB.92 Meeting regularly at the same pub was the primary risk factor, and no cases occurred from investigation of the usual close contacts from family and households. A similar report from Wales found nine cases, seven with identical typing, from relatively young persons who were part of a network of regular drinkers at four pubs in a city suburb.93 In this and in other reports, investigators found that conventional contact tracing was insufficient in outbreaks linked to pubs, in particular when
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cases or contacts were alcohol abusers.94 In another report of a 2-month-old infant hospitalized with suspected tuberculous meningitis in Canada, investigation of the family and household revealed that the father, originally from Haiti, was found to have cavitary pulmonary TB with a cough for nearly a year.95 He worked in a bar with a dining room; extensive TST conversions led investigators to broaden the investigation to employees and regular (at least twice per month) patrons of the establishment. In this outbreak, TST positivity in bar employees (35%) and regular patrons (30%) was close to that of extended family and friends of the index case (49%). In another report, a man who had been homeless for 6 months was hospitalized in Minneapolis, Minnesota, and diagnosed with highly infectious pulmonary TB, including 4+ positive smear, productive cough, fever, chills, and extensive cavitary infiltrates on chest X-ray.96 He reported that as he was getting progressively sicker, he spent most of his time in a bar and its adjacent rooming house. Contact investigation included 97 persons, bartenders and regular patrons, and 42% were infected with TB. Fourteen cases of active TB were found, four additional cases missed in the contact investigation occurred, and there were two secondary cases; none were due to coinfection with HIV and all isolates tested had common DNA fingerprint by RFLP. Of 19 with LTBI, 13 refused isoniazid therapy or were non-compliant; and in three of these (23%), active TB developed within 2 years. Investigators speculated on the role of heavy alcohol use facilitating progression from infection to active disease as well as high infectivity of the index case as factors. The index case had alcohol and mental health problems that may have been barriers to healthcare, despite the close proximity of the bar to a health clinic. They commented also on the lack of intervention by bar patrons and workers despite his clearly worsening health yet eligibility for government programmes and healthcare. This report illustrates the role of a confined setting to amplify transmission of TB, the interaction among factors associated with risk of infection and progression to disease, the need to reconsider concentric circles traditionally defined for contact investigation, as ‘family’ and ‘neighbourhood’ may be redefined for some vulnerable populations, and the difficulty in contact tracing in a tight social network of alcohol and other substance abusers. By contrast, a report linking transmission by molecular typing in Texas demonstrated a wider and more difficult set of transmission dynamics.97 In this outbreak 48 persons were infected with the same strain, but few were linked to more than one or two other persons; virtually all men (40 of 43) and three of five women were regular customers of 17 small bars in a relatively small geographic area within walking distance of each other. More than two-thirds were HIV-positive, and the bars served as social gathering points, with their proximity allowing patrons to regularly bar-hop, an average of 3.5 bars per day (median 3.0). A large proportion had other risk factors, including injection and non-injection drug use and a history of jail or prison. A major outbreak of isoniazid-resistant TB in north London, England, demonstrated a similar phenomenon in a social group of young adults of mixed ethnic backgrounds, some with professional and business backgrounds and others with drug and prison detention histories.98 Investigators speculated that the 70 confirmed cases in this ongoing epidemic were linked by use of ‘soft drugs’ and involvement in music, bands, and concerts. Reports of further dissemination to over 260 cases, with emergence of MDR-TB, demonstrate the scope and unique characteristics of this outbreak.99 Use of DNA fingerprinting in the investigation was critical in identifying links in those who seemed
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unrelated. From each of the outbreaks of this kind, investigators called for non-traditional approaches such as location-based analyses and the study of social networks.100 Persons in social networks linked by drug use, or by sexual identification or characteristics sometimes marginalized by society, may be reluctant to provide useful information critical for investigation and management in an outbreak.101
AUTOMOBILES A relatively new confined space was identified as a factor in TB transmission related to illicit drug-related activities in Seattle, Washington.102 In a 3-month period matched M. tuberculosis isolates were recovered from four young East-African immigrants with histories of incarceration and illicit drug use. Eleven active cases were found through self-report and observation of a tight social network of marijuana users. Cases and close contacts, none of which were family, spent most of the days in closed cars and in a single-bedroom apartment. All cases reported ‘hotboxing’, the practice of smoking marijuana with others with the car windows closed so that exhaled smoke can be repeatedly inhaled. Boards were nailed over the windows of the apartment to conceal activities, limiting ventilation. Fourteen of 22 friends (64%) identified as close contacts and six of other contacts (23%) converted from negative to positive TST. The disease progressed rapidly in this social network, in which one was HIV-positive. This outbreak revealed that the confined space of an automobile with closed windows served as an amplifier for TB transmission related to drug use. The space was made more efficient for inhalation of drugs as well as airborne pathogens, and smoking marijuana may have increased coughing in those with active disease, thus facilitating the dissemination of droplet nuclei. Others have identified sharing a water pipe and ‘shotgunning’, inhaling smoke and exhaling it directly into another’s mouth, as similar practices associated with transmission, and the confined space plays an added role if this activity is done in closed spaces to conceal activities from view.103,104 As in the outbreaks related to pubs, the investigation of social networks was complex – made more so by illegal drug use by contacts. Special techniques for exploring transmission have been developed for these and other complex social networks.105
AEROPLANES AND OTHER LONG DISTANCE TRAVEL Because of high density and close proximity of persons, long-duration, increased travel to and from countries with high prevalence of TB, and increased mobility of people worldwide, airplanes have been considered a congregate setting for TB transmission. This has become a topic of concern to many travellers, and a source of fear as well as a marketplace for devices to provide travellers with their ‘own air’ during flight. Reviews of risks to passengers and crew for a number of infectious diseases, however, have found little research linking cabin air quality and ventilation rates to increased risk for TB as compared to other modes of transport or office buildings,106 but outbreaks have been reported. Examination of the inside of most standard aeroplanes demonstrated that most pressurized aircraft cabins allow ventilation and control of temperature, humidity and air flow: usually at a 4,0008000-foot altitude (for an aircraft flying at 30–40,000 feet), and 10–20% humidity, with temperatures 18–30 C.107 Air coming from the outside is essentially sterile and is usually mixed 50:50
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with recirculated air, then passed through high-efficiency particulate air (HEPA)-type filters, rated using 0.3 mm, similar to those used in hospitals. Ventilation systems in most aircraft are designed so that air entering the cabin at a given seat row (above) is exhausted at that same seat row (below), limiting the amount of air flowing forward and backward through the cabin. Cabin air is exchanged at least 20 times per hour, compared with 12 in a typical office building and five in most homes. Thus some have concluded that it is a common misconception that one infectious person increases the risk to all others on the plane.107 With air flowing from top to bottom and dilutions by frequent air exchanges, travellers most at risk are probably those in close proximity to the infectious person – highlighting the importance of the infectiousness of the passenger who is ill.107 However, there are no requirements for airlines to monitor cabin air quality, and therefore the few studies done cannot be generalized to the numerous aircraft and volume of air travel; but they suggest that air travel itself does not carry a greater risk of transmission than activities in other confined spaces. Transmission of MDR-TB was reported involving a highly infectious passenger who travelled on a commercial flight from Honolulu to Chicago and Chicago to Baltimore, with a return trip 1 month later.108 Using airline records, 1,042 passengers and crew were identified; 117 were not notified, being residents of other countries or not locatable. Of 925 found, 802 were evaluated. Forty-two contacts were excluded because of previous positive TST, death including one AIDS-related death with no clinical evidence of TB, and a contact with AIDS who was already receiving rifabutin prophylaxis and had negative smears and cultures. The investigation was complicated by characteristics common in air travel: passengers and crew with other risk factors for TB including birth or residence in countries with high rates of TB, history of BCG, exposure to TB in a family member, or occupational exposure. Of 760 contacts remaining for analysis, 15 had positive TST: six, including four who were determined to be conversions, had no other risk factors and all sat in the same section as the index case. Transmission was thought to occur only on one of the four legs of the case’s journey, possibly because the patient experienced increased symptoms during the season of this flight, as well as longer flight-time for that leg. Passengers seated within two rows of the case were 8.5 times as likely to have a positive TST compared to those in the rest of the section. This finding was confirmed in computer modelling, demonstrating that the TB transmission is most likely to occur within close proximity of the TB patient.109 Following this outbreak investigation, the authors, who were with the Centers for Disease Control and Prevention, indicated that unsolicited reports of passengers with TB, both known and unknown at the time of flights, occurred between July and December 1994.108 Taking into account underreporting, they concluded that passengers and crew have a relatively low risk of TB on commercial aircraft in the USA, and a report revealed additional information on five outbreaks: in one, transmission occurred from a flight attendant with active disease to other crew, and risk for transmission was more likely to occur when the flight time exposure was > 12 hours; in four others no evidence was available to confirm transmission.110–112 The combination of travellers and crew from highly endemic countries by either birth or current residence, delayed time to investigation, low response rates and difficulties in locating exposed persons, and the likelihood of boosted immune response from prior exposure complicated these and other investigations in New Zealand and Taiwan.113,114 No reported investigations of
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Tuberculosis outbreaks in confined situations
aircraft that revealed confirmed active TB in contacts exposed to cases on the flight were found. Findings related to length of exposure as a risk factor for transmission were in agreement with an investigation demonstrating no conversions in persons on two short flights (1.5 hours) following exposure to a highly infectious case.115 Likewise, no transmission occurred from a pilot with active TB, in investigation of 48 pilots exposed in 6 months flying with the active case.116 Although little is known about smaller or older aircraft with poor ventilation, flights within countries with high TB prevalence, or travel among persons with additional risk factors including HIV, the risk of transmission of TB in this confined setting is thought to be rare. And a report of multiple travel modes – passenger trains (29 hours) and buses (5.5 hours) over a 2-day period by a 22-year-old man with culturepositive TB – also revealed limited transmission. As with investigations of air travel, this investigation was made more difficult by problems with interpretation of positive TST – but among 240 completing screening, two converters with no other risk factor but exposure were found, and no new active cases of TB occurred,117 and authors concluded that transmission was possible but limited. Because of the concerns raised in the 1990s related to these investigations – in particular the transmission of MDR-TB108 – and increases in international air travel, the WHO provided revised International Health Regulations to promote early and prompt action and collaboration among countries to prevent transmission of TB as well as other dangerous pathogens.118 Travel by a US citizen initially diagnosed with XDR-TB between the USA and a number of countries prompted new fears and further discussion of collaboration between airlines, public health agencies, and government authorities.119 While countries have different requirements for immigrants, refugees and asylum seekers, and visitors, it is not possible to medically assess persons prior to flight and screening per se is not a requirement for air travel. Therefore the WHO guidelines summarize evidence to-date and provide guidance both to clinicians and to public health officials and airlines on issues related to travel, ventilation and recirculation of air while airborne and on the ground, and procedures for investigating potential outbreaks.118
CONCLUSIONS AND IMPLICATIONS Although much is known about the epidemiology of TB, many questions remain unanswered related to confined spaces and transmission in outbreaks. Molecular epidemiological methods have begun to provide insights into distinguishing between outbreaks and sporadic, epidemiologically unrelated cases.120 In low-resource, high-incidence countries, most cases of TB are not attributable to household contact but rather social or occasional contact. This finding has been demonstrated in traditional epidemiological studies as well as those using molecular methods, explained by the notion that many people exposed to a small risk can account for more disease than a few exposed to a large risk.121 As TB incidence decreases in a population, persons with active disease are concentrated in high-risk groups who share particular risk factors for disease, as seen in confined spaces such as prisons and homeless shelters and similar settings that seem focal points for TB in the USA. The traditional approaches to contact investigation have been useful in low-incidence countries but remain imprecise and likely to underestimate the level of transmission.122,123 Molecular techniques have changed our understanding of TB transmission, and
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these strategies should be expanded and enhanced, and made available to all. Molecular methods for evaluating contact investigations have shown that in a number of outbreaks, extensive transmission was associated with what would be considered casual contact, as seen in the outbreaks related to bar-hopping, pubs, and contact in automobiles. In others, not only was contact casual but also among persons with few of the traditional risk factors for TB. The imprecision of contact tracing alone may underestimate transmission among high-risk groups that are not epidemiologically linked using traditional methods.123 Rather, evidence of complex transmission patterns may reinforce the idea that non-traditional sites and social networks may actually become the ‘confined spaces’ of higher risk than household and living situation for some groups. In a neighbourhood with high rates of violence, drug use, and poverty – and associated high rates of HIV and TB – the household may be a fortress with boarded windows, and families reluctant to leave for safety reasons. In this case the household is indeed the confined space where transmission may be enhanced. In other circumstances, young adults with widely varying risk factors may spend time in confined spaces together, epidemiologically linked only by text messaging or social interests. In this case the household is not the innermost circle, and reluctance to reveal contacts or activities – especially if illegal or not widely accepted by society – will present barriers to investigation. And mobility of people who emigrate to new countries, whether to escape war or violence or for the promise of a new life, results in economic burdens. Family members may well hold more than one job, resulting in the workplace rather than the home as the site for transmission because of long hours of exposure, and barriers to investigation may include fear of deportation. From many of the outbreaks reviewed in this chapter, investigators called for non-traditional approaches such as location-based analyses and the study of complex social networks.100,105 Mathematical methods such as network analysis may prove useful in the prediction of likely transmission to prioritize for screening.124 Use of network visualization, where links between cases can be seen and the magnitude of an outbreak can be measured, may be useful in areas while awaiting results of DNA fingerprinting, and valuable as a tool for TB controllers in areas where typing is unavailable. In resource-poor countries some of the strategies of network visualization, such as pursuing and evaluating repeatedly named contacts, can become part of usual practices for TB programme workers; for those with computer access, free network software is available.124 Evaluation of this as a complement to contact investigation is under way.125 In this chapter, common themes in outbreaks related to confined spaces have emerged, and are well established: size, ventilation, and duration of exposure. The ingredients of an infectious case, combined with persons at risk, resulted in transmission in the closed environment; but in most cases the development of an outbreak was due to human error. In every setting, whether resource-rich or resourcelimited, failure to recognize an active TB case and failure to promptly or effectively initiate infection control practices have been consistently demonstrated in facilitating outbreaks. In resource-rich countries, a low index of suspicion is unacceptable, given the recent attention to TB and the emergence of MDR- and XDR-TB and the plethora of guidelines, training, and resources for TB diagnosis, management, and prevention. In resource-limited countries, clinicians are hampered from early diagnosis by limited or non-existent laboratory facilities and
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lack of isolation facilities, and high rates of both TB and HIV virtually assure continued transmission. Special attention must be paid by public health planners and healthcare providers to congregate settings that house or are frequented by persons with HIV who are at greatest risk for active TB. The WHO guidelines for recognition of TB suspects, and the recent International Standards for Tuberculosis Care (ISTC)
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77. Comstock GW. Epidemiology of tuberculosis. In: Reichman LB, Hershfield ES (eds) Tuberculosis: A Comprehensive International Approach, 2nd edn. New York: Marcel-Dekker, 2000. 78. Valin N, Antoun F, Chouaid C, et al. Outbreak of tuberculosis in a migrants’ shelter, Paris, France, 2002. Int J Tuberc Lung Dis 2005;9(5):528–533. 79. Centers for Disease Control and Prevention. Tuberculosis transmission in a homeless shelter population—New York, 2000-2003. MMWR Morb Mortal Wkly Rep 2005;54(6):149–152. 80. McElroy PD, Southwick KL, Fortenberry ER, et al. Outbreak of tuberculosis among homeless persons coinfected with human immunodeficiency virus. Clin Infect Dis 2003;36:1305–1312. 81. Miller AC, Butler WR, McInnis B, et al. Clonal relationships in a shelter-associated outbreak of drugresistant tuberculosis, 1983-1997. Int J Tuberc Lung Dis 2002;6(10):872–878. 82. Macaraig M, Agerton T, Driver CR, et al. Strainspecific differences in two large Mycobacterium tuberculosis genotype clusters in isolates collected from homeless patients in New York City from 2001 to 2004. J Clin Microbiol 2006;44(8):2890–2896. 83. Nardell E, McInnis B, Thomas B, et al. Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med 1984;315(25):1570–1575. 84. Lathan M, Mukasa LN, Hooper N, et al. Crossjurisdictional transmission of Mycobacterium tuberculosis in Maryland and Washington, DC, 1996-2000, linked to the homeless. Emerg Infect Dis 2002;8(11):1249–1251. 85. Lofy KH, McElroy PD, Lake L, et al. Outbreak of tuberculosis in a homeless population involving multiple sites of transmission. Int J Tuberc Lung Dis 2006;10(6):683–689. 86. Allos BM, Genshelmer KF, Bloch AB, et al. Management of an outbreak of tuberculosis in a small community. Ann Intern Med 1996;125:114–117. 87. Raffalli J, Sepkowitz KA, Armstrong D. Communitybased outbreaks of tuberculosis. Arch Intern Med 1996;156:1053–1060. 88. Phillips L, Carlile J, Smith D. Epidemiology of a tuberculosis outbreak in a rural Missouri high school. Pediatrics 2004;113(6):e514–e519. 89. Muecke C, Isler M, Menzies D, et al. The use of environmental factors as adjuncts to traditional tuberculosis contact investigation. Int J Tuberc Lung Dis 2006;10(5):530–535. 90. Stein-Zamir C, Volovik I, Rishpon S, et al. Tuberculosis outbreak among students in a boarding school. Eur Respir J 2006;28:986–991. 91. Dewan PK, Banouvong H, Abernethy N, et al. A tuberculosis outbreak in a private-home family child care center in San Francisco, 2002 to 2004. Pediatrics 2006;117(3):863–869. 92. Gaber KA, Maggs A, Thould G, et al. An outbreak of tuberculosis in the South West of England related to a public house. Primary Care Respir J 2005;14:51–55. 93. Vidal-Alaball J, Hayes S, Jones R. Tuberculosis outbreak linked to pubs in South Wales. Eurosurv 2006;11(9):7–9. 94. Diel R, Meywald-Walter K, Gottschalk R, et al. Ongoing outbreak of tuberculosis in a low-incidence community: a molecular-epidemiological evaluation. Int J Tuberc Lung Dis 2004;8(7):855–861. 95. Decarie D, Grenier J-L, Allard A. Outbreak of tuberculosis in the Laurentian region, 2005. Canad Communic Dis Rep 2006;32(19):1–3. 96. Kline SE, Hedemark LL, Davies SF. Outbreak of tuberculosis among regular patrons of a neighborhood bar. New Engl J Med 1995;333:222–227. 97. Yaganehdoost A, Graviss EA, Ross MW, et al. Complex transmission dynamics of clonally related virulent Mycobacterium tuberculosis associated with barhopping by predominantly human immunodeficiency virus-positive gay men. J Infect Dis 1999;180:1245–1251. 98. Ruddy MC, Davies AP, Yates MD, et al. Outbreak of isoniazid resistant tuberculosis in north London. Thorax 2004;59:279–285. 99. Maguire H, Ruddy M, Bothamley G, et al. Multidrug resistance emerging in North London outbreak. Thorax 2006;61:547–548.
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122. Taylor Z, Nolan CM, Blumberg HM; American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Controlling tuberculosis in the United States: recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep 2005; 54(RR-12):1–81.
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123. Mathema B, Kurepina NE, Bifani PJ, et al. Molecular epidemiology of tuberculosis: current insights. Clin Microbiol Rev 2006;19(4):658–685. 124. Andre M, Ijaz K, Tillinghast JD, et al. Transmission network analysis to complement routine tuberculosis contact investigations. Am J Public Health 2007; 97(3):470–477.
125. Centers for Disease Control and Prevention. Tuberculosis Epidemiologic Studies Consortium (TBESC). Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention. [online]. Accessed January 27, 2007. Available at: http://www.cdc.gov/tb/TBESC/ default.htm
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General management of tuberculosis in different clinical settings
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Mary E Edginton
INTRODUCTION A patient’s journey from the onset of symptoms through to successful completion of TB treatment is apparently simple. Diagnostic tests (despite techniques that are primitive and in desperate need of updating) and treatment (constrained by drugs that take a long time to overcome the bacilli) are effective and are described in detail elsewhere in this book. However, the reality of the journey to patient cure and disease control is that the road has many twists and turns, pitfalls and delays manifesting as difficult access to health facilities, severe illness that needs special care, social and cultural barriers, inappropriate or inadequate care from uninformed or unsupported or deficient numbers of health professionals, shortages of drugs due to inadequate ordering or deliveries, deficient budgets, and poor management. This chapter will describe what happens to patients with suspected TB, where they need to go, options for treatment, what the treatment process includes and situations that require special consideration. Much of the content has a sub-Saharan country perspective; details of practices will be different in many other countries and regions. However, the chapter tries to emphasize principles that should guide those working in TB control programmes.
INITIAL PRESENTATION AND DIAGNOSIS OF TUBERCULOSIS AT HEALTH FACILITIES Patients frequently present to health services when their disease is already at an advanced stage. Strategies to change this in high-incidence countries include community education and advocacy campaigns that aim to destigmatize TB and encourage early presentation for testing. Case finding may be passive (symptomatic patients present themselves at health facilities), but active case finding through house surveys, screening of contacts, and other methods is a more efficient way for identifying patients earlier.1 Innovative approaches to increasing global case detection of tuberculosis (FIDELIS) is a global initiative that seeks to discover best case detection practices. Funded projects seek to demonstrate cost-effective ways of increasing access to TB care in low-income countries.2 Patients who have symptoms present initially to one or more of several places including primary care clinics or health centres, private practitioners, hospitals, pharmacists, traditional practitioners, and prison health services. Figure 58.1 illustrates where patients might present and the referral paths between facilities. Among
the reasons for selection are culture, social pressures, accessibility, availability (open hours), affordability, and previous experiences. How a patient is then managed depends on the knowledge and skill of the healthcare provider, the condition of the patient, the availability of the necessary resources, and whether other ‘higher care’ facilities are available and willing to accept referral. In many areas sick people who are subsequently diagnosed with TB go first to a hospital. Reasons include patients’ beliefs that hospital care is better, that going to hospital ensures better confidentiality than attending a local clinic, and that test results are available sooner than at clinics. Many doctors and nurses working at primary care level have insecurities or other reasons for referring patients to hospitals in the mistaken belief that they cannot diagnose and manage TB. Uncomplicated pulmonary TB and some forms of extrapulmonary TB including pleural effusions and lymph node TB can be diagnosed at clinics and health centres with greater convenience for patients and less risk of spread of disease in busy hospitals. For sick patients with suspected TB who require hospitalization, some would argue that they should be referred directly to ‘suspect’ wards in special TB hospitals for investigation rather than to general hospitals where contact with many other patients results in spread of TB as well as adding to the burden of overcrowded general hospitals.
INFECTION CONTROL IN HEALTH FACILITIES Patients (especially adults) attending clinics or hospitals or admitted to general district, regional, or specialist hospitals should as far as possible be separated from other patients if there is a strong suspicion of pulmonary TB. The diagnosis should be made as rapidly as possible so that confirmed cases can be isolated from other patients. Basic infection control principles of good ventilation and frequent exchanges of air (minimum of 6–12 air changes per hour) must be implemented.3 Sputum collection for diagnosis should take place in defined, well-ventilated areas supervised by trained workers. It should take place in the open air with staff protected by wearing masks. Nosocomial spread of TB must account for a proportion of cases, particularly to susceptible patients within health facilities. The reported increase of TB in health workers also indicates risks and the need for more careful management of infectious cases in hospitals. A report from South Africa highlights the problem. A study of health workers at a number of hospitals in KwaZulu-Natal measured an incidence rate of 1,133 per 100,000.4
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CLINICAL MANAGEMENT OF TUBERCULOSIS Diagnosis Private doctor
Treatment
Clinic
Hospital
Clinic / health centre
TB hospital
Other facility Private practitioner Prison Hospice
Fig. 58.1 Facilities and referrals involved in the diagnosis and treatment of a patient with TB.
WHERE SHOULD PATIENTS WITH TUBERCULOSIS BE TREATED? Tuberculosis treatment takes many months and can be an arduous process for patients. Although there are many factors involved in successful treatment outcomes, there is evidence that patients’ attitudes and behaviours are determined by the information and education given initially at the place where the diagnosis is made.5 Previous recommendations that most patients with TB should be hospitalized were based on ensuring that medication was supervised and that the spread within communities was limited, at least once the diagnosis was made. A landmark controlled clinical trial in Madras in 1956 demonstrated that ambulatory treatment was highly effective, providing the evidence that universal sanatorium or TB hospital treatment was unnecessary.6 Ambulatory treatment, for those able to manage it, reduces the burden of prolonged hospitalization away from family and social networks and access to employment. In addition, for countries with high TB burdens hospitals were unable to manage the increasing numbers of TB patients and the costs of hospitalization. The South African policy changed to ambulatory treatment when short-course chemotherapy became widely available and used from the 1970s. In countries and areas where there are no specific TB hospitals, patients are admitted to general hospitals, preferably to wards in a separate section from other patients. The referral network that exists in many countries is illustrated in Fig. 58.1. Decentralization of TB services from hospitals to peripheral services has proved successful.7,8 District clinics are well equipped to manage patients with TB as part of the primary healthcare comprehensive package. The primary healthcare principles of accessibility and affordability are important for patients expected to attend regularly. The clinical condition of patients at the time of diagnosis usually determines where they should receive or access their initial TB treatment. Sometimes other factors play a part in the decision, which needs to be made by a team including the patient, the clinician, the family, and relevant others. The family may feel unable to manage the patient at home, the patient may have strong negative feelings about hospitalization, or there may be other compelling arguments.
REFERRAL OF PATIENTS BETWEEN FACILITIES If the place where patients can receive their treatment for TB is different from the place where the diagnosis was made, they need to be formally referred to the treatment facility. Hospitals or clinics would refer to the dedicated TB sections of clinics. Referral from
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hospitals has been identified as a weakness in many TB programmes.9,10 The process must ensure that patients know they have TB and that they understand the treatment process since their progress to cure depends on their adherence to a long treatment regimen. Patients need to be told exactly where to go and when, and the referral form must provide details about the patient and the disease so that these can be correctly entered into the clinic TB register and so the clinic nurse can implement the appropriate treatment regimen. Hospital staff often lack the time for proper patient education, may have language constraints, and lack knowledge about district facilities where patients must go. These problems often result in patients not arriving at clinics. A dedicated hospital TB centre should provide education and information to patients before discharge. Details of a successful process and results have been described.5 In smaller institutions, an individual can fulfil the role. The referral form recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Diseases has details of the patient (name, identity number if available, health facility number, age, gender, home, work, and nearest relative addresses), and how the TB was diagnosed and managed before referral. Patients may be referred as described from hospitals to clinics and from one clinic to another. The same process applies. The referral form in use in South Africa can be seen in Fig. 58.2. Wherever patients diagnosed with TB are managed, there is a basic set of standards to which providers must adhere. These are detailed in a recent document International Standards of Tuberculosis Care.11 A lesson from China, where large numbers of TB patients are managed with success in areas where the directly observed treatment, short-course (DOTS) strategy has been implemented, is a ‘system of TB institutions’ whereby TB guidelines are disseminated and implemented at all levels.9
CLINIC-BASED TREATMENT Patients able to manage ambulatory clinic-based treatment and who have the necessary support from family and friends are best referred to a health facility most convenient to them. The basic facility, variously called a clinic, health post, or health centre, is staffed by nurses and provides basic primary care (in some countries, including South Africa, a clinic is usually run by nurses, while a health centre is larger, has more resources, and usually has doctors as well). Referring staff need to know health facilities in the district in which they work as well as in neighbouring districts so that they can suggest and discuss facilities nearest to patients’ homes. Being sent to the ‘local’ clinic is not always helpful to patients. At the clinics details of each patient are entered into the TB register and the clinic takes responsibility for the duration of the treatment. Some patients prefer to attend another clinic for their treatment. This may be because another is more convenient, perhaps on a transport route, or because they do not wish to be seen attending their local clinic regularly. Such requests may conflict with the policy that patients should be registered at ‘their own’ clinics so they can be followed. However, if treatment adherence is at stake, some negotiated arrangement should be made to accommodate the patient’s wishes. Nurses in these primary care facilities are essential to good TB control programmes. They know their districts and the
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Fig. 58.2 Tuberculosis referral form.
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communities they serve and are thus ideally placed to understand local beliefs, family and social structures, health facilities, and infrastructures including roads, and communication and transport systems, all of which influence treatment adherence. However, it is unreasonable to expect nurses to manage all components of primary health care including TB unless they have regular in-service training, access to advice for clinical problems, and reliable deliveries of drugs and supplies. There must also be policies and resources for communication with other facilities for advice and support, and for patient referral, and there must be support visits from district and programme managers.
MANAGEMENT ISSUES AT CLINICS For patients known to have TB, district clinics usually have a defined service area. This helps to maintain the TB section as a priority within clinics, with trained experienced staff, systems for laboratory specimen collection, storage, and dispatch, with ‘fast tracking’ of patients who attend daily for directly observed treatment (DOT). It is important that TB patients are not stigmatized by insensitive labelling of the section, or inconvenienced by putting the section distant from the rest of the clinic. Clinic managers must be knowledgeable about the numbers of TB patients being cared for, about how TB is managed, and what resources (staff, drugs, stationery, and equipment) are needed. Staff must be trained in all the procedures including record keeping and should be transferred to other sections only after a minimum period. This provides consistency for patients and allows for the best use of skills and experience. Larger clinics and health centres may have doctors available either daily or at certain times. They too need updates on TB management, especially on difficult diagnoses and management of adverse drug reactions, so that such problems can be managed at clinic/ health centre level rather than being referred to hospitals. Consideration needs to be given to the place in clinics where TB patients are managed. In the past and even now in some clinics in both urban and rural settings, the TB section is relegated to a small room often without a telephone. The environment should be airy and comfortable for patients and staff, with facilities and materials for education about TB and related health problems. Care should be taken to prevent transmission of TB within clinic settings. The danger lies in undiagnosed cases rather than in those already on treatment. Patients become non-infectious within a few days of starting anti-TB therapy and are practically non-infectious after 14 days.12,13 Where climate and weather permit, waiting areas should be in an open area with a roof to protect them from the elements, while providing excellent ventilation.
PATIENT EDUCATION Wherever patients receive their TB treatment, they need education with regular reinforcement to encourage adherence. This may be given during individual counselling sessions with TB nurses and supplemented by group discussions during which audio-visual presentations are given. The necessary equipment and resources should be available in every clinic and hospital to provide messages that are locally applicable, understandable, feasible, and within patients’ social and cultural context. Education about TB should encompass a wider socioeconomic– political–cultural context than a purely biomedical perspective and aim to influence the patient and his or her family and community, as well as occupational groups, healthcare providers, and policy makers.14
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SUPPORT FOR PATIENTS ON TREATMENT How patients manage to take treatment for TB and the factors involved in their adherence is the subject of a number of studies and reviews detailed elsewhere. Access to healthcare and staff attitudes are crucial.15–17 DOT is a process for helping and supporting patients and making treatment accessible and acceptable. It means that the actual swallowing of the daily TB pills is watched over by an observer or supporter. (The term supervisor implies a more formal authoritarian process.) DOT is not used because patients are mistrusted, but as a support mechanism to help and encourage. Although initially claimed by WHO to be ‘the single most important development’ in TB control,18 there is evidence that self-administered treatment and DOT achieve equal success.19 Patients considered to be at high risk for non-adherence, including those being retreated, are in greater need of support; however, universal DOT may be unnecessary.20 The supporting person needs firstly to be acceptable to the patient – a trusted, kindly person – and secondly, accessible. It is not helpful to patients if they must take a taxi ride or a long walk to be supported! Patients able to attend a clinic every day can take their pills observed and supported by the clinic nurse. A supporter can, however, be anyone who fits the criteria of convenience and acceptability. The patient must be part of the decision-making process. The initial identification of and communication with a potential supporter by the clinic nurse can take time and needs to be a defined part of her job. Successful supporters include family members, friends, neighbours, teachers, community leaders, church members, traditional healers, employers, shop keepers, and trained community health workers. It has been shown that family members can be excellent supporters; they certainly are convenient to patients!21 How the supporter system operates varies in different places. The patient or the supporter may collect the supply of TB pills from the clinic; they may be kept by either. Some patients go to their supporters each day to take the pills, others are visited by the supporter. Exactly how the system operates is not important as long as the principles of mentorship and encouragement are maintained. The clinic nurse needs to explain to supporters what is expected of them and suggest how the system can work. They must record when pills are taken by ticking the patient TB card. Training courses are run for community health workers in some areas and provision is made in some for a token payment. Not all patients accept treatment support; their wishes must be respected.
CLINICAL MONITORING OF PATIENTS ON TREATMENT Patients on treatment at clinics should be seen regularly to discuss progress and any problems, for education and encouragement, to be weighed, and to check that the correct phase of the treatment regimen is being used. The frequency of this monitoring depends on a number of factors, especially the reliability of the patients in taking treatment and of supporters in reporting any problems, where the daily observed treatment occurs, and whether clinics are easily accessible to patients. In situations where a reliable supporter is responsible for ensuring daily treatment, monthly monitoring may be sufficient.
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RECORDING ATTENDANCES AND ACTION FOR NON-ATTENDERS
departments and facilities should be a priority for TB control programmes.
Systems for keeping records of TB patients must be used at clinics. Records must be organized so they are easily accessible (at some clinics patients find their own records) and so that problem patients are identified immediately for appropriate action. Problem cases are usually irregular or non-attenders, and the appropriate action is to look for them. The TB nurse or someone delegated to this job must go either on foot or using some means of transport dedicated to the TB section or available on request. This important task is frequently overlooked, with the reasons given being that there is no time to leave the busy clinic, there are no vehicles, it is unsafe, or patients often leave their given addresses (or give incomplete or incorrect addresses). Whatever the reasons, solutions must be found with the help of clinic and district managers. Reducing the proportion of treatment interrupters would significantly increase cure rates in many districts.
Patient cards At the time of registration, every patient is issued with a patient TB card, which acts as a TB ‘passport’ with all the information required should a patient attend a facility other than the usual one.
REGISTRATION AND CARDS
Clinic cards Patient information in the same format as in the register and in the patient card is recorded on a clinic-based card for each patient. This includes clinical progress notes. Notification In many countries TB is a notifiable disease and details of patients are required for local and national surveillance. Before the introduction of TB-specific records, this was the only means of measuring numbers and trends in TB, and the only information available for following patients to their homes to identify risk situations and other suspected TB cases. Although still used, the notification system will probably become redundant with the use of more detailed TB registration systems.
A TB register and clinic card format are shown in Fig. 58.3.
TB registers All TB patients must be registered in a national recording system for TB using internationally recommended principles.22 Country details may vary. Registers are kept at health facilities responsible for patients’ treatment and outcomes. In South Africa that means at clinics, health centres, and TB hospitals. The two main sections of the register are ‘Case-finding’ where demographic and diagnostic details are recorded and ‘Treatment outcome’ where the results of treatment are noted. In addition the results of bacteriological monitoring during treatment are recorded. Register details are referred as quarterly reports to districts where data are checked, reported locally, submitted to provincial and/or national TB offices for collation and reporting, thence to the WHO. Some countries including South Africa have computerized their TB registers, which allows data checks and easier and more efficient analysis. There are six possible treatment outcomes for smear-positive patients, as listed and defined in Box 58.1. A particular challenge for health workers is patients who move to different areas or across country borders in search of work or places to live. This is well known in many southern African countries and is also reported as a particular problem in China, where TB patients in ‘floating populations’ are difficult to manage.23 Transfer rates of TB patients in the 22 high-burden countries in 2003 ranged from less than 1% (India and China) to 7% (South Africa) and 10% (Zimbabwe).24 Solutions need to focus on developing patients’ trust and encouraging them to inform the clinic where they are registered of intended moves so that they can be formally transferred and followed up. Some patients disappear without notice. Collecting all possible current and other addresses of patients and their families at the time they are registered would help. Those who move to known destinations need to be referred, but this requires resources for communicating with other clinics, particularly in other districts, provinces, or countries. Systems for notifying health authorities and facility staff about patients who translocate (or who fail to attend) need urgent attention from TB programme managers. Electronic systems, telephones, or faxes must be available at some level in the service. Better cooperation and coordination between health
DRUG SUPPLIES Tuberculosis patients frequently make significant sacrifices to attend health facilities to collect treatment. If the standard TB drugs are not available, this is a very serious reflection on the drug management system. It may result from poor calculations and ordering by facilities, problems with delivery, insufficient stock at district or other level depots, bad ordering from manufacturers, or delay in production. Delays and confusions about national or provincial tendering, for countries where this is used, or problems with the global drug supply system can also affect constant supplies of TB drugs on the shelves of facilities. Effective TB control programmes depend on many individuals ensuring that processes and systems related to drug supplies work and are routinely monitored. The Stop TB strategy, recognizing the importance of sustainable drug supplies for TB treatment, includes this as a key element.25 Nonavailability of drugs has been shown to affect health-seeking behaviour.26
BACTERIOLOGICAL MONITORING Patients with pulmonary TB need to have regular sputum microscopy (two specimens) checks at internationally recommended time points in the treatment.22 These are after 2 months of treatment and at the end (6 months for new patients or 8 months for those on re-treatment). There are standardized responses to positive microscopy at either of these times.
Two months The rationale for sputum testing after 2 months of treatment is explained and justified as an important tool for deciding whether the intensive phase of treatment requires extending and for monitoring the quality of patient follow-up.27 If positive at 2 months, the intensive phase of treatment is continued and another sputum check done at 3 months. If this is negative the continuation phase should be started and given for 4 months (total treatment duration of 7 months). If the 2-month specimen is positive, a sputum specimen must be sent for TB culture and drug susceptibility testing. Until results are available, the continuation phase is started.
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Fig. 58.3 (A) Tuberculosis register.
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Continued
Fig. 58.3—cont’d (B) Tuberculosis register.
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Fig. 58.3—cont’d (B) Clinic card—front page (of 4 pages).
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Box 58.1 Treatment outcome definitions Cured
Completed Interrupted Failed Died Transferred out
Initial smear-positive patients who convert to negative in the last month of treatment and on at least one previous occasion. Patients who complete treatment but do not meet the criteria to be classified as cure or failure. Patients whose treatment was interrupted for 2 consecutive months or more. Patients who remain smear-positive at 5 months or later during treatment. Patients who die for any reason during the course of treatment. Patients who are transferred to another recording unit and for whom the treatment outcome is not known.
End of treatment If the sputum is positive at the end of treatment, the outcome is defined as ‘failed’ treatment, a specimen is sent for TB culture and drug susceptibility testing, and the re-treatment regimen is started. Such patients should be watched carefully until results are available; if drug-resistant TB is suspected, they should be admitted to a designated section of a TB or general hospital. If resistant TB is confirmed, they should be transferred to a hospital or section for that type of TB. MANAGEMENT OF LABORATORY SPECIMENS The process of taking and sending sputa and other specimens to a laboratory and receiving results back is critical to successful diagnosis and bacteriological monitoring of patients. Good specimens are obtained by educating patients how to cough. In some hospitals physiotherapists may be available to assist. The procedure is hazardous to whoever supervises unless they are trained in safe techniques and unless they wear appropriate masks (N95 masks, not paper surgical masks). Specimens should be collected outside buildings wherever possible, or at least in defined places where there is good ventilation and a time lapse of 5 minutes before another patient enter the same room. The health worker should explain to the patient what to do, then stand behind the patient and supervise, and when sputum is obtained, close the container properly. The habit in some health facilities of sending patients to an area, often a toilet, to produce the specimen is not always effective and usually dangerous in terms of aerosols of organisms being released into confined spaces where they can spread to other patients and to staff who enter these confined, often poorly ventilated spaces soon thereafter. If microscopy services are not available at facilities where patients are seen, systems must be arranged for the transport of specimens and delivery of results as soon as possible. The ‘turn-around-time’, defined as the time from the production of the sputum specimen from a patient to the delivery of microscopy results back to the sending facility, should be within 48 hours according to South African policy guidelines.28 This is not achieved in many urban subdistricts, and probably rarely at rural clinics.29 Options for specimen transport in practice include dedicated laboratory couriers, local taxi or bus drivers, and staff visiting clinics for various purposes. Results can be faxed, sent as SMS (cellular phone) messages, or delivered by the means the specimen was collected from the clinic.
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Delays in results being available at clinics may well be a reason for patients to seek help from persons and places other than health services. Many argue that decentralized microscopy services at clinics, especially where large numbers of patients are cared for, are essential.
HOSPITAL-BASED TREATMENT Some countries have hospitals specifically for patients with TB. Others use wards in general hospitals. Increasing proportions of patients with TB and acquired immunodeficiency syndrome (AIDS) are too sick, at least initially, to cope with ambulatory treatment and thus require hospitalization. Admission and discharge criteria are used to guide health workers about who should be admitted and when discharge is appropriate (Box 58.2). Apart from the clinical condition, admission may be necessary for those on retreatment or drug-resistant regimens who require daily injectable drugs, those who live in remote areas without access to clinics, those who have previously interrupted treatment and are identified as ‘high risk’ for treatment non-adherence, and those where social situations are deemed unsuitable for home-based treatment (alcohol abusers, disruptive families, etc.).28 Children with disseminated disease such as TB meningitis or miliary TB, with extensive or complicated disease, or who have social circumstances that will most likely lead to poor treatment adherence are also often admitted. Sick patients admitted to TB hospitals benefit from treatment, good diet, and rest. Those who are eligible should receive antiretroviral treatment. The period in hospital provides good opportunities for education about TB and the treatment. Social workers should be available to discuss social and financial issues as needed. In South Africa, TB hospitals maintain TB registers. On discharge patients are referred to clinics convenient to where they will live, with TB registers reflecting transfer or move (to facilities in a different or the same district, respectively). See earlier section Registration and cards.
PRIVATE PRACTITIONERS AND TUBERCULOSIS TREATMENT In many countries a large proportion of the population seek healthcare from private practitioners. In India, about 50% of private doctors treat patients with TB.30 In Kenya one-third of health facilities
Box 58.2 Criteria for admission and discharge of patients Criteria for admission Medical reasons
Social reasons
Criteria for discharge Patients should be
Patients too ill or weak to go home Re-treatment and/or drug-resistant TB patients requiring injectable drugs that cannot be managed at a clinic. High-risk groups including alcohol or drug dependence, patients with mental disorders, previous interrupters. Medically fit Able to access treatment from a clinic
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are private although the proportion of TB patients managed privately is unknown. About one-third of all people with symptoms of TB consulted private practitioners in the Philippines, while in Bangladesh informal private practitioners provide most of the care for the rural population, which accounts for 75% of the total.31 In South Africa, as in many other high-TB-burden countries, national figures of patients diagnosed or treated in the private sector are not known, but private doctors are widely consulted. Reasons for seeking private care are important to consider as they probably indicate undesirable characteristics in the public sector health services. They include easier accessibility, more convenient opening times, shorter waiting periods, availability of doctors and drugs, staff with acceptable attitudes, good continuity of care, and better confidentiality.32 The long queues of overcrowded public facilities with fixed open hours, staffed by overburdened nurses working under difficult conditions, often without the support of doctors and where drug supplies are erratic, contrast starkly with situations at most private practices. However, there are reports of private practitioners deviating from internationally recommended practices, where diagnoses are inadequate and delayed, patients with TB under-reported, nonrecommended drug regimens used, and treatment adherence is unmonitored and non-attenders not followed up.33 Negative feelings about fee for service and costs to poor patients further aggravate TB programme staff. In some countries the suspicion and mistrust emanate from government departments and reflect in lack of any collaborative activities. Private providers have doubts about public service competence and ability and some lack knowledge about evidence-based internationally recommended TB programme components. Neither public nor private groups have a complete understanding of each other, nor of the potential strengths or opportunities for collaboration, nor consider the negative effects on TB control of failure to work together. TB patients suffer from poor management and incur costs for their care that they can ill afford. If private doctors would diagnose TB using recommended tests and provide anti-TB drugs for these and other patients referred to them, monitor progress, register and record outcomes, and provide all data to TB programme centres, they could be an important part of national TB programmes. Patients unable to afford extra costs should not have to pay more than they would at public health facilities. This ideal model is the extreme end of a range of possible roles for private practitioners in TB management. There are many variations that may be more feasible and acceptable to all. Initial registration and final recording of treatment outcomes could remain the responsibility of the public TB programme, initial diagnosis could be made at public facilities (or the cost reimbursed by the TB programme), drugs could be provided free or at subsidized rates, private doctors could support patients (DOT), and TB clinics could take responsibility for tracing non-attending patients. Collaboration between public and private TB services (referred to as the public–private mix (PPM)) aims at optimizing patient care in TB with applications for other health problems as well. Tuberculosis programme staff and private healthcare organizations and individuals need to discuss options that improve the standard of care of patients. A review of practices of several countries describes a range of successful practices which includes joint training on TB management and subsidized drugs for private doctors who comply with national TB guidelines (Kenya, Philippines, and DR Congo), and patients referred to public hospitals for diagnosis, referred back to
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private facilities for supervised treatment with drugs provided by the TB programme (India). A way of avoiding exploitation of drugs is described from areas in India where programme staff provide private doctors with treatment boxes containing a full course of TB drugs for each patient, with agreements that ensure supported treatment without cost to patients. Rewards for private doctors, apart from the satisfaction of contributing to the control of a major health problem, are establishing relationships with patients and their families, making it likely that they will return for other health needs.34 A regular supply of whatever practical tools are required (agreements, recording and referral stationery, and drugs) is essential for successful collaborations. A WHO publication on PPM highlights recent efforts to establish collaborations.31 The successes and cost savings to both patients and TB programme in India by cross-referrals of patients have been replicated in other areas. Another example is collaboration between the TB programme and chest physicians in Kenya. Courses on the TB control programme are offered for private practitioners and they can access TB drugs at subsidized rates. The TB register has a column to reflect whether a referral was from a private doctor so that this contribution can be measured. An active PPM is seen in the Philippines where TB control efforts are coordinated by a national group consisting of all stake holders (PhilCAT). The important role of the private village doctors in Bangladesh has been improved by training, supplies of simple enabling equipment, and recognition and encouragement from the TB programme. In South Africa and elsewhere, a weakness in the system of diagnosis by private doctors is that patients must pay for their microscopy tests. If they are unable to afford these, the diagnosis may be delayed. Consideration must be given and operational research done to see whether the costs of diagnostic tests could be paid by the public service. Priorities in PPM are training for programme staff about PPM, certification of trained and approved care providers, consideration of incentives, development of surveillance and monitoring systems for data collection by private practitioners to send to TB programme staff, and provision of free TB drugs for patients treated by private doctors.33 A simple level of involvement by private practitioners or their staff is support for patients on TB treatment. This requires organization and monitoring by the responsible clinic. The management of patients with TB must remain the overall responsibility of public sector TB programme staff, who must remain responsible for ensuring high-quality care in all sectors.35
SPECIAL SITUATIONS IN TUBERCULOSIS MANAGEMENT HIV-INFECTED PATIENTS Tuberculosis and human immunodeficiency virus (HIV) are intimately associated and thus require an integrated approach from health services.36 All the interventions for HIV-infected people need to be integrated into a combined TB/HIV programme delivered at facilities convenient to patients, preferably by the same or closely connected staff.
Antiretroviral treatment (ART) Tuberculosis services are an important entry point for identifying ART-eligible patients. This has been shown from estimates in
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18 sub-Saharan countries that between 2% and 18% of HIVinfected patients with TB are in this category.37 Tuberculosis patients with HIV infection who fit eligibility criteria for ART should receive this, preferably from the same facility as from where the TB service and medication are provided. A useful contribution with practical suggestions highlights how facilities can be organized to facilitate TB treatment and ART.38 Tuberculosis and HIV details should both be entered on the TB register and cards and not kept in separate records, HIV testing should be done at the time TB is diagnosed and registered (in case patients cannot wait for yet another service to which they are referred from the TB clinic), and cotrimoxazole must be made available for long term use, not only for the duration of TB treatment. In most situations, ART and TB treatment cannot be issued from the same clinic because ART may not be issued by health assistants (or in South Africa by staff of non-accredited facilities). To facilitate easy access to both TB drugs and ART, either an ART clinician should be part of the TB consultation to provide the ART service or the TB staff member should join the ART clinic to manage the TB aspects.
Prevention of tuberculosis in HIV-infected persons People with HIV infection are at increased risk of developing TB disease. HIV-infected persons must be protected from exposure to TB as far as possible, with special care needed in health facilities especially hospitals. Tuberculosis suspects and diagnosed TB patients should be managed in separate places as far as possible and environmental controls including good ventilation must be in place. The recommended specific TB preventive strategy for HIVinfected persons is isoniazid (INH) for at least 6 months.39,40 The following conditions are recommended: active TB disease has been excluded; the tuberculin skin test is positive; and the person is willing to take the full course of the drug, has not had a course of TB treatment within the previous 2 years, and does not have active liver disease. Prevention of other infections in HIV-infected tuberculosis patients Opportunistic diseases other than TB can be prevented in people infected with HIV. Cotrimoxizole prevents Pneumocystis jiroveci pneumonia and several other infections and should be prescribed for people with WHO stage 3 HIV disease, which includes those with TB. DRUG-RESISTANT TUBERCULOSIS Patient with multidrug-resistant (MDR) and extensively drugresistant (XDR) TB require management according to set principles as detailed in a WHO document.41 There should be accurate and timely diagnosis of suspected drug-resistant TB by qualitycontrolled laboratories and appropriate second-line treatment. Some countries use standardized regimens, others individualized drugs according to drug susceptibility results. Regular supplies of second-line drugs must be assured. For countries unable to afford the necessary expensive drugs, a WHO Green Light Committee can provide these at concession prices. There should be a specific recording and reporting system and integration of MDR-TB management into the national TB programme. Multidisciplinary teams are necessary to manage the complex medical and social issues presented by drug resistance and by confinement for periods in hospital. Attention to patient comfort is essential; basic and other necessities and recreational resources and activities must be supplied.
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The decision about where to treat these patients should be made according to infectiousness to contacts and the need for isolation, the need for strict adherence to drugs and to monitor storage and use of the drugs, and according to patients’ clinical conditions including adverse drug reactions. Many countries including South Africa have a policy of managing patients in specific hospitals for drug-resistant TB at least until two TB cultures at monthly intervals are negative. Once discharged, each patient then receives drugs from the nearest clinic, packed and dispatched individually for that patient. At regular intervals they return to the MDR-TB hospital for monitoring. Follow-up of non-attenders is part of the policy, and should be a collaborative role of the district health service and the MDR-TB hospital.1,51
POVERTY, GRANTS, AND FOOD SUPPLEMENTS Most of the world’s high-burden TB countries are poor by World Bank standards and TB patients are frequently malnourished and unemployed. The associations between poverty, TB disease, and non-adherence to TB treatment are well known. Poor nutrition is both a contributing factor to TB, as situations of poverty, unemployment, and destitution contribute to its development, and a consequence of TB, especially in those who have had untreated disease for a period of time. A case-control study in China demonstrated the poverty disease association, and in addition that accessing treatment actually caused poverty because costs were incurred.43 Lack of money for food and other basic needs for themselves and their families can result in delayed presentation to health services and patients taking irregular treatment. Tuberculosis patients in Nepal who lacked money were significantly more likely to interrupt their treatment.44 Approaches to poverty require a comprehensive global commitment to reversing the world’s economic imbalances. A WHO review focuses on the need to identify poor and vulnerable groups and their particular constraints in accessing care, so that solutions can be developed and necessary resources made available.45 Many would argue that the groups and their problems are well known. Practical needs encountered by those who care for TB patients are money and food.
Disability grants Applications for financial payments for disabled patients need a medical certificate that describes the health problem. These can be organized with the help of social workers. A grant is worthwhile if it could be organized within weeks rather than months, if it improves the quantity and quality of food and other basic needs of the patient, and as long as receiving extra funds is not seen by the patient as a reason not to take TB treatment so that he or she remains sick and qualifies for the grant for longer. Patients who have lost a good proportion of their lungs, usually due to long-standing poorly treated TB, would definitely be eligible for disability grants. Many health workers are reticent to apply routinely for grants for a disease that can be cured. Food supplements Food parcels provided to TB patients undoubtedly help them. In many situations there have been problems with their provision (government health services, especially those of poor countries, who have the greatest needs, do not usually include these in their budgets), with storage (problems of community or even staff theft) or with equitable distribution to those in greatest need. In povertystricken communities food parcels may be used by entire families, with minimal impact on the patients for whom they were intended.
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None of these problems should prevent TB programme staff and the wider community from organizing the availability of basic necessities for TB patients. It needs to be a defined strategy within TB programmes rather than isolated charitable gestures. Nongovernment organizations with capacities for fund raising have an important role to play in organizing food parcels for TB patients. The South African National Tuberculosis Association (SANTA) supplies nutritious supplements to TB clinics for clinic staff to distribute appropriately. However, the need is always greater than the supply.
WORKING PATIENTS There is no reason why people who have TB who feel able to work should not be employed. Negative attitudes of employers are largely based on the fear of spread of disease within the workplace. The danger of spread is from patients not yet identified and not on treatment. Once on treatment, the majority of patients become smear-negative within 2 weeks or less.12,13 Information about this has changed attitudes of many employers, some of whom are actively involved in facilitating treatment or supporting workers who have TB. Education is still needed for those who dismiss staff when they hear they have TB. There are different options for ensuring that workers can get TB treatment. There are many examples of clinics within inner cities and main centres that open very early so that patients can collect and take their pills on the way to work. Some work places have an occupational health service where responsibility will be taken for ensuring that employees with TB are cared for. Another option is a supporter at work (a colleague, supervisor, human resources manager, or other) who stores the TB pills, observes the swallowing, and maintains the patient card record. Wherever and however patients get and take their treatment, it is usually best for each to be registered at the district clinic nearest to their home. This facilitates any necessary follow-up, as well as visits and checks to close family contacts, particularly young children. The clinic TB nurse should communicate regularly with whoever is looking after the patient at work, and must see the patient during and at the end of treatment to do required bacteriological checks for those with pulmonary TB, and to record treatment outcomes. A WHO document describes employers’ roles in identifying TB suspects among workers, referring them for diagnosis, and helping them to complete treatment.46
PRISONERS Prisoners with TB pose particular problems. The overcrowding and inadequate ventilation found in many prisons provide the conditions in which TB spreads and progresses, especially in the malnourished, immune-compromised, and substance abusers. It is estimated that there are more than 10 million prisoners on any given day world-wide. Three countries reported very high rates of prisoners per 100,000 population – Russia 690, USA 668, and South Africa 327. There are limited data on the rates of TB among prisoners, but where these are available they are much higher than in the rest of the population (100 times in Brazil and Spain, 40 times in Rwanda and Georgia, an ex-USSR state). HIV rates are very high where they are known.47 Prison health services must manage numbers of sick inmates, which can delay identification of cases and constrain effective
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monitoring of treatment. Prisons can act as reservoirs of TB for inmates and staff and for communities into which prisoners may be released.48 TB control in prisoners relies on the universal principles of any TB control programme (early diagnosis and effective treatment). Respect for the rights of prisoners, improvement in prison conditions, and provision of high-standard health services are the focus of penal reform in many countries.47 Health providers need to coordinate services with those outside prisons, particularly when prisoners are released and need to be referred to a clinic for further treatment. This is difficult for those who do not have a fixed address (a risk factor for this population) and who may have lost contact with family and friends who might support them. Suggested strategies for addressing problems are integrating prison and civilian TB services and using opportunities for health promotion and healthcare to a confined group.47 In many situations there are great needs for better facilities and more prison health service staff.
MOBILE PEOPLE Mobile people may be those whose jobs take them away from home regularly, those who move around seeking employment, and those who are displaced from their homes because of natural or unnatural events. ‘Floating populations’, a term used to describe such groups, need cooperation between health facilities (as discussed earlier under Registration and cards).23 Patients should be informed and educated that they should advise the clinic where they are registered if they intend to move so they can be transferred with enough treatment until they reach another clinic. For those displaced under emergency situations, it is important to identify them in disaster areas and refugee camps and try to ensure continuity of treatment.
HOSPICE CARE Very ill patients requiring palliative care that cannot be provided by families should be managed in a hospice. Such institutions are scare and usually dependent on donations. Staff, although dedicated, may lack skills and resources to manage the clinical needs of terminally ill patients with AIDS, which patients nearly always have TB. Tuberculosis and appropriate HIV care must be organized for those patients.
CONTACTS OF TUBERCULOSIS PATIENTS All close contacts of persons with TB, particularly pulmonary TB, are at risk of TB infection and disease. Close contacts are members of the same household, people who share accommodation as in hostels and dormitories, close work colleagues, and any people who are regularly close to those with infectious TB. The most vulnerable populations of close contacts are children under the age of 5 years because their immune systems are not yet fully developed, and immune-compromised patients. An essential role of staff responsible for TB patient care is the follow-up and management of child contacts under the age of 5 years. The burden of patients attending clinics often means that this is neglected. The most important way for preventing the spread of TB to contacts is to treat patients with active pulmonary disease. However, contact infection may already have occurred by the time patients are diagnosed, making contact management necessary. Tuberculosis preventive treatment of HIV-infected people has been outlined earlier in the chapter. All children under the age of
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General management of tuberculosis in different clinical settings
5 years should be assessed and, if clinically ill, TB must be excluded or, if diagnosed, treated. Those without signs or symptoms should be given prophylactic INH for 6 months.49,50 The TB programme staff at district level need to determine ways of including this strategy in their work. Children on prophylactic treatment are not registered as TB patients; there needs to be a separate register so that attendance and outcomes can be monitored. Child contacts of known cases of MDR-TB should be investigated in a similar way and followed for a period of at least 2 years. Prophylactic INH is unlikely to have any effect.
REFERENCES 1. Golub JE, Mohan CI, Comstock GW, et al. Active case finding of tuberculosis: historical perspective and future prospects. Int J Tuberc Lung Dis 2005;9: 1183–1203. 2. Rusen ID, Enarson DA. FIDELIS Innovative approaches to increasing global case detection of tuberculosis. Am J Public Health 2006;96:14–16. 3. Jensen PA, Lamber LA, Iademarco MF, et al. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep 2005;54(17):1–141. 4. Naidoo S, Jinabhai CC. TB[IT 2] in health care workers in KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2006;10:676–682. 5. Edginton ME, Wong ML, Hodkinson HJ. Tuberculosis at Chris Hani Baragwanath hospital: an intervention to improve patient referrals to district clinics. Int J Tuberc Lung Dis 2006;10:1018–1022. 6. Anon. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21:51– 145. 7. Nyirenda TE, Harries AD, Gausi F, et al. Decentralisation of tuberculosis services in an urban setting, Lilongwe, Malawi. Int J Tuberc Lung Dis 2003;7(Suppl 1):S21–28. 8. Edginton ME. Tuberculosis patient care decentralized to district clinics with community-based directly observed treatment in a rural district of South Africa. Int J Tuberc Lung Dis 1999;3:445–450. 9. Xianyi C, Fengzeng Z, Hongjin D, et al. The DOTS strategy in China: results and lessons after 10 years. Bull World Health Organ 2002;80:430–436. 10. Edginton ME, Wong ML, Phofa R, et al. Tuberculosis at Chris Hani Baragwanath hospital: numbers of patients diagnosed and outcomes of referrals to district clinics. Int J Tuberc Lung Dis 2005;9:398–402. 11. Tuberculosis Coalition for Technical Assistance. International Standards of Tuberculosis Care (ISTC). The Hague: Tuberculosis Coalition for Technical Assistance, 2006. 12. Jindani A, Aber VR, Edwards EA, et al. The early bacteriocidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980;121:939–949. 13. American Thoracic Society. Control of tuberculosis in the United States. Am Rev Respir Dis 1992; 146:1623–1633. 14. Narayan T, Narayan R. Educational approaches in tuberculosis control: building on the ‘social’ paradigm. In: Porter JDH, Grange JM (eds). Tuberculosis: An Interdisciplinary Perspective. London: Imperial College Press, 1999: 489–509. 15. Sumartojo E. When tuberculosis treatment fails: a social behavioral account of patient adherence. Am Rev Respir Dis 1993;147:1311–1320. 16. Rubel AJ, Garro LC. Social and cultural factors in the successful control of tuberculosis. Public Health Rep 1992;107:626–636. 17. Lerner BL. From careless consumptives to recalcitrant patients: the historical construction of noncompliance. Soc Sci Med 1997;45:1423–1431.
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Close contacts over the age of 5 years should be advised to have checks at health facilities if they develop symptoms suggestive of TB. Tuberculosis staff in countries of high TB prevalence rarely have the time and resources to visit homes and work places of all patients to screen contacts for possible active TB disease. Patients are usually asked to advise adult and older children contacts who have symptoms suggestive of TB to go to a health facility to be checked. The messages are usually given to the TB patients to take home. More active case finding of contacts may be a cost-effective option for identifying people with TB.1,51
18. World Health Organization. Breakthrough in TB control announced by WHO (WHO/23). Geneva: World Health Organization, 19 March 1997. 19. Volminck J, Garner P. Directly observed therapy for treatment of tuberculosis. Cochrane Database Syst Rev 2006;2:CD003343. 20. Kironde S, Meintjies M. Tuberculosis treatment delivery in high burden setting: does patient choice of supervision matter? Int J Tuberc Lung Dis 2002;6:599– 608. 21. Newell JN, Baral SC, Pande SB, et al. Familymember DOTS and community DOTS for tuberculosis control in Nepal: cluster-randomised controlled trial. Lancet 2006;367:903–909. 22. Enarson DA, Rieder HL, Arnadottir T, et al. Management of Tuberculosis: A Guide for Low Income Countries, 5th edn. Paris: International Union against Tuberculosis and Lung Disease, 2000. 23. Tang S, Squire SB. What lessons can be drawn from tuberculosis control in China in the 1990s? An analysis from a health system perspective. Health Policy 2005;72:93–104. 24. World Health Organization. Global tuberculosis control: surveillance, planning, financing (WHO/ HTM/TB/2006.362). Geneva: World Health Organization, 2006. 25. World Health Organization. The global plan to stop TB 2006–2015 (WHO/HTM/STB/2006.35). Geneva: World Health Organization, 2006. 26. Baltussen R, Ye Y. Quality of care of modern health services as perceived by users and non-users in Burkina Faso. Int J Qual Health Care 2006;18:30–34. 27. Trebucq A, Rieder HL. Two excellent management tools for national tuberculosis programmes: history of prior treatment and sputum status at two months. Int J Tuberc Lung Dis 1998;2:184–186. 28. Department of Health, South Africa. The South Africa national tuberculosis control programme: practical guidelines. Department of Health, Pretoria, South Africa, 2004 (unpublished). 29. Edginton ME, Barnard A. A study of TB microscopy turn-around times at clinics and laboratories in the city of Johannesburg. Unpublished report, 2007. 30. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912–916. 31. World Health Organization. Engaging all health care providers in TB control: guidance on implementing public–private mix approaches (WHO/HTM/TB/ 2006.360). Geneva: World Health Organization, 2006. 32. Brugha R, Zwi AB. Tuberculosis treatment in the public and private sectors—potential for collaboration. In: Porter JDH, Grange JM (eds). Tuberculosis: An Interdisciplinary Perspective. London: Imperial College Press, 1999: 167–192. 33. Lonnroth K, Uplekar M, Arora VK, et al. Public– private mix for DOTS implementation: what makes it work? Bull World Health Organ 2004;82:580–586. 34. Uplekar M. Involving private health care providers in delivery of TB care: global strategy. Tuberculosis 2003;83:156–164. 35. Frieden T. How can public and private sectors cooperate to detect, treat, and monitor tuberculosis cases? In: Frieden T (ed.). Toman’s Tuberculosis Case Detection, Treatment and Monitoring, 2nd edn. Geneva: World Health Organization, 2004: 92–95.
36. World Health Organization. Guidelines for implementing collaborative TB and HIV programme activities (WHO/CDS/TB/2003.319 and WHO/ HIV/2003.01). Geneva: World Health Organization, 2003. 37. Bwire R, Nagelkerke NJ, Borgdorff MW. Finding patient eligible for antiretroviral therapy using TB services as entry point for HIV treatment. Trop Med Int Health 2006;11:1567–1575. 38. Harries AD, Boxshall M, Phiri S, et al. Providing HIV care for tuberculosis patients in sub-Saharan Africa. Int J Tuberc Lung Dis 2006;10:1306–1311. 39. World Health Organization. Annex 2. Essential antituberculosis drugs. In: Treatment of Tuberculosis: Guidelines for National Programmes (WHO/CDS/TB/ 2003.313), 3rd edn. Geneva: World Health Organization, 2003. 40. World Health Organization. Preventive therapy against tuberculosis in people living with HIV: policy statement. Wkly Epidemiol Rec 1999;74:385–398. 41. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis (WHO/HTM/TB/2006.361). Geneva: World Health Organization, 2006. 42. Department of Health and Medical Research Council, Republic of South Africa. DOTS-Plus for standardised management of multidrug-resistant tuberculosis in South Africa. Pretoria, South Africa, 2004. 43. Jackson S, Sleigh AC, Wang G-J, et al. Poverty and the economic effects of TB in rural China. Int J Tuberc Lung Dis 2006;10:1104–1110. 44. Mishra P, Hansen EH, Sabroe S, et al. Socioeconomic status and adherence to tuberculosis treatment: a case-control study in a district of Nepal. Int J Tuberc Lung Dis 2005;9:1134–1139. 45. World Health Organization. Addressing poverty in TB control: options for national TB control programmes (WHO/HTM/TB/2005.352). Geneva: World Health Organization, 2005. 46. World Health Organization. Guidelines for workplace TB control activities: the contribution of workplace TB control activities to TB control in the community (WHO/CDS/TB/2003.323). Geneva: World Health Organization, 2003. 47. World Health Organization. Tuberculosis control in prisons: a manual for programme managers (WHO/ CDS/TB/2000.281). Geneva: World Health Organization, 2000. 48. Pelletier AR, DiFerinando GT Jr, Greenberg AJ, et al. Tuberculosis in a correctional facility. Arch Intern Med 1993;153:2692–2695. 49. Stop TB Partnership Childhood TB Subgroup. Chapter 4: Childhood contact screening and management. Int J Tuberc Lung Dis 2007;11:12–15. 50. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children (WHO/HTM/TB/ 2006.371). Geneva: World Health Organization, 2006. 51. Becerra MC, Pachao-Torreblanca IF, Bayona J, et al. Expanding tuberculosis case detection by screening household contacts. Public Health Rep 2005;120: 271–277.
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Antituberculosis drugs Peter R Donald and Helen McIlleron
INTRODUCTION There are three main properties desirable of an anti-TB agent. It should rapidly eliminate the bulk of actively metabolizing bacilli, sterilize TB lesions by killing dormant or intermittently metabolizing organisms responsible for relapse and prevent the emergence of resistance to companion drugs. A dynamic combination of host, microbe and drug factors determines the three activities. Moreover, the drug should be easily absorbed, penetrate TB lesions, act under the varying conditions present in these lesions and do so with minimum toxicity. The commencement of chemotherapy induces a rapid clearance of Mycobacterium tuberculosis from the sputum, with 90% of viable bacilli being killed within 48 hours; this is followed by a slower rate of decline until cultures become negative.1 This bi-exponential clearance of bacilli from the sputum demonstrates that mycobacteria in tuberculous lesions are not uniformly susceptible to antiTB agents. It has been postulated that the diverse metabolic responses of M. tuberculosis to various microenvironments within the host result in several subpopulations of mycobacteria with distinct expressions of the various drug targets.2 A large actively metabolizing population (108 bacilli) in the congenial surroundings of pulmonary cavities (where there is adequate oxygen and an alkaline pH) is rapidly killed by isoniazid. A smaller number (104 to 105) of bacilli are in less satisfactory ambiences; the intermittently metabolizing organisms in caseation tissue are most susceptible to rifampicin, while pyrazinamide is effective against bacilli in acidic surroundings such as those in areas of active inflammation or within macrophage phagolysosomes. Lastly, a population of dormant bacilli is probably not killed by any of the currently available anti-TB agents. Drug concentrations at the site of action are also likely to contribute to the heterogeneous mycobacterial susceptibility within a host; bacilli residing in tissues or cells where drug penetration is poor may evade elimination.
BACTERICIDAL ACTIVITY A decline in the number of viable colony-forming units of M. tuberculosis in the sputum of patients with pulmonary TB can be demonstrated immediately after starting treatment.1 This early bactericidal activity (EBA) reflects the ability of an agent to kill
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rapidly metabolizing bacilli in tuberculous cavities. An agent with a high EBA, such as isoniazid, rapidly renders the patient’s sputum non-infectious, hastens symptom control and reduces the risk of resistance by reducing the population from which mutants emerge. Isoniazid has the highest EBA of the available agents and reduces the number of viable colony-forming units (cfu) of M. tuberculosis in sputum by 90% within 2 days (0.55 log10 cfu/mL sputum/ day).1,3 Isoniazid is closely followed in EBA by several newer fluoroquinolones (0.4–0.45 log10 cfu/mL sputum/day) and rifampicin (0.2 log10 cfu/mL sputum/day).4,5
STERILIZING ACTIVITY Before the availability of rifampicin and the reintroduction of pyrazinamide, TB was treated for at least 18 months to prevent relapse. When rifampicin and pyrazinamide were introduced it became possible to prevent relapse with a 6-month multidrug regimen.6 Sterilizing activity is now considered the most important property of an agent and one of the aims of modern TB drug research is to identify agents with potent activity against persisting organisms, thus allowing shorter treatment regimens.
PREVENTION OF RESISTANCE Shortly after the introduction of the first anti-TB agents, streptomycin and para-aminosalicylic acid (PAS), it became apparent that the beneficial effects were short-lived due to the emergence of drug resistance. Such resistance was prevented by giving both drugs together.7 Thus, an important problem of TB therapy was identified, as was the means of preventing it. Since then a major therapeutic aim has been the prevention of drug resistance. Antituberculosis agents differ in their ability to prevent resistance to companion drugs, but agents with a high EBA will, usually, also be effective in preventing resistance to companion drugs. The 6-month, short-course, regimen recommended by the World Health Organization (WHO) for patients with drug-susceptible disease (comprising rifampicin and isoniazid, supplemented by pyrazinamide and ethambutol in the initial 2-month intensive phase) is effective in about 95% of patients with pulmonary TB under clinical trial conditions.8 The less favourable results achieved by treatment programmes have focused emphasis on ensuring reliable
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59
Box 59.1 General precautions for standard recommended treatment regimens including rifampicin, isoniazid, pyrazinamide and ethambutol
The total daily amount of each drug should be taken as a single dose; splitting of doses may result in subtherapeutic levels. Drug doses should preferably be taken on an empty stomach but may be taken with food if gastric irritation occurs. Orange to brown discoloration of body fluids including urine, faeces, saliva, sputum, sweat and tears should be expected. Contact lenses may be stained; avoid wearing soft contact lenses. Concurrent alcohol consumption should be avoided. Patients should report promptly to a healthcare practitioner if signs or symptoms develop that could indicate hepatotoxicity (loss of appetite, nausea or vomiting, unusual tiredness or weakness), peripheral neuritis (clumsiness, numbness, tingling, burning or pain in the hands and feet), or hypersensitivity reactions (e.g. flu-like syndrome). It is important that the healthcare practitioner is alerted to the use of any other medications. Drug–drug interactions may have clinically important consequences. Alternative contraception is advised if taking oestrogen-containing oral contraceptive concurrently. Rifampicin may cause a bleeding tendency; it is advisable to defer elective dental procedures. Pyridoxine supplementation is indicated in those with malnutrition or with other risk factors for developing peripheral neuropathy (diabetes, human immunodeficiency virus (HIV) infection, excessive alcohol consumption). Monitoring of liver function tests is advised in patients at risk of drug-induced hepatitis (those with chronic viral hepatitis, alcoholics, or those taking other potentially hepatotoxic drugs). Liver function should be measured at baseline and then monthly, and when symptoms occur. Visual acuity and colour vision should be tested at baseline and visual symptoms should be sought at monthly intervals. If streptomycin is included in the treatment regimen, baseline audiograms, vestibular tests and serum creatinine should be performed. Monthly renal function testing is advised. Auditory and vestibular symptoms should be sought monthly.
supplies of high-quality products to patients and a patient-centred approach to supporting treatment adherence. Fixed dose combination tablets (two to four drugs formulated together) are widely used to reduce the risk of drug resistance and simplify drug supply, dispensing and administration. General precautions on implementing the recommended short-course regimen are listed in Box 59.1. Isoniazid, rifampicin, pyrazinamide, streptomycin and ethambutol are listed as essential anti-TB agents by WHO.9 Rifabutin and
rifapentine may replace rifampicin in certain specific situations. Streptomycin is still regarded as an essential agent and, in some circumstances, is used in initial treatment, although increasing resistance to this agent in many parts of the world and the requirement for parenteral administration have decreased its usefulness. The remaining WHO reserve drugs are used in cases of drug resistance, drug intolerance or toxicity. Tables 59.1 and 59.2 list the WHO essential and reserve drugs and their suggested dosages.
Table 59.1 Daily and thrice-weekly dosages of WHO essential drugs
9
Drug
Daily (range)
Three times weekly (range)
Isoniazid Rifampicin Pyrazinamide Streptomycin Ethambutol
5 mg/kg (4–6) 10 mg/kg (8–12) 25 mg/kg (20–30) 15 mg/kg (15–18) 15 mg/kg (15–20)
10 mg/kg 10 mg/kg (8–12) 35 mg/kg (30–40) 15 mg/kg (15–18) 30 mg/kg (25–30)
Table 59.2 Dosages of WHO reserve drugs Drug Aminoglycosides Kanamycin Amikacin Cyclic polypeptide Capreomycin Carbothionamides Ethionamide, prothionamide Fluoroquinolones Ofloxacin Ciprofloxacin D-Alanine analogue Cycloserine (terizidone) p-Aminosalicylic acid
Daily (range)
Comments
15 mg/kg 15–20 mg/kg
Total dose may be given three times weekly Total dose may be given three times weekly
15–20 mg/kg
After 40–120 days reduce dose to three times weekly
15–20 mg/kg (maximum 1 g daily)
—
600–800 mg 1000–1500 mg
— —
10–15 mg/kg (in 2 divided doses) 150 mg/kg (or 10–12 g daily) 12 hourly
— —
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CLINICAL MANAGEMENT OF TUBERCULOSIS
ISONIAZID Isoniazid (isonicotinic acid hydrazide) was introduced in 1952 and has exceptional qualities that have ensured its place as an essential component of anti-TB regimens for more than 50 years; only recently has this position been questioned.10
Mode of action Isoniazid is a pro-drug activated by M. tuberculosis katG-encoded catalase-peroxidase. The target of activated isoniazid is the NADH-dependent enoyl-acyl carrier protein reductase, coded for by the inhA gene, which promotes formation of long fatty acyl chains of mycolic acids and, consequently, bacilli on which isoniazid acts lose their acid-fastness. The minimal inhibitory concentration (MIC) of isoniazid varies from 0.02 to 0.05 mg/mL in broth and from 0.1 to 0.2 mg/mL on solid media.11 Mutants resistant to isoniazid occur with a frequency of approximately 1 in 107 cell divisions,12 and resistance has two main forms. Mutations of the katG gene prevent activation of the pro-drug, resulting in high-level isoniazid resistance. Lower level resistance (0.2–2 mg/ml), encountered in a minority of cases, is caused by InhA gene mutations which also confer ethionamide resistance.13 In approximately 30% of cases the cause of isoniazid resistance remains unidentified. Pharmacokinetics Isoniazid is a small water-soluble molecule and is easily absorbed from the gastrointestinal tract. Although subject to a considerable hepatic extraction (or first-pass effect) after oral dosing, it reaches concentrations well above the MIC of M. tuberculosis in most tissues and TB lesions when given in standard doses. The proposed target range for 2-hour isoniazid serum concentrations lies between 3 and 5 mg/mL.14 Genetic polymorphisms of the N-acetyltransferase-2 enzyme (NAT2) are the major determinants of the rate of isoniazid elimination, although other patient and treatment factors may also contribute to the considerable differences in isoniazid concentrations between individuals.15 Homozygous rapid, heterozygous rapid and homozygous slow isoniazid acetylators have been described.16 Hepatic and intestinal NAT2 acetylates isoniazid before further metabolism and renal excretion.17 Clinical efficacy In vitro, isoniazid is most active against rapidly dividing M. tuberculosis. Its activity diminishes as the metabolic activity of the bacilli decreases; little isoniazid activity is demonstrable against dormant or lag phase organisms. Studies on patients with pulmonary TB indicate a clear dose-related response with a maximum activity between doses of 150 and 300 mg.3 The potent EBA of isoniazid (a decline of 0.55 log10 cfu/mL sputum/day) reduces the patient’s infectivity and the risk of drug resistance. In modern 6-month, short-course chemotherapy isoniazid contributes little to sterilizing activity although, in the absence of rifampicin and pyrazinamide, isoniazid is probably responsible for the greater part of the sterilizing activity of regimens. There is little evidence that the NAT2 genotype influences treatment outcome amongst compliant patients receiving daily or thrice-weekly treatment. Homozygous fast acetylators are, however, at a disadvantage during once-weekly treatment with isoniazid in combination with rifapentine.18 Isoniazid offers valuable protection against the development of resistance to companion agents. Because of its high bactericidal activity, and the somewhat lesser activity of its companion drugs, it is also usually the first agent against which resistance develops and this is
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often the first step in the emergence of multidrug resistance. Isoniazid has long been used as the mainstay of prophylactic chemotherapy.
Side effects The dose-related neurotoxicity of isoniazid is putatively related to competition with pyridoxal phosphate in the synthesis of g-aminobutyric acid by L-glutamic acid decarboxylase. Slow acetylators and malnourished patients are at increased risk of peripheral neuropathy. Pyridoxine is used to reverse neurotoxicity and prophylactic supplementation is indicated in those with malnutrition or predisposed to peripheral neuropathy (e.g. alcoholics, diabetics and human immunodeficiency virus (HIV)-infected patients). Elevation of liver enzymes is transient in 10–20% of patients receiving isoniazid, but progresses to overt hepatitis, which may be fatal, in less than 1%. The risk of hepatitis is increased in older patients (2% in patients over the age of 50 years), women, homozygous slow acetylators, patients with underlying liver disease or alcoholism and when isoniazid is combined with other drugs (2.7% with rifampicin; 1.6% with other agents).19 Further side effects and drug interactions are listed in Appendix 2 of this book.
RIFAMYCINS In 1957 a rifamycin complex active against Gram-positive and -negative bacteria and mycobacteria was isolated from a new Streptomyces species, Streptomyces mediterranei.20 From this complex a lipid-soluble semisynthetic product, rifampicin, was developed and has proved to be a most valuable anti-TB agent. The newer rifamycins, rifapentine and rifabutin, are in clinical use and rifalazil is under evaluation. The latter has shown promising activity in mice and, with a half-life of close to 60 hours, it is potentially suitable for intermittent dosing. Although the sterilizing activity of the rifamycins is essential to contemporary anti-TB chemotherapy, doses higher than those currently used may be more effective.21 Using the currently advocated doses, highly intermittent (i.e. once- or twice-weekly) continuation phase regimens should be avoided in the treatment of HIV-associated TB.
RIFAMPICIN Mode of action Rifampicin prevents DNA-directed mRNA synthesis by binding to RNA polymerase. The mutations responsible for the majority of rifampicin resistance lie in the rpoB gene and occur with a frequency of 1 in 107 to 1 in 108 cell divisions.22 The MIC of rifampicin is 0.25 mg/mL in broth and 0.5 mg/mL on agar. Pharmacokinetics Rifampicin reaches peak concentrations 1.5–4 hours after oral administration. Following a meal, absorption is delayed and reduced by about 20%.23,24 It is highly (80–90%) protein bound but, nevertheless, penetration into lung tissue, tuberculous cavities and kidneys is good, reaching concentrations higher than that in serum. Less satisfactory concentrations are achieved in pyogenic bone lesions, pleural empyema and cerebrospinal fluid.25 Following a dose of 600 mg, peak concentrations of 6–14 mg/mL can be expected at the start of treatment.5 Rifampicin is converted principally to the active 25-desacetyl metabolite. Metabolism is self-induced, resulting in reductions in the area under the
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Antituberculosis drugs
concentration–time curve of 25–45% after repeated doses.5,26 Elimination is primarily hepatic and competition with bilirubin for hepatic excretion may cause transient hyperbilirubinaemia. A serum concentration of rifampicin between 8 and 24 mg/mL 2 hours after drug administration has been recommended,14 but a number of studies in patients have shown widely variable serum concentrations with median 2-hour concentrations of less than 8 mg/mL. HIV infection, diabetes, male sex, alcohol use and undernutrition are factors reported to predispose patients to lower rifampicin concentrations.15,27–29 Significant differences in bioavailability between various rifampicin-containing formulations on the market have also been reported.30
Clinical efficacy At a 600-mg dose, rifampicin has moderate bactericidal activity, approximately half that of isoniazid,5 but its unique ability is to sterilize TB lesions within 6–9 months. This is thought to be due to the particularly rapid onset of action of rifampicin which enables it to kill intermittently metabolically active bacilli.31 Acting with pyrazinamide, rifampicin is essential for the efficacy of modern 6-month, short-course therapy.6 Rifampicin should be administered daily during the intensive phase of treatment as intermittent dosing is associated with delayed culture conversion and with acquired rifamycin resistance in patients coinfected with HIV.32 The loss of rifampicin as an effective agent when resistance to it develops constitutes a major setback for patients and TB control programmes. Studies of the EBA of rifampicin at a dose of 600 mg show that it is moderately active with a 2-day reduction of bacillary numbers of approximately 2.0 log10 cfu/mL sputum/day. When given in a two-drug combination with isoniazid it allowed isoniazid resistance to emerge in 0.5% of patients.21 Side effects Rifampicin potently induces the expression of several proteins that affect the metabolism of other drugs. These proteins include microsomal enzymes (e.g. cytochrome P450 3A4/5, 2A6, 2C8/9/19, 2B6), phase II enzymes (e.g. UDP-glucuronosyltransferases and glutathione-S transferases) and drug transporters (e.g. p-glycoprotein) amongst others. As a result, the concentrations of some drugs are profoundly reduced. Thus administration of rifampicin together with other drugs may result in reduced efficacy of the concomitant drug, or increased toxicity if the concentrations of a toxic metabolite are increased (Appendix 2). The hepatotoxicity of isoniazid, pyrazinamide and a variety of other drugs, including non-anti-TB agents, may be potentiated by rifampicin, and rifampicin-associated hepatoxicity is more likely in patients with chronic liver disease. Other severe reactions to rifampicin are rare; these are usually associated with sensitization and are more common with intermittent doses. Patients should be warned that the orange discoloration of body fluids caused by the rifamycins can permanently stain clothing and soft contact lenses. The occurrence of thrombocytopenia is considered to be an absolute contraindication to using rifampicin again. Side effects and drug–drug interactions are listed in Appendix 2. RIFAPENTINE Rifapentine is a semisynthetic derivative of rifampicin and almost complete cross resistance between these two agents exists.33 The MIC of rifapentine is 0.02 mg/mL in Tween-albumin liquid medium (2–3 times less than that of rifampicin), and its in vitro
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bactericidal activity against log phase cultures of M. tuberculosis is slightly less than that of rifampicin.34 It is highly lipophilic and absorption is improved by about 50% when it is taken with a fatcontaining meal. The drug is highly (98%) bound to plasma proteins and this contributes to a long half-life (14–25 hours),26 which renders it suitable for intermittent use. The extensive binding to proteins may, however, limit its penetration into tuberculous lesions. Once-weekly intermittent regimens of rifapentine combined with isoniazid have been evaluated in clinical studies. In comparison with rifampicin and isoniazid twice or thrice weekly during the continuation treatment phase, a higher relapse rate was encountered in the rifapentine arm and was particularly likely in the presence of pulmonary cavitation and more extensive disease.35 Moreover, treatment failure in HIV-infected patients was associated with the development of rifamycin mono-resistance and with low isoniazid concentrations in homozygous rapid acetylators.18 Current US guidelines for rifapentine recommend a once-weekly dose of 600 mg during the continuation phase of treatment for pulmonary TB patients with non-cavitary TB whose sputum smears are negative on microscopy and who are not infected with HIV.36
RIFABUTIN Rifabutin, a semisynthetic derivative of rifamycin-S, has an MIC considerably lower than that of rifampicin, in one estimate 0.06 mg/mL or less, whether determined on agar or in broth.37 Peak serum concentrations of rifampicin are seven times higher than those of rifabutin after equivalent dosages.38 Although highly protein-bound, it penetrates readily into tissues. Rifabutin induces drug-metabolizing enzymes, including those responsible for its own metabolism, but to a lesser extent than rifampicin. Studies on the EBA of rifabutin have shown it to have considerably lower activity than rifampicin at similar doses.38,39 Notwithstanding, rifabutin-based regimens appear to have equal efficacy to rifampicin-containing regimens in the treatment of patients with newly diagnosed pulmonary TB.40 Although cross resistance with rifampicin exists, between 25% and 30% of patients with rifampicinresistant TB may respond to rifabutin. At present rifabutin is used mainly for management of disease due to members of the Mycobacterium avium complex in acquired immunodeficiency syndrome (AIDS) patients. Because rifabutin does not affect serum concentrations of antiretroviral agents as much as rifampicin, it has also been used in place of rifampicin in HIV-related TB.41 Intermittent doses should, however, be avoided, especially in HIV-infected patients with advanced immunosuppression. In a study of twice-weekly rifabutin with isoniazid during the continuation phase of treatment a rate of treatment failure or relapse (5%) similar to that of rifampicin-containing regimens was found, but relapses and treatment failures were associated with the acquisition of rifamycin resistance in eight out of nine cases.32 For side effects and drug–drug interactions see Appendix 2.
PYRAZINAMIDE Despite significant activity being demonstrated in early clinical trials,42 and a remarkable sterilizing effect in murine studies,43 pyrazinamide was abandoned following high rates of hepatic toxicity observed in trials in which high doses were given.44 It was some 20 years before its unique potential to augment the action of rifampicin in shortening the treatment of TB to 6 months was recognized.6
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Mode of action Pyrazinamide is a pro-drug converted by nicotinamidase/ pyrazinamidase to pyrazinoic acid after entering M. tuberculosis by passive diffusion. Pyrazinoic acid, in its turn, is excreted by a weak efflux pump, is protonated, re-enters the cell and accumulates due an inefficient efflux pump. This accumulation causes non-specific damage to the bacillus. Pyrazinamide is most active in the acid milieu of tuberculous lesions that are actively inflamed.45 The MIC of pyrazinamide is influenced by pH; on 7H10 agar an MIC of 20 mg/mL has been reported, but in liquid media the MIC varied from 50 mg/mL at pH 5.5 to 400 mg/mL at pH 5.95.46 This variability makes the determination of pyrazinamide resistance very difficult and many laboratories do not report it. Although it is stated that acquisition of pyrazinamide resistance is unusual this may not necessarily be so.47 The use of molecular techniques to detect resistance is an alternative approach but is complicated by the diversity of mutations involved, which are irregularly distributed along the pncA regulatory gene.48 It should be noted that Mycobacterium bovis and its derivative Bacillus Calmette–Gue´rin (BCG) are naturally resistant to pyrazinamide. Pharmacokinetics Pyrazinamide is reliably absorbed with and without food; peak concentrations from 30 to 50 mg/mL are achieved 1–2 hours after doses of 20–35 mg/kg body weight. Clearance of pyrazinamide is largely non-renal; approximately 30% is converted to pyrazinoic acid before renal excretion, with only 4% appearing unchanged in urine during the 24 hours following ingestion. Clinical efficacy Studies on the EBA of pyrazinamide reveal sustained activity against the extracellular bacilli in cavity walls from the fourth to 12th day of treatment.1 Pyrazinamide has a unique sterilizing capacity; regimens of isoniazid, streptomycin and pyrazinamide (given at a dose of 2 g daily) and isoniazid, streptomycin and rifampicin had relapse rates on 2-year follow-up of 8% and 3% (p ¼ 0.06), respectively.49 Further studies demonstrated that pyrazinamide added to rifampicin for the first 2 months of treatment enabled the duration of therapy to be shortened from 9 to 6 months with acceptable relapse rates.6 Although these studies did not support the use of pyrazinamide during the continuation phase there was evidence for a therapeutic benefit in continuing pyrazinamide beyond the intensive phase in patients with disease due to drug-resistant strains. There is also evidence that pyrazinamide acting essentially alone in the presence of isoniazid resistance may contribute to sterilization in regimens not containing rifampicin.50 Side effects Hepatoxicity occurs in less than 1% of patients when pyrazinamide is used at the currently recommended doses of about 25 mg/kg daily. Higher doses and use for longer periods confer greater risks of hepatotoxicity. Repeated doses, despite rising liver enzyme concentrations, may lead to severe liver damage and fulminant hepatitis. Less serious side effects are common and are listed in Appendix 2.
ETHAMBUTOL Early clinical studies of ethambutol at doses of 60–100 mg/kg were associated with marked therapeutic efficacy, but also optic neuritis, which was usually reversible, in more than 40% of patients.51 This
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toxicity is dose-related, but is experienced at virtually any effective dose and this has led to a continual erosion of the recommended dose of ethambutol.
Mode of action Ethambutol inhibits formation of the mycobacterial cell wall by affecting the synthesis of arabinogalactan. Its MIC is 0.5–2.0 mg/mL in the Bactec 460-TB automated system.52 Genetic and biochemical evidence suggests that the primary ethambutol target is arabinosyl transferase, encoded by the embA and embB genes.53 Pharmacokinetics Peak serum concentrations of ethambutol are proportional to dose; early studies reported concentrations of 10 and 5 mg/mL, respectively, after doses of 50 and 25 mg/kg bodyweight. Approximately 80% of the drug is excreted unchanged in urine and there is no evidence of accumulation with repeated daily doses. Concentrations peak at 2–4 hours, and absorption is slightly reduced when it is taken after a meal (3.8 mg/mL compared with 4.5 mg/mL when fasting).54 Tissue distribution of ethambutol is good and concentrations in some tissues are higher than in blood. A notable exception is the central nervous system as penetration of ethambutol into cerebrospinal fluid is limited. Reductions in ethambutol concentrations of approximately 20% are reported in patients with HIV infection; higher concentrations are reported in males and older patients.15,55 Clinical efficacy In early studies on drug-resistant TB, ethambutol alone brought about ‘reversal of infectiousness’ in 30–40% of patients. Resistance to ethambutol emerged in the remaining patients. A dose of 25 mg/kg has moderate EBA of 0.246 log10 cfu/mL sputum/ day.1 In keeping with this, ethambutol is considered moderately successful in protecting companion drugs against development of resistance. At a dose of 15 mg/kg, however, the EBA drops precipitously to 0.05 log10 cfu/mL sputum/day. Ethambutol contributes little to the sterilization of tuberculous lesions,21 and a higher proportion of unfavourable outcomes with a continuation phase of 6 months of isoniazid and ethambutol, compared with 4 months of isoniazid and rifampicin, has been demonstrated.8 The currently recommended dose of ethambutol is 15 mg/kg (range 15–20 mg/kg) and, for thrice-weekly treatment, 25–35 mg/kg. Its main function is to assist in the prevention of the emergence of drug resistance in companion drugs and to limit further extension of existing resistance. Side effects Retrobulbar neuritis occurs in 3% of patients receiving 25 mg/kg of ethambutol and in 18% of those taking more than 30 mg/kg on a daily basis. One or both eyes may be affected. It usually involves the central optic nerve fibres, causing blurred vision, reduced visual acuity, abnormalities of colour perception and a central scotoma. Less frequently, involvement of axial fibres results in constriction of the peripheral visual field. Rare and less severe adverse effects are listed in Appendix 2.
AMINOGLYCOSIDES STREPTOMYCIN Streptomycin was one of the first anti-TB agents to be discovered, but the development of drug resistance when it was given alone
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soon became apparent and, in a 5-year follow-up of patients in the Medical Research Council study, a mortality in treated patients of 53% compared with 63% amongst untreated patients was found.7
Mode of action Streptomycin is a broad-spectrum antibiotic that binds to ribosomes and thereby inhibits protein synthesis. Missense mutations have been identified in the rrs and rpsL genes and the average mutation rate is 1 in 108 cell divisions.12 Using the radiometric Bactec 460-TB system, the MIC of streptomycin was 0.5–2.0 mg/mL.52 The bactericidal activity of streptomycin (and other aminoglycosides) decreases as acidity increases, so that the MIC was 0.32 mg/mL at pH 8.0, 2.5 mg/mL at pH 7.0 and 5 mg/mL at pH 6.0.56 Pharmacokinetics Streptomycin must be given by deep intramuscular injection. Absorption from the injection site is then rapid and peak serum concentrations are reached within 1–2 hours. Streptomycin is approximately 50% protein-bound. Low cerebrospinal fluid concentrations have been reported, particularly if the meninges are not inflamed. After a mean streptomycin dose of 14.2 mg/kg, mean serum concentrations of 30.5 mg/mL and cerebrospinal fluid concentrations of 2.1 mg/mL were found 2 hours post-dose.57 Streptomycin penetration is reported to be good in uninfected pleural exudates,58 but poor in empyema.58,59 Streptomycin elimination is mainly renal with 50–60% being excreted unchanged; renal function should be assessed regularly in patients receiving streptomycin, and it should be used with caution when renal function is suboptimal. The recommended streptomycin dose is 15 mg/kg (range 12–18 mg/kg) with a maximum in adults of 1 g daily. The dose should be reduced in the elderly. Clinical efficacy In vitro, streptomycin is amongst the most bactericidal of all antiTB agents,60 but in vivo it has a relatively low EBA.1 This may be due to the acidic environment in the cavity wall combined with relatively low streptomycin concentrations in this environment (mean 9.4 mg/mL 1 hour after dosing).61 Streptomycin does, however, have a long post-antibiotic effect that has proved valuable in intermittent regimens. Streptomycin is still listed by the WHO as an essential anti-TB agent,9 although since the introduction of rifampicin and pyrazinamide its main role has been to help prevent resistance and to strengthen regimens against isoniazid-resistant strains. More recently, streptomycin has been increasingly replaced by ethambutol because of concern for the transfer of HIV and other live virus infections in situations where needle sterilization may be unsatisfactory. Streptomycin is a valuable drug when hepatotoxicity occurs or one or more of the other major drugs is contraindicated. Side effects Toxic damage to the eighth cranial nerve is related to the dose and duration of exposure. Permanent damage may result if the drug is not discontinued or the dose not reduced when early symptoms occur. Administration during pregnancy may result in permanent hearing defects in the child. Streptomycin should preferably be avoided in patients with renal impairment as it is excreted by the kidneys and is also nephrotoxic. Generalized and cutaneous hypersensitivity reactions are common; anaphylactic shock and fatal exfoliative dermatitis are rare. Other side effects are listed in Appendix 2.
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KANAMYCIN AND AMIKACIN Like other aminoglycosides, kanamycin must be given parenterally and its activity in vitro (MIC in Bactec 460 of 2–4 mg/mL) is approximately half that of streptomycin.52 It carries a significant risk of ototoxicity and renal toxicity. Amikacin is a semisynthetic derivative of kanamycin with less toxicity, but there is complete cross resistance between the two agents. In an experimental murine model, amikacin was more active on a weight-for-weight basis than streptomycin, but in a clinical evaluation of a small number of patients with multiply resistant organisms it did not cause a consistent reduction in the degree of sputum smear or culture positivity.62 In EBA studies amikacin and streptomycin, each at a dose of 15 mg/kg, had a similarly low efficacy (0.053 and 0.043 log10 cfu/mL sputum/day, respectively).63 The most important role of kanamycin and amikacin is in the management of drug-resistant TB and they are classified by the WHO as reserve drugs. Their recommended dose is 15–20 mg/kg daily or 5–6 days weekly. When considered necessary during the continuation phase the same total dose can be given twice or thrice weekly, for a treatment duration of 3–4 months. More recently it has been recommended that the initial phase of treatment for MDR-TB should last 6 months.
CAPREOMYCIN AND VIOMYCIN Capreomycin and viomycin are structurally similar antibiotics and both inhibit bacterial protein synthesis by binding to 30S and 50S ribosomal subunits. Capreomycin is more active than viomycin in animal experiments, but not as active as streptomycin or kanamycin; it is less active than PAS in preventing development of resistance to companion drugs. The MIC of capreomycin in liquid or on solid media is 1.25–2.5 mg/mL.52 Both drugs require parenteral administration. Interestingly, capreomycin is active against non-replicating M. tuberculosis in vitro, in a manner similar to metronidazole but unlike other anti-TB agents.64 Earlier researchers were aware of a complex pattern of cross resistance between capreomycin, kanamycin and viomycin. Recent molecular studies have identified the genetic basis for these patterns.65 Isolates with high-level kanamycin resistance will generally be capreomycin-resistant, while those with a low-level kanamycin resistance will often be capreomycin-susceptible. As the main function of capreomycin is the management of drug-resistant TB it is clear that access to a specialized laboratory would greatly assist the appropriate use of capreomycin. Capreomycin is listed by the WHO as a reserve drug for the management of patients with drug-resistant TB. Renal toxicity requiring discontinuation of this agent in up to 25% of patients limits its role. The usual dose is 1 g in a single daily dose, not exceeding 20 mg/kg, for 40–120 days. Thereafter the dose should be reduced to twice or thrice weekly to reduce the risk of side effects which become more common with continued exposure to the drug. Viomycin is used almost exclusively for cases of extreme drug resistance and is given in a dose of 15 mg/kg.
ETHIONAMIDE Ethionamide (thioisonicotinamide) and prothionamide are thioamides derived from isonicotinic acid.66 Because of considerable gastrointestinal intolerance ethionamide remains a ‘second-line’ agent.
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Prothionamide is the propyl analogue of ethionamide which, it was hoped, would be better tolerated but this hope was not realized.
Mode of action In initial studies it was noted that ethionamide, like isoniazid, caused actively growing bacilli to lose acid fastness; furthermore, although ethionamide was effective against strains of M. tuberculosis highly resistant to isoniazid, it was less effective against strains ‘only slightly resistant to isoniazid’.66 It is now clear that both isoniazid and ethionamide are pro-drugs which, following activation, inhibit mycolic acid synthesis and that co-resistance to isoniazid and ethionamide can be caused by mutations in the inhA promoter region.13 Between 7% and 25% of isoniazid-resistant isolates have inhA mutations. The MIC of ethionamide in broth is 0.25– 0.5 mg/mL and the intracellular activity of ethionamide is less than that of rifampicin, but equivalent to that of isoniazid.52 Pharmacokinetics Ethionamide is readily absorbed from the gastrointestinal tract. After a 500 mg oral dose in healthy volunteers, peak plasma concentrations of 2.2–3 mg/mL are attained in 1–2 hours; food and antacids have little effect.67 After a dose of 250 mg, serum concentrations range from 0.9 to 1.1 mg/mL and are similar in patients with and without AIDS.68 It is rapidly distributed and concentrations close to serum concentrations are reached in the lungs, tuberculous lesions69 and cerebrospinal fluid.70 Considerably higher concentrations have been found in pulmonary epithelial lining fluid than in serum or lung alveolar cells.68 Significant variations in serum concentrations occur, both in individual patients and between patients. Only a very small proportion of the drug is excreted unchanged and the principal metabolites are sulphoxides that have an anti-TB activity similar to that of the parent compound. Clinical efficacy Shortly after it became available ethionamide was evaluated as a component in a number of two- and three-drug regimens. It showed favourable activity in the ‘reversal of infectiousness’ and in the prevention of development of drug resistance to companion drugs.71 In a direct randomized comparison in a large group of patients the response to treatment with ethionamide and streptomycin did not differ significantly from that of isoniazid and streptomycin.72 Nevertheless gastrointestinal intolerance is a significant problem that has prevented ethionamide from playing a major role in first-line regimens. At present ethionamide is classed as a reserve drug by the WHO and is used for the management of drug-resistant TB. The usual dose of ethionamide is 500–1000 mg daily, but intolerance frequently precludes a dose of more than 750 mg. Dividing the dose into 250 mg three or four times daily at the start of treatment, before consolidating the dosage into a single daily dose, or giving it with milk or orange juice, may aid tolerance. Side effects Nausea can be severe. Vomiting, anorexia, metallic taste, abdominal discomfort, diarrhoea and weight loss are also common. Hepatotoxicity is reported in about 2% of patients taking the drug. Nervous system toxicity may be responsive to niacin or pyridoxine (see Appendix 2).
CYCLOSERINE AND TERIZIDONE Cycloserine is a cyclic derivative of serinehydroxamic acid and terizidone is a condensation product containing two cycloserine molecules.
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Mode of action Cycloserine is a broad-spectrum antibiotic with only moderate anti-TB activity. It inhibits cell wall synthesis. The MIC of cycloserine in the Bactec 460-TB system is 25–75 mg/mL.52 Pharmacology Cycloserine is water-soluble and well absorbed orally. It is not protein-bound and excretion is mainly renal. Concentrations peak between 2 and 4 hours after doses of 250, 500 and 750 mg of cycloserine or terizidone, and terizidone generally gives serum concentrations higher than those of cycloserine. Younger patients tend to have lower serum concentrations than older patients.73 Cycloserine penetrates well into most tissues and compartments and cerebrospinal fluid concentrations are approximately half those of serum concentrations. Urinary elimination of cycloserine is about 70% and it accumulates in patients with impaired renal function. Cycloserine is given in two doses daily: 250 mg in the morning and 500 mg 12 hours later. It is recommended that terizidone be given as 300 mg twice daily. When conventional twice-daily dosing is used, serum concentrations are maintained at close to 25–30 mg/mL. Clinical efficacy and safety Frequent dose-related neurological effects (see Appendix 2) restrict the role of cycloserine and terizidone. Cycloserine is a pyridoxine antagonist and increases its renal excretion; pyridoxine requirements may be increased during therapy. They are reserve drugs used mainly for the management of patients with disease resistant to many anti-TB agents.
PARA-AMINOSALICYLIC ACID (PAS) Although only bacteriostatic, PAS played an important part in early regimens by preventing the development of drug resistance to companion drugs. It is now used in certain cases of drug resistance and is classified as a reserve drug by the WHO. It is unpleasant to take as the tablets are bulky and cause considerable gastrointestinal discomfort. The usual dose is 150 mg/kg or 10–12 g daily in two divided doses.
THIOACETAZONE Thioacetazone was one of the first agents to be used for treatment of TB and was widely used in Germany after the Second World War. It is associated with a high incidence of toxic reactions including severe exfoliative dermatitis and gastrointestinal and neurological effects, particularly in those infected with HIV. The advent of isoniazid and other more effective and less toxic agents relegated thioacetazone to the role of a reserve drug. It did, however, enjoy a renaissance when a cheap, but effective, oral regimen was required for use in the developing world and it replaced PAS as it could be given once daily. The combination of isoniazid and thioacetazone in a single tablet provided an economical and efficacious continuation phase for countries in Africa, Latin America and Asia. Until recently thioacetazone was listed as an essential anti-TB agent by the WHO. As, however, it predisposes to severe toxic epidermal necrolysis in association with HIV infection it is no longer recommended and is no longer available in most countries.
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FLUOROQUINOLONES The fluoroquinolones are fluorinated derivatives of nalidixic acid with a broad spectrum of antibiotic activity, including activity against M. tuberculosis and other mycobacteria. Despite a lack of controlled clinical trials, the fluoroquinolones, and in particular ofloxacin, have been used with increasing frequency for the treatment of patients with multidrug-resistant TB.74,75 Ofloxacin and ciprofloxacin are listed as reserve drugs by the WHO, but there is considerable interest in the potential of some of the newer fluoroquinolones, such as moxifloxacin, gatifloxacin and levofloxacin, to replace some of the current drugs in first-line regimens.
Mode of action DNA gyrase encoded by the gyrA and gyrB genes and DNA topoisomerase IV encoded by parC and parD genes are the targets for fluoroquinolone activity. Cross resistance has been demonstrated among several of these agents. MICs for M. tuberculosis determined on 7H11 solid media of 0.500, 0.707, 0.354, 0.177 and 0.125 mg/mL have been reported for ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin and gatifloxacin, respectively.76 Pharmacokinetics The fluoroquinolones are rapidly absorbed after oral administration and peak serum concentrations are reached after 1–2 hours. Peak serum concentrations of levofloxacin (1,000 mg), gatifloxacin (400 mg) and moxifloxacin (400 mg) are 15.6, 4.8 and 6.1 mg/mL, respectively.4 Good penetration occurs into tissues and macrophages,77 and reported peak concentrations in the cerebrospinal fluid of ofloxacin and ciprofloxacin have varied from 10% to 60% of simultaneous peak serum concentrations. Elimination is hepatic and renal; for most of the fluoroquinolones, a substantial proportion of the drugs is excreted unchanged in the urine (approximately 40–70%, 70–90%, 80–90%, 70% and 20% for ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin, respectively). Clinical efficacy Studies of the EBA of fluoroquinolones have, with the exception of ciprofloxacin,78 demonstrated bactericidal activity close to that of isoniazid.4,79 Despite this, a recent Cochrane review of the fluoroquinolones (including ciprofloxacin, ofloxacin, levofloxacin and sparfloxacin) as additional or substitute components of standard regimens in 10 controlled clinical trials failed to show any benefit.80 It was concluded that ciprofloxacin should not be considered for substitution in any standard regimen. Conversely, an uncontrolled trial of ofloxacin added to a standard regimen of isoniazid, rifampicin and pyrazinamide given for 4 or 5 months resulted in very low relapse rates,81 but these findings require confirmation. Studies in mice of moxifloxacin combined with rifampicin and pyrazinamide, but not with isoniazid, revealed exceptional sterilizing activity and the results of clinical trials in patients are eagerly awaited. The usual recommended dose of ofloxacin is 800 mg daily for TB but if this dose is poorly tolerated it can be reduced to 400 mg during the continuation phase of treatment.9 Side effects Although they are generally well tolerated, the fluoroquinolones frequently cause gastrointestinal disturbances. Neurological effects and hypersensitivity reactions are amongst other adverse effects (see Appendix 2).
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CLARITHROMYCIN Clarithromycin is a macrolide antibiotic with a broad spectrum of anti-bacterial activity, including anti-mycobacterial activity. Despite being one of the most active agents for the treatment and prophylaxis of infections due to the M. avium complex, it has proved disappointing in the treatment of disease due to M. tuberculosis and, when used alone in murine TB, it had no demonstrable effect.82 Clarithromycin is not recommended by the WHO for the management of multidrug-resistant TB and it should only be used as a last resort in patients who are otherwise therapeutically destitute.
CLOFAZIMINE Clofazimine is a phenazine dye with weak anti-mycobacterial activity. It is primarily used for the management of leprosy, but there is anecdotal evidence of its value in the treatment of multidrug-resistant TB.83 The use of clofazimine, as with clarithromycin, should be a last resort and preferably limited to specialized units for the treatment of drug-resistant TB.
LINEZOLID Oxazolidinones are a novel class of protein synthesis inhibitors with in vitro activity against a range of bacteria, including mycobacteria. Several members of this class of drugs have been shown to have activity in a murine TB model and linezolid was used successfully in five patients with resistance to an extensive range of anti-TB agents. All of the patients became sputum culture-negative after 6 weeks of treatment with this agent together with a relatively weak regimen of clofazimine, thiacetazone or amoxicillin/clavulanate.84 Toxicity is, however, a major problem with its prolonged use: anaemia, pancreatitis and peripheral neuropathy have been described. This is an agent that should not be used outside of specialized units capable of detecting and managing these complications.
AMOXICILLIN AND CLAVULANIC ACID Mycobacterial beta-lactamase is susceptible to clavulanic acid and in vitro studies have shown that the combination of sulbactam and amoxicillin is highly bactericidal against exponential-phase cultures of M. tuberculosis.85 Several case reports describe its use in the management of multidrug-resistant patients,86,87 but EBA studies have given conflicting results.88,89 This is a drug that should be reserved for those patients for whom all other therapeutic possibilities have been exhausted.
NEW DRUGS For the first time in three decades there is the prospect of new antiTB drugs becoming available within the next few years. This process is being expedited by the Global Alliance for TB Drug Development (‘TB Alliance’), a not-for-profit corporation formed in 2002 to accelerate the development of new anti-TB agents and to ensure that these agents are affordable and available to countries
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with a high burden of TB. Under the auspices of the TB Alliance, the pharmaceutical industry and academic institutions, there is now a pipeline of over 20 compounds being developed and in various stages of evaluation. Several existing or newly developed compounds are either entering or have already completed in vivo studies and the first phases of clinical evaluation. TMC207, a diarylquinoline with a completely new anti-mycobacterial activity inhibiting ATP synthase, has shown very promising characteristics in a murine model.90 OPC-67683 is a nitro-dihydro-imidazooxazole that also has very promising anti-mycobacterial activity in murine studies.91 PA-824, a nitroimidazopyran and the first novel
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compound in the TB Alliance portfolio, has a mechanism of action distinct from all known TB agents and in a murine model had sterilizing activity that matched that of rifampicin and bactericidal activity equal to that of isoniazid.92 Despite the promising nature of this pipeline of new agents there is still a considerable amount of developmental work to be done before they can enter routine TB treatment programmes; at any point in the developmental programme they could come to grief. It is thus incumbent on the TB community to continue to use our existing drugs with as much care as possible and to continue to focus on the prevention of drug-resistance.
patients with tuberculosis. Am J Respir Crit Care Med 1997;155:1717–1722. Hickman D, Sim E. N-acetyltransferase polymorphism. Comparison of phenotype and genotype in humans. Biochem Pharmacol 1991;42:1007–1014. Weiner M, Burman W, Vernon A, et al. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine. Am J Respir Crit Care Med 2003;167:1341–1347. Kopanoff DE, Snider D, Caras G. Isoniazid related hepatitis: a US Public Health Service cooperative surveillance study. Am Rev Respir Dis 1979;117: 991–1001. Sensi P, Margalith P, Timbal MT. Rifamycin, a new antibiotic. Preliminary report. Farmaco (Sci) 1959;14:146–147. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000;4:796–806. Telenti A, Imboden P, Marchesi F, et al. Detection of rifampicin resistance mutations in Mycobacterium tuberculosis. Lancet 1993;341:647–650. Peloquin CA, Namdar R, Singleton MD, et al. Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids. Chest 1999;115:12–18. Zent C, Smith P. Study of the effect of concomitant food on the bioavailability of rifampicin, isoniazid and pyrazinamide. Tuber Lung Dis 1995;76:109–113. Binda G, Domenichini E, Gottardi A, et al. Rifampicin, a general view. Arzneimittelforschung 1971;21:1907–1977. Acocella G. Pharmacokinetics and metabolism of rifampin. Rev Infect Dis 1983;5(supp 3):S428–S432. Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996;30:919–925. Nijland HMJ, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006;43:848–854. Tappero JW, Bradford WZ, Agerton TB, et al. Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis 2005;41:461–469. McIlleron H, Wash P, Burger A, et al. Widespread distribution of a single drug rifampicin formulation of inferior bioavailability in South Africa. Int J Tuberc Lung Dis 2002;6:356–361. Dickinson JM, Mitchison DA. Experimental models to explain the high sterilizing activity of rifampin in the chemotherapy of tuberculosis. Am Rev Respir Dis 1981;123:367–371. Burman W, Benator D, Vernon A, et al. Acquired rifamycin resistance with twice-weekly treatment of HIV-related tuberculosis. Am J Respir Crit Care Med 2006;173:350–356. Bodmer T, Zu¨rcher G, Imboden P, et al. Mutation position and type of substitution in the sub-unit of the RNA polymerase influence on in vitro activity of rifamycin resistant Mycobacterium tuberculosis. J Antimicrob Chemother 1995;35:345–348. Dickinson JM, Mitchison DA. In vitro studies on the suitability of new rifamycins for the intermittent
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(6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet 1973;1:1331–1338. Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423–430. Carr RE, Henkind P. Ocular manifestations of ethambutol. Toxic amblyopia after administration of an experimental antituberculous drug. Arch Ophthal mol 1962;67:566–571. Rastogi N, Labrousse V, Goh KS. In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against virulent H37Rv strain in human macrophages. Curr Microbiol 1996;33:167–175. Belanger AE, Besra GS, Ford ME, et al. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for antimycobacterial drug ethambutol. Proc Natl Acad Sci USA 1996;93: 11,919–11,924. Peloquin CA, Bulpitt AE, Jaresko GS, et al. Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids. Antimicrob Agents Chemother 1999;43:568–572. Zhu M, Burman WJ, Starke JR, et al. Pharmacokinetics of ethambutol in children and adults with tuberculosis. Int J Tuberc Lung Dis 2004;8:1360–1367. McDermott W, Tompsett R. Activation of pyrazinamide and nicotinamide in acidic environments in vitro. Am Rev Tuberc 1954;70: 748–754. Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis 1993; 148:650–655. Thys JP, Vanderhoeft P, Herchuelz A, et al. Penetration of aminoglycosides in uninfected pleural exudates and in pleural empyemas. Chest 1988; 93:530–532. Elliott AM, Berning SE, Iseman MD, et al. Failure of drug penetration and acquisition of drug resistance in chronic tuberculosis empyema. Tuber Lung Dis 1995;76:463–467. Dickinson JM, Aber VR, Mitchison DA. Bactericidal activity of streptomycin, isoniazid, rifampicin, ethambutol and pyrazinamide alone and in combination against Mycobacterium tuberculosis. Am Rev Respir Dis 1977;116:627–635. Canetti G, Grumbach F. Diffusion de la streptomycin dans les lesions case´euses des tuberculeux pulmonaires. Ann Inst Pasteur (Paris) 1953;85: 380–383. Allen B, Mitchison DA, Chan YC, et al. Amikacin in the treatment of pulmonary tuberculosis. Tubercle 1983;64:111–118.
63. Donald PR, Sirgel FA, Venter A, et al. The early bactericidal activity of amikacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2001;5:533–538. 64. Heifets L, Simon J, Pham V. Capreomycin is active against non-replicating M tuberculosis. Ann Clin Microbiol Antimicrob 2005;4:6. 65. Maus CE, Plikaytis BB, Shinnick TM. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2005; 49:3192–3197. 66. Rist N, Grumbach F, Libermann D. Experiments on the antituberculous activity of alpha-ethylthioisonicotinamide. Am Rev Tuberc 1959;79:1–5. 67. Auclair B, Nix DE, Adam RD, et al. Pharmacokinetics of ethionamide administered under fasting conditions or with orange juice, food, or antacids. Antimicrob Agents Chemother 2001;45: 810–814. 68. Conte JE, Golden JA, McQuitty M, et al. Effects of AIDS and gender on steady-state plasma and intrapulmonary ethionamide concentrations. Antimicrob Agents Chemother 2000;44:1337–1341. 69. Tsukamura M. Permeability of tuberculous cavities to antituberculous drugs. Tubercle 1972;53:47–52. 70. Donald PR, Seifart HI. Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis. J Pediatr 1989;115:483–486. 71. Brouet G, Marche J, Rist N, et al. Observations on the antituberculous effectiveness of alpha-ethylthioisonicotinamide in tuberculous humans. Am Rev Tuberc 1959;79:6–18. 72. Schwartz WS. Comparison of ethionamide with isoniazid in original treatment cases of pulmonary tuberculosis. XIV. A report of the Veterans Administration-Armed Forces cooperative study. Am Rev Respir Dis 1966;93:685–692. 73. Zı´tkova´ L, Tousˇek J. Pharmacokinetics of cycloserine and terizidone. A comparative study. Chemotherapy 1974;20:18–28. 74. Tsukamura M, Nakamura E, Yoshii S, et al. Therapeutic effect of a new antibacterial substance ofloxacin (DL8280) on pulmonary tuberculosis. Am Rev Respir Dis 1985;131:352–356. 75. Cohn DL, Iseman MD. Treatment and prevention of multidrug-resistant tuberculosis. Res Microbiol 1993;144:150–153. 76. Hu Y, Coates ARM, Mitchison DA. Sterilizing activities of fluoroquinalones active against rifampintolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003;47:653–657. 77. Rastogi N, Blom-Potar MC. Intracellular bactericidal activity of ciprofloxacin and ofloxacin against Mycobacterium tuberculosis H37Rv multiplying in the J-774 macrophage cell line. Zentralbl Bakteriol 1990; 273:195–199. 78. Sirgel FA, Botha FJ, Parkin DP, et al. The early bactericidal activity of ciprofloxacin in patients with
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pulmonary tuberculosis. Am J Respir Crit Care Med 1997;156:901–905. Sirgel FA, Donald PR, Odhiambo J, et al. A multicentre study of the early bactericidal activity of anti-tuberculosis drugs. J Antimicrob Chemother 2000;45:859–870. Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2005 July 20;(3):CD004795. Tuberculosis Research Centre. Shortening short course chemotherapy: A randomized clinical trial for treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase. Indian J Tuberc 2002;49:27–38. Truffot-Pernot C, Lounis S, Grosset JH, et al. Clarithromycin is inactive against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1995;39: 2827–2828. Seung KJ. Should isoniazid and clofazimine be used to treat multidrug-resistant tuberculosis? (With reply by Van Deun A, Salim AH, Das PK, et al.) Int J Tuberc Lung Dis 2005;9:231–232. Fortu´n J, Martin-Da´vila P, Navas E, et al. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother 2005;56:180–185. Herbert D, Paramasivan CN, Venkatesan P, et al. Bactericidal action of ofloxacin, sulbactam-ampicillin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis. Antimicrob Agents Chemother 1996;40:2296–2299. Nadler JP, Berger J, Nord JA, et al. Amoxicillinclavulanic acid for treating drug-resistant Mycobacterium tuberculosis. Chest 1991;99:1025–1026. Yew WW, Wong CF, Lee J, et al. Do betalactam-beta-lactamase inhibitor combinations have a place in the treatment of multidrug-resistant pulmonary tuberculosis. Tuber Lung Dis 1995;76: 90–92. Chambers HF, Kocago¨z T, Sipit T, et al. Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin Infect Dis 1996;26:874–877. Donald PR, Sirgel FA, Venter A, et al. Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis. Scand J Infect Dis 2001;33:466–469. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307:223–227. Matsumoto M, Hashizume H, Tomishige T, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006;3:2131–2144. Tyagi S, Nuermberger E, Yoshimatsu T, et al. Bactericidal activity of the nitroimidazopyran PA824 in a murine model of tuberculosis. Antimicrob Agents Chemother 2005;49:2289–2293.
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Drug interactions in the treatment of HIV-related tuberculosis William J Burman
INTRODUCTION Human immunodeficiency virus (HIV) infection has profound effects on the global epidemiology of TB as it is the most potent risk factor known for the development of active disease among persons with latent TB infection.1 Furthermore, HIV infection markedly increases the risk of recurrent active TB among patients who have had an initial course of treatment for this disease.2 As a result, TB case rates have increased two- to 10-fold in countries with high prevalence of HIV infection, and in such settings up to 80% of all persons with active TB are coinfected with HIV.3 Also, HIV infection increases the risk of death during treatment for TB. Between 20% and 50% of patients with active TB and advanced HIV disease (CD4+ lymphocyte count < 200/mm3) die during treatment of TB.4–6 Potent combination antiretroviral therapy results in dramatic decreases in the risk of death and the occurrence of new opportunistic infections among persons with advanced HIV disease. Although no randomized trials of combination antiretroviral therapy have been conducted specifically among patients with active TB, several observational cohort studies suggest that the benefits of such therapy are similar among persons with and without active TB.7,8 Patients with TB and advanced HIV disease should therefore be targeted for initiation of antiretroviral therapy while they are being treated for TB. Fortunately, antiretroviral therapy is increasingly available in countries in which there is a high prevalence of HIV-related TB. The use of antiretroviral therapy during anti-TB treatment is complicated by the challenges of coordinating the systems of care for HIV disease and TB, the demands on the patients to adhere to taking many medications for the two diseases, overlapping adverse effect profiles of anti-TB and antiretroviral drugs, drug– drug interactions between antiretroviral drugs and the rifamycins, and the occurrence of immune reconstitution disease following the initiation of antiretroviral therapy.9 None of these complicating factors are reasons for deferring antiretroviral therapy until after completion of the course of anti-TB treatment, but all must be considered and managed if antiretroviral therapy during anti-TB treatment is to be successful. In this chapter drug–drug interactions and their management during the treatment of HIV-related TB will be reviewed. Such interactions are particularly common in the treatment of HIV-related TB because the rifamycins and four of the available classes of antiretroviral drugs (HIV-1 protease inhibitors, non-nucleoside reverse-transcriptase inhibitors (NNRTIs), integrase inhibitors and oral fusion inhibitors) share
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metabolic pathways in the gut wall and liver.10-12 Therefore, management of drug–drug interactions during the treatment of HIV-related TB will be a clinical challenge for the foreseeable future. Although it may be intimidating to the practising clinician, an understanding of the mechanisms of drug–drug interactions, particularly those involving the rifamycins, is critical to the management of patients being treated with anti-TB and antiretroviral agents. There is substantial and growing information on the effect of rifamycins on the serum concentrations of antiretroviral drugs and vice versa. Gauging the clinical relevance of drug–drug interactions requires a review of pharmacodynamics – the relationships between concentrations of a drug (usually in serum) and its antimicrobial activity and toxicity. The controversies in this field largely revolve around uncertainties about the pharmacodynamic properties of the rifamycins and antiretroviral drugs but, despite these controversies and uncertainties, practical guidance for managing drug–drug interactions in the treatment of HIV-related TB will be provided later in this chapter.
MECHANISMS OF DRUG–DRUG INTERACTIONS Any review of current knowledge on drug interactions in the treatment of HIV-related TB will rapidly be out of date as additional knowledge is gained on interactions between currently available drugs and as new antiretroviral anti-TB drugs are introduced. An understanding of the mechanisms of drug–drug interactions, particularly those involving the rifamycins, will allow the clinician to anticipate interactions likely to occur with new combinations of available antiretroviral drugs and novel classes of these drugs. Clinicians should also consult a regularly updated source for new information on drug interactions in the treatment of HIV-related TB (e.g. the guidelines from the US Centers for Disease Control and Prevention (CDC), available at http://www.cdc.gov/tb/ tb_hiv_Drugs/default.htm). Particular attention to those interactions involving drug-metabolizing enzyme systems in the gut wall and liver is required; while other mechanisms of drug–drug interactions exist, they are infrequently encountered in the treatment of HIV-related TB. Physicochemical binding in the lumen of the gastrointestinal tract may result in decreased absorption of a drug. This is particularly evident in the case of the fluoroquinolone antibiotics which are standard agents in the treatment of multidrug-resistant TB and are being evaluated in clinical trials for the treatment of drug-susceptible disease. The absorption of fluoroquinolones is markedly decreased by
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Drug interactions in the treatment of HIV-related tuberculosis
administration with di- and trivalent cations, such as those in antacids or iron supplements. The original formulation of didanosine contained antacids, and could thereby decrease absorption of fluoroquinolones.11 While not adequately studied, this effect is not likely to occur with currently marketed sustained-release formulations of didanosine.
P-GLYCOPROTEIN Drug metabolism in the gut wall and liver is mediated by three separate, though related, enzyme systems (Table 60.1). Cells lining the gastrointestinal tract contain many transport proteins including the ATP-dependent P-glycoprotein that pumps a diverse set of molecules back into the lumen of the gastrointestinal tract, thereby limiting their net absorption. P-glycoprotein is also found within cells in other parts of the body and may be important in biliary and renal tubular excretion of some drugs, the function of the blood–brain barrier, and the intracellular concentrations of drugs within lymphocytes. P-glycoprotein is inhibited by some drugs (e.g. ritonavir), and its synthesis is upregulated by others (e.g. rifampicin), thereby increasing its activity. Inhibition of P-glycoprotein decreases the amount of a drug pumped back into the gastrointestinal lumen, hence increasing the net absorption and serum concentrations of the drug. Induction of P-glycoprotein increases the concentration of the transport protein in enterocytes, thus increasing the amount of drug pumped back into the lumen and decreasing the absorption and serum concentrations of the drug.
CYTOCHROME P450 Once absorbed, two other enzyme systems are important in drug metabolism in the gut wall and the liver. The best known is cytochrome P450 (CYP450), a family of haem-containing drugTable 60.1 Overview of drug-metabolizing enzymes in the gut wall and liver Pathway
Anatomic localization
Mechanism of drug– drug– interaction
Example of drug– drug interaction
P-glycoprotein
Gut wall, liver, kidney
Enzyme induction
Rifampicinmediated decrease in digoxin concentrations Ritonavirmediated increase in saquinavir bioavailability Rifampicinmediated decrease in atazanavir concentrations Ritonavirmediated increase in indinavir concentrations Rifampicinmediated decrease in zidovudine concentrations
Enzyme inhibition
Cytochrome P450
Gut wall, liver
Enzyme induction
Enzyme inhibition
Cytosolic enzymes
Liver
Enzyme induction
60
metabolizing enzymes located in the endoplasmic reticulum of hepatocytes and, to a lesser extent, enterocytes. The CYP3A isozyme is the member of the CYP450 family most often involved in drug–drug interactions during treatment of HIV-related TB, though other isozymes (including CYP2B6) may be relevant. In common with P-glycoprotein, CYP3A can be inhibited or induced. A number of agents commonly used in the treatment of patients with HIV infection are potent inhibitors of CYP3A, namely, HIV-1 protease inhibitors (particularly ritonavir), azole antifungal drugs (e.g. itraconazole), and macrolide antibiotics (e.g. clarithromycin). Inhibition of CYP3A results in increased serum concentrations of those drugs that are substrates for this enzyme, thereby increasing their efficacy (e.g. boosting of other protease inhibitors by ritonavir) or toxicity (e.g. rifabutin toxicity when administered with ritonavir). Induction of the synthesis of CYP3A takes 4–7 days, but eventually results in increased metabolism of a drug that is a substrate of this isozyme, thereby decreasing its serum concentrations and decreasing its efficacy. Rifampicin is the most potent inducer of CYP3A used in clinical medicine, and thereby interacts with a wide range of other therapeutic agents, notably HIV-1 protease inhibitors and NNRTIs. The latter agents, nevirapine and efavirenz, are themselves relatively potent CYP3A inducers. The potential for clinically relevant drug interactions in the treatment of HIV-related TB is evident in that the simultaneous treatment of these two infections often involves the administration of a combination of potent inhibitors and inducers of CYP3A. It is noteworthy that the inhibitors and inducers of CYP3A affect the P-glycoprotein system in the same manner. For example, ritonavir is an inhibitor of CYP3A and P-glycoprotein. As a consequence, the effect of ritonavir on serum concentrations of other drugs is in the same direction – increased serum concentrations due to increased bioavailability (inhibition of P-glycoprotein) and/or decreased hepatic metabolism (inhibition of CYP3A). Similarly, the effect of rifampicin on the CYP3A and P-glycoprotein systems is in the same direction – decreased serum concentrations, whether due to decreased absorption (induction of P-glycoprotein) or increased metabolism (induction of CYP3A). The similarity in the effects of inhibition or induction of these two enzyme systems makes it difficult to delineate the relative contributions of P-glycoprotein and CYP3A to an overall drug–drug interaction, although such delineation is seldom of importance in the management of the resulting drug interactions.
CYTOSOLIC DRUG-METABOLIZING ENZYMES Cytosolic enzymes form a third part of the system involved in the metabolism of drugs used for treating HIV-related TB. Glucuronosyl transferase is, for example, a cytosolic enzyme involved in the metabolism of a number of therapeutic agents including zidovudine and the new integrase inhibitor, raltegravir.14 The synthesis of cytosolic enzymes is also inducible by rifampicin and it is therefore not sufficient to screen for rifamycin-related interactions by investigating CYP450 metabolism alone as drug interactions may occur at the level of cytosolic enzymes (e.g. the interaction between rifampicin and zidovudine). On the other hand, inhibition of cytosolic enzymes does not appear to occur to such an extent that it causes recognized drug–drug interactions.
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CLINICAL MANAGEMENT OF TUBERCULOSIS
The various inhibitors and inducers differ in their effects on their target enzymes. Particularly potent CYP3A inhibitors include ritonavir and other HIV-1 protease inhibitors (other than tipranavir), ketoconazole and itraconazole, and the macrolide antibiotics (other than azithromycin). The rifamycins differ in their potency as inducers of CYP3A and cytosolic enzymes with rifampicin being the most potent, rifapentine nearly as potent as rifampicin, and rifabutin substantially less so. These differences in potency as inhibitors or inducers can be used to manage some drug–drug interactions, such as that between the rifamycins and the protease inhibitors.
MIXED INHIBITOR/INDUCER DRUGS Yet another complication in the already complex network of drug– drug interaction is the ability of drugs to inhibit one enzyme system while inducing the activity of a second such system. Ritonavir, for example, is a remarkably potent inhibitor of P-glycoprotein and CYP3A, leading to the prediction that its use would increase serum concentrations of voriconazole, a new azole antifungal drug that is a CYP3A substrate. In practice, co-adminstration of ritonavir (100 mg twice daily) and voriconazole results in marked decreases in concentrations of the latter agent (39% decrease in the area under the concentration–time curve (AUC)).15 This surprising finding may be explained by the induction by ritonavir of CYP2C9, another cytochrome P450 isozyme involved in the metabolism of voriconazole. Therefore, while it is tempting to try to make simple categorizations of drugs (e.g. that ritonavir is an inhibitor and will therefore increase the concentrations of other drugs), the complexity of hepatic and gut wall drug metabolism negates such simple rules. Accordingly, while an understanding of the pathways of metabolism of antiretroviral and anti-TB drugs is useful for predicting the outcomes of their interactions, simple prediction rules need to be tempered with the knowledge that hepatic and gut wall drug metabolism is complex and may involve multiple pathways which might be affected differently by the same drug. In particular, prediction rules for drug–drug interactions may not perform well when there are three or more interacting drugs. To take one notable example, ritonavir is used as a pharmacokinetic enhancer of other protease inhibitors, such as lopinavir and amprenavir. Resistance testing predicted that the use of lopinavir, amprenavir, and ritonavir together might be effective for viral strains having some resistance to protease inhibitors. Furthermore, it was thought that, since all three drugs are CYP3A inhibitors and substrates, each drug would increase the concentrations of the other. Clinical trials of this combination of drugs were, however, terminated when it was shown that co-administration of these protease inhibitors resulted in marked decreases in serum concentrations of amprenavir and lopinavir.13
EFFECTS OF RIFAMYCINS ON NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS Antiretroviral regimens based on a NNRTI plus two nucleoside analogues combine potency, a low pill burden, simple storage conditions, and low production cost. In developing countries with high burdens of HIV and TB, NNRTI-based regimens are the standard for initial antiretroviral therapy. The simplicity and durability of the activity of NNRTI-based regimens makes them popular in high-income countries as well. Interactions between the
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rifamycins and NNRTIs are therefore particularly important, notably interactions with nevirapine and efavirenz (the third licensed NNRTI, delavirdine, is seldom used because of its pill burden and drug interaction profile).
EFFECT OF RIFAMPICIN ON EFAVIRENZ A general point about drug interactions due to rifampicin is that, while this agent causes many drug–drug interactions, its metabolism is not affected by other drugs (although it induces its own metabolism via a cytosolic enzyme). Efavirenz is metabolized by CYP2B6 and CYP3A. As a potent CYP3A inducer, rifampicin results in decreased efavirenz concentrations, although the magnitude of the interaction (10–20% decrease in the AUC and the trough concentration14,15 ) suggests that CYP2B6, which is not thought to be affected by rifampicin, is the major metabolic pathway (Fig. 60.1). An elegant study has shown that increasing the efavirenz dose from 600 to 800 mg/day compensates for this modest interaction with rifampicin.14 Although the rifampicin– efavirenz interaction has been well described, its interpretation and implications remain the subject of an ongoing controversy, illustrating the uncertainties about the pharmacodynamic relevance of well-described pharmacokinetic drug interactions. As with other drugs metabolized in the liver, there are large interpatient differences in the pharmacokinetics of efavirenz. For example, in a study comparing 600-mg/day with 800-mg/day dosage in HIV-infected TB patients, there were 10-fold differences in serum concentrations of efavirenz.15 Polymorphisms in the CYP2B6 account for part of this interpatient difference,16 and, as these polymorphisms are associated with race, there are significant differences in efavirenz pharmacokinetics in different racial groups, with Africans and Asians showing slower elimination rates and higher concentrations of this agent.16,17 Despite these large interpatient differences in pharmacokinetics, regimens based on a standard dose of efavirenz (600 g daily) plus two nucleoside analogues are highly successful in achieving complete viral suppression.18 If the therapeutic window of efavirenz allows highly efficacious therapy despite 10-fold differences in concentrations, the effect of the modest changes in efavirenz concentrations due to coadministration of rifampicin (10–20% decreases) are unlikely to be virologically or clinically relevant. Indeed, a randomized trial comparing the 600- and 800-mg/day doses among Thai patients showed a small difference in efavirenz concentrations but no differences in viral suppression.15 Similar studies need to be conducted in other patient populations before this issue can be regarded as settled.
Percentage of NNRTI concentrations in the absence of rifampicin
7
100 90 80 70 60 50 40 30 20 10 0
AUC Cmin
Efavirenz
Nevirapine
Fig. 60.1 The effect of rifampicin on serum concentrations of efavirenz and nevirapine. AUC, area under the concentration–time curve; Cmin, trough concentration.
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Drug interactions in the treatment of HIV-related tuberculosis
There are, however, potential problems in prescribing higher doses of efavirenz for patients on rifampicin, namely, an increased risk of dosing errors when a non-standard dose is given, an increased risk of efavirenz toxicity,19 and the unavailability of combination formulations, such as a combination of tenofovir, emtricitabine, and efavirenz in one pill, that contain other than the standard amounts of the drugs. The clinical experience of administering efavirenz-based antiretroviral therapy to patients receiving rifampicin-based anti-TB treatment has been uniformly positive. In several studies on patient populations of different racial and ethnic backgrounds, high proportions of patients being treated with rifampicin-based TB regimens achieved complete viral suppression on this combination,15,20 and the CD4+ count response to therapy was similar to that of patients who were not being treated for TB.21 No unusual pattern or frequency of adverse events was observed in these studies.
EFFECT OF RIFAMPICIN ON NEVIRAPINE Nevirapine is widely used in initial antiretroviral regimens in countries with a high burden of HIV-related TB as it is inexpensive to produce, it is available in a liquid suspension and convenient combination formulations, and it appears be safe during pregnancy. Rifampicin–nevirapine interactions are therefore very important. In common with efavirenz, nevirapine is metabolized by CYP450, primarily CYP3A and CYP2B6. Rifampicin causes 30–50% decreases in the AUC and trough concentrations of nevirapine (Fig. 60.1).22,23 Increasing the dose of nevirapine from 200 to 300 mg twice daily partially compensates for this interaction,23 but this dose adjustment appears to increase nevirapine-related toxicity. The use of nevirapine during rifampicin-based anti-TB treatment raises concerns about its antiretroviral potency and the overlapping adverse effect profiles of these drugs. In a large randomized trial, regimens of two nucleoside analogues with either nevirapine or efavirenz had similar virological, immunological, and clinical outcomes.24 Nevertheless, the trend towards decreased viral suppression among patients with high baseline loads who received nevirapine suggests that the therapeutic margin of nevirapine may not be as broad as that of efavirenz.24 Notably, patients with HIV-related TB often have high baseline viral loads.7 In this context, the 30–50% decrease in serum concentrations of nevirapine when given with rifampicin is a cause for concern and suggests the need for increasing the dosage of this agent.23 However, a recent multicentre trial of enhanced dose nevirapine (300 mg twice daily) versus the standard dose (200 mg twice daily) among patients being treated with rifampicin-based TB treatment demonstrated excess toxicity (both nevirapine hypersensitivity and hepatotoxicity) among patients randomized to higher dose nevirapine.25 Prior studies demonstrating an association between polymorphisms in the gene for P-glycoprotein (the MDR-1 gene) and nevirapine-associated hepatitis26,27 suggested that hepatotoxicity may be related to the pharmacokinetics of nevirapine. Early reports suggested that concentrations of nevirapine remained therapeutic, despite this interaction.25,31,32 However, more recent studies suggest that nevirapine concentrations may be subtherapeutic among patients on rifampicin,33 and patients whose nevirapine concentrations are at the lower end of the distribution (Fig. 60.2) probably have an increased risk of virological failure of therapy when rifampicin is added. Moreover, in a recent large cohort study from South Africa the antiretroviral activity of nevirapine-based antiretroviral therapy is inferior to that of
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efavirenz-based therapy among patients on rifampicin-based tuberculosis treatment.34 Patients on nevirapine also had therapy interrupted for toxicity more often than those on efavirenz.34 However, in all studies reported to date, a high percentage of patients had complete viral suppression while on nevirapine-based antiretroviral therapy and rifampicin-based TB treatment (even if somewhat less than that achieved with efavirenz-based antiretroviral therapy).34 Rifampicin also has effects on several recently approved antiretroviral agents. Trough concentrations of the integrase inhibitor raltegravir are decreased by ~60% by rifampicin.11 However, because of the remarkable potency of raltegravir,43 an increased dose is not recommended when the drug is used with rifampicin.11 Trough concentrations of the CCR5 inhibitor maraviroc are decreased by 78% when given with rifampicin,12 and a dose increase to 600 mg twice daily of maraviroc is recommended.44 However, both of these recommendations are based solely on preliminary drug–drug interaction studies, not studies of the outcomes of treatment of patients with HIV-related TB. Until additional data are available, combinations of rifampicin with either raltegravir or maraviroc should only be used if other, better-studied antiretroviral combinations cannot be used. Finally, serum concentrations of etravirine, an NNRTI that retains activity against strains of HIV that are resistant to efavirenz and nevirapine, are predicted to be markedly decreased by rifampicin, so this combination should not be used.45 The clinical experience with nevirapine-based antiretroviral therapy among patients on rifampicin-based anti-TB treatment has been generally favourable.22,28–30 Most patients have trough nevirapine concentrations that have been associated with successful viral suppression,28,29 and virological outcomes of therapy have been generally successful. Furthermore, preliminary results of a large observational study in South Africa suggest that risks of hepatotoxicity were comparable among patients on nevirapine-based regimens who did and did not receive concomitant anti-TB treatment.30 Studies to date have, however, not had sufficient statistical power to permit a determination of whether patients whose nevirapine concentrations are at the lower end of the distribution (Fig. 60.2) have an increased risk of virological failure of therapy when rifampicin is added. Nevirapine will continue to be used with rifampicin-based TB treatment because it can be prescribed for pregnant women and small children and because of its widespread availability in high-burden countries.
EFFECT OF RIFAMYCINS ON HIV-1 PROTEASE INHIBITORS EFFECTS OF RIFAMPICIN Rifampicin coadministration results in dramatic decreases in the serum concentrations of all currently available HIV-1 protease inhibitors.10 Previous reviews of this subject have emphasized the decrease in the AUC of the protease inhibitors when given with rifampicin,10 but the effect of this agent is probably even greater than that predicted by changes in the AUC. The pharmacokinetic parameter most closely associated with antiviral efficacy of the protease inhibitor class is the trough concentration (adjusted for binding to serum proteins), and rifampicin has a greater effect on trough concentrations of the currently available members of this class (92–99% decreases) than it does on the AUC of these drugs (Fig. 60.3).31–33
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25.0
25.0
22.5
22.5
20.0 17.5 15.0
p = 0.048
12.5 10.0 7.5
6.6 mg / L
5.4 mg / L
5.0
3.4 mg / L
2.5 0
NVPRFP Treatment group
Trough plasma NVP level (median mg/L)
Trough plasma NVP level (mg/L)
CLINICAL MANAGEMENT OF TUBERCULOSIS
20.0 17.5 15.0 12.5 Interquartile
10.0
Median
7.5 5.0 2.5 0
NVP
1.5 interquartile
NVPRFP
NVP
Treatment group
120 AUC Cmin
100 80 60 40
Rifampicin
AMP
ATZ / RTV
LPV/ RTV
AMP
0
ATZ / RTV
20 LPV/ RTV
Percentage of protease inhibitor concentrations in the absence of rifamycin
Fig. 60.2 Comparison of trough concentrations of nevirapine among patients receiving concomitant rifampicin-based anti-TB treatment (NVP-RFP) and those not on anti-TB treatment (NVP). Reproduced with permission from Manosuthi et al.29 Scientific Foundations of Urology Vol 1, Chapter 30 (eds. D. Innes Williams and G.D.Chisholm), pp 211–217. London, Heinemann. Figure 14.
Rifabutin
Fig. 60.3 The effect of rifampicin (left) or rifabutin (right) on serum concentrations of co-formulated lopinavir (400 mg) /ritonavir (100 mg) twice daily (LPV/RTV, Kaletra), atazanavir (300 mg) + ritonavir (100 mg) daily (ATZ/RTV), and amprenavir (AMP). AUC, area under the concentration–time curve; Cmin, trough concentration.
Various strategies allowing the use of protease inhibitor therapy in patients receiving rifampicin-based anti-TB treatment have been suggested. The effect of rifampicin on ritonavir, a 35% reduction in AUC, is less marked than its effects on other protease inhibitors. The limited clinical experience with full-dose ritonavir (600 mg twice daily) with rifampicin suggests that this combination is poorly tolerated, although it may have beneficial effects on HIV infection among those who tolerate the combination. Ten out of 18 patients (56%) started on therapy with rifampicin and full-dose ritonavir discontinued treatment within 8 weeks, though there were substantial reductions in HIV RNA levels and elevations of CD4+ lymphocyte counts among the eight patients who tolerated this combination.34 The poor tolerability of full-dose ritonavir in the general patient population has led to its near abandonment in the treatment of HIV infection, so this strategy is unlikely to be an
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effective way of allowing protease-inhibitor therapy in the context of rifampicin-based anti-TB treatment. A second strategy for using protease inhibitors with rifampicin takes advantage of the ability of ritonavir to block the effect of rifampicin on the metabolism of another protease inhibitor. Small doses of ritonavir (100 mg daily or twice daily) can markedly increase serum concentrations of other protease inhibitors including lopinavir, atazanavir, and fos-amprenavir. This interaction is the basis for ‘boosted’ protease inhibitor therapy, now the standard way of administering protease inhibitor therapy. These low doses of ritonavir do not, however, block the effect of rifampicin on a second protease inhibitor. For example, the trough concentration of atazanavir (300 mg daily) boosted with ritonavir (100 mg daily) was decreased by 94% in the presence of rifampicin (Fig. 60.3). Higher doses of ritonavir can block the effect of rifampicin, leading to a strategy that might be termed ‘super-boosted’ protease inhibitor therapy. When given with high-dose ritonavir (400 mg twice daily), trough lopinavir concentrations in the presence of rifampicin were similar to those achieved by the standard twice daily lopinavir/ritonavir combination formulation (Kaletra, which contains 100 mg of ritonavir) in the absence of rifampicin.32 A final strategy for managing this interaction is to use both ritonavirboosting and an increased dose of the second protease inhibitor. Using a double dose of co-formulated lopinavir/ritonavir, a total of 200 mg of ritonavir per dose, almost restored trough concentrations of lopinavir to the normal range.32 There are concerns about the tolerability of the strategy of super-boosted protease inhibitor therapy in the setting of rifampicin-based anti-TB treatment. The combination of rifampicin and boosted saquinavir or lopinavir was poorly tolerated in drug interaction studies on healthy volunteers, with high rates of gastrointestinal symptoms and drug-induced hepatitis.32,35 On the other hand, the high rates of hepatitis seen among healthy volunteers have not been seen in initial studies on patients with HIV-related TB treated with super-boosted protease inhibitors,36,37 leading to continued interest in this strategy.
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Drug interactions in the treatment of HIV-related tuberculosis
EFFECT OF RIFAMPICIN ON OTHER ANTIRETROVIRAL DRUGS Rifampicin decreases serum concentrations of zidovudine, via induction of glucuronidation,38 and it may have a similar effect on abacavir. While not fully evaluated in clinical studies, the interactions between rifampicin and these nucleoside analogues are not thought to be clinically relevant. The pharmacologically active form of zidovudine is the intracellular triphosphate metabolite, and it is unclear whether rifampicin affects concentrations of this metabolite. Rifampicin is predicted to decrease the concentrations of several new antiretroviral drugs that are still under investigation. Raltegravir (MK-0518), a potent integrase inhibitor, is metabolized via glucuronidation, and its concentrations are decreased by approximately 50% when given with rifampicin. Investigational oral CCR-5 inhibitor maraviroc is metabolized by CYP3A, and by rifampicin. Finally, TMC-125, an NNRTI that retains activity against strains of HIV resistant to efavirenz and nevirapine, is also metabolized by CYP3A. Interactions between rifampicin and antiretroviral agents will therefore continue to present clinical challenges.
EFFECTS OF RIFABUTIN Another strategy for allowing potent anti-TB treatment and protease inhibitor-based antiretroviral therapy to be administered together is based on the use of rifabutin which, at doses of 150 mg daily or 300 mg thrice weekly, has activity equivalent to that of rifampicin in the treatment of TB.39–41 Rifabutin is an inducer of CYP3A, but has much less effect on CYP3A substrates than does rifampicin (Fig. 60.3),10 and it can therefore be given with any of the currently licensed protease inhibitors, other than unboosted saquinavir. The pharmacokinetic challenge of using rifabutin with protease inhibitors is the effect of the latter on concentrations of rifabutin, rather than the reverse. Rifabutin has several metabolic pathways, among them CYP3A. As potent CYP3A inhibitors, the protease inhibitors increase the concentrations of rifabutin two- to four-fold, and increase the concentrations of 25-O-desacetyl rifabutin (a major metabolite) by 10- to 25-fold.10,33 High concentrations of rifabutin and its metabolites result in increased rates of uveitis, skin discoloration, arthralgias, and neutropenia.42,43 A reduced dose of rifabutin should therefore be used when protease inhibitors are given. Several combinations of reduced dose rifabutin and protease inhibitor-based antiretroviral therapy have been used. Rifabutin at 150 mg daily or 300 mg thrice weekly has been used with
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protease inhibitors that are less potent CYP3A inhibitors, such as nelfinavir.44,45 An even greater reduction in the dose of rifabutin, as low as 150 mg two or three times weekly, appears to be necessary in the presence of ritonavir.46 There are, however, two concerns about using reduced dose rifabutin with ritonavir. First, twice-weekly rifabutin-based anti-TB treatment is associated with an increased risk of treatment failure or relapse with acquired rifamycin resistance,7,47 as a result of low serum concentrations of rifabutin.48 Notably, twice-weekly rifampin-based treatment of HIV-related TB was also associated with acquired rifamycin resistance,47,49 suggesting that it is the dosing frequency that is the risk factor for acquired rifamycin resistance rather than the choice of rifamycin. Second, suboptimal adherence with protease-inhibitor therapy is common and may not be evident to the clinician. If a patient stopped taking ritonavir, the reduced dose of rifabutin would be insufficient for effective anti-TB treatment.
THE EFFECTS OF RIFAMYCINS ON CONCENTRATIONS OF DRUGS USED TO PREVENT OR TREAT OPPORTUNISTIC INFECTIONS Although the principal clinical focus has been on interactions between the rifamycins and antiretroviral drugs, there are clinically relevant interactions between this class of antibiotics and a number of drugs used to prevent or treat other opportunistic infections in HIV-infected patients (Table 60.2). Because of the frequency of serious fungal infections among patients with advanced HIV disease, the interactions between rifampicin and the azole antifungal drugs are particularly important. Rifampicin has a moderate effect on fluconazole concentrations (22% decrease in AUC), but it is unlikely that this effect is clinically relevant in the treatment of most fungal infections. There are some concerns that even moderate decreases in fluconazole concentrations might affect the outcome of treatment of cryptococcal meningitis, but no published studies have addressed this possibility. Higher doses of fluconazole are generally well tolerated, so this interaction could probably be overcome, if necessary. In contrast to fluconazole, the dramatic effect of rifampicin on serum concentrations of other azole antifungal drugs (80–96% decrease in AUC) has led to failure of antifungal therapy,57,58 and is a strong contraindication to their concomitant use.
Table 60.2 The effect of rifampicin on serum concentrations of drugs used to prevent or treat opportunistic infections Drug Azole antifungal agents Fluconazole Ketoconazole Itraconazole Voriconazole Caspofungin Clarithromycin Cotrimoxazole Trimethoprim Sulfamethoxazole Atovaquone Dapsone
Effect of rifampicin (ref)
Possible clinical relevance
22% # (AUC)50 80% # (AUC)51 88% # (AUC)52 96% # (AUC)12 14–31% # (trough concentration)53 87% # (AUC) 54
Monitor clinically Avoid concomitant use Avoid concomitant use Avoid concomitant use Consider dose increase to 70 mg daily Use with caution
47% # (AUC)55 23% # (AUC)55 52% # (average concentration)56
Uncertain Uncertain Avoid concomitant use Uncertain
AUC, area under the concentration-time curve.
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Rifampicin markedly decreases concentrations of clarithromycin, though the clinical relevance of this interaction has been questioned because the resultant metabolite also has antibacterial activity.59 Fortunately, there is no evidence of an interaction between the rifamycins and azithromycin,60 so this azalide drug can be used in place of clarithromycin if treatment with rifampicin is required. Rifampicin decreases concentrations of drugs used as prophylaxis or treatment of Pneumocystis jiroveci. While the effects of rifampicin on trimethoprim and sulfamethoxazole (cotrimoxazole) are statistically significant, they are unlikely to be clinically relevant. Doses of cotrimoxazole as low as one doublestrength tablet thrice weekly are highly effective for prophylaxis against pneumocystosis,61 suggesting that currently recommended doses are not close to a critical threshold for the activity of this agent. Similarly, pharmacokinetic simulations suggest that the standard dose of dapsone (100 mg daily) would probably retain efficacy for prophylaxis.62 The effect of rifampicin on atovaquone concentrations is a greater cause of concern as this agent is inherently less potent than cotrimoxazole in preventing and treating pneumocystosis. In common with the protease inhibitors, rifabutin has less effect on those drugs used to prevent or treat opportunistic infections. The question of whether the lower hepatic induction potential of rifabutin would allow effective treatment with azoles other than fluconazole has not been answered. Being CYP3A inhibitors, the azole antifungals and clarithromycin increase serum concentrations of rifabutin, and this may result in toxicity if the dose of rifabutin is not reduced.63
RECOMMENDATIONS FOR MANAGING INTERACTIONS BETWEEN RIFAMYCINS AND ANTIRETROVIRAL THERAPY THE IMPORTANCE OF THE RIFAMYCINS IN THE TREATMENT OF TUBERCULOSIS One possible strategy for managing the interactions between the rifamycins (rifampicin, rifabutin, and rifapentine) and key antiretroviral drugs would be to use a rifamycin during the initial intensive phase of anti-TB therapy and then to start antiretroviral therapy during a continuation phase that does not include a rifamycin. The problem with this strategy is that anti-TB treatment regimens that do not contain a rifamycin at all or only during the initial intensive phase of treatment are markedly less effective than regimens that contain a rifamycin throughout.64,65 The inferiority of regimens not containing a rifamycin throughout is particularly evident among HIVinfected patients,65 illustrating the general rule that HIV-mediated immunodeficiency magnifies the weaknesses of any anti-TB treatment regimen. Therefore, unless a patient has rifamycin-resistant TB or a severe intolerance to rifamycins, a regimen containing a rifamycin for the duration of TB treatment should be used for all HIVinfected patients. The drug interactions between rifamycins and antiretroviral drugs should be managed, not avoided.
CHOICE OF ANTIRETROVIRAL REGIMENS FOR SIMULTANEOUS USE WITH RIFAMPICIN-BASED ANTITUBERCULOSIS TREATMENT Regimens of efavirenz plus two nucleoside analogues are the clear choice for use with rifampicin-based anti-TB treatment regimens. The potency, convenience, and durability of efavirenz-based
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regimens make them highly recommended for any patient starting antiretroviral therapy. The clinical experience with these regimens among patients receiving rifampicin-based anti-TB therapy has been uniformly positive with virological, immunological, and clinical outcomes comparable to those of patients without TB. The only controversy surrounding the use of efavirenz-based therapy in the setting of HIV-related TB has been whether there is a need to increase the dose of efavirenz. While additional studies are needed, the data available at present suggest that the standard dose of efavirenz can be used with rifampicin-based anti-TB treatment. The important question of the optimal time to start antiretroviral therapy during anti-TB treatment is outside the scope of this chapter.
ALTERNATIVES TO EFAVIRENZ-BASED THERAPY Efavirenz is not available in a suspension formulation for use in young children, and it cannot be used during pregnancy (at the very least, during the first two trimesters of pregnancy). Furthermore, some patients are intolerant to this agent owing to adverse neuropsychological effects, and some patients are infected with HIV strains with primary or acquired resistance to efavirenz. There is thus a need for alternatives to efavirenz for use during anti-TB treatment. Nevirapine is the usual alternative to efavirenz in most highburden countries, and it can be used in young children and during pregnancy. While nevirapine appears to be less active than efavirenz among patients on rifampin-based TB therapy, most patients on nevirapine-based antiretroviral therapy do achieve complete viral suppression. Therefore, it can be used when efavirenz is not available and for patients intolerant to efavirenz. Because serum concentrations of nevirapine are particularly low if the usual dose escalation is used (200 mg daily for the first 2 weeks of therapy),66 nevirapine should be started at 200 mg twice daily among patients on rifampicin.28 There is almost complete cross resistance between nevirapine and efavirenz, and alternative agents are therefore needed for the patient infected with a strain of HIV resistant to this class of drugs. If available, rifabutin-based TB treatment can be used with antiretroviral regimens based on protease inhibitors, and clinical experience with this drug combination has been quite good.66,67 One way to prevent inadvertent rifabutin underdosing in the patient who stops ritonavir is to administer both anti-TB treatment and antiretroviral therapy at the same time under direct supervision. Unfortunately, rifabutin is either not available or is prohibitively expensive in countries with high burdens of HIV-related TB. While there are concerns about both the safety and efficacy of the strategy of super-boosting protease inhibitors to overcome the effects of rifampicin, this alternative can be considered for a patient with an NNRTI-resistant isolate or with an inability to tolerate NNRTIs. Although the clinical experience reported to date with super-boosted protease inhibitors includes only a few patients, it has been positive.36,37 Additional pharmacokinetic and clinical data on super-boosted protease-inhibitors in the setting of rifampicinbased anti-TB treatment are clearly needed. Finally, an antiretroviral regimen composed only of nucleoside analogues, or the nucleotide analogue tenofovir, could be considered. The regimen of zidovudine, lamivudine, and abacavir is not predicted to have clinically relevant interactions with rifampicin but this regimen is less active than efavirenz-based therapy,68 and is not therefore generally recommended. Although an alternative
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Drug interactions in the treatment of HIV-related tuberculosis
regimen of zidovudine, lamivudine, and tenofovir has been used for patients being treated with rifampicin-based anti-TB regimens,69 this nucleoside/nucleotide regimen has not been compared against efavirenz-based regimens. Finally, a quadruple nucleoside/nucleotide regimen of zidovudine, lamivudine, abacavir, and tenofovir had antiviral activity comparable to efavirenz-based therapy in an initial pilot study.71 While these regimens of nucleosides and nucleotides cannot be recommended as preferred therapy among patients receiving rifampicin, their lack of predicted clinically significant interactions with rifampicin make them an acceptable alternative for patients unable to take NNRTIs.
AREAS IN NEED OF ADDITIONAL RESEARCH Given the frequency and severity of TB in those who are infected with HIV, there is a great need for additional studies on the interactions between drugs used to treat TB and HIV disease. Many of the studies of these interactions have been performed on healthy volunteers but there are reasons for concern about their applicability to the clinical situation given the effects of HIV on drug absorption and the effect of immunological factors on the activity of drug-metabolizing enzymes. While there are unlikely to be fundamental differences in the interactions among healthy volunteers and patients with HIVrelated TB, these interactions should be investigated in the highest risk patients – severely ill patients with HIV-related TB. As pointed out in the discussion of efavirenz, the metabolism of antiretroviral and anti-TB agents may differ substantially between populations of
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different racial and ethnic backgrounds so that additional studies in diverse patient populations are required. Finally, much more work needs to be done to evaluate these drug interactions in key subgroups of patients with HIV-related TB: pregnant women, very young children, and severely ill patients.70
CONCLUSIONS Despite the complexities, HIV-related TB can be managed very effectively. With attention to detail, the outcomes of these patients, in terms of both anti-TB and antiretroviral therapy, can be very similar to the outcomes of patients without this deadly coinfection. Tuberculosis should be treated with a rifamycin throughout – the drug–drug interactions between rifamycins and antiretroviral drugs should be managed rather than avoided altogether. The first choice for the antiretroviral therapy regimen is efavirenz plus two nucleoside analogues, with alternatives for those who cannot take efavirenz. There are few clinical responses in medicine as dramatic and gratifying as that of a patient with HIV-related TB started on potent antiretroviral therapy.
ACKNOWLEDGEMENTS This work was supported in part by the Tuberculosis Trials Consortium, Centers for Disease Control and Prevention, Atlanta, GA.
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22. Brennan-Benson P, Lyus R, Harrison T, et al. Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all. AIDS 2005;19:1541–1543. 23. Pedral-Sampaio DB, Alves CR, Netto EM, et al. Efficacy and safety of efavirenz in HIV patients on rifampin for tuberculosis. Braz J Infect Dis 2004;8:211–216. 24. Patel A, Patel K, Patel J, et al. Safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with tuberculosis and HIV-1. J Acquir Immune Defic Syndr 2004;37:1166–1169. 25. Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV- infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001;28:450–453. 26. Ramachandran G, Hemanthkumar AK, Rajasekaran S, et al. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration. J Acquir Immune Defic Syndr 2006;42:36–41. 27. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263. 28. Avihingsanon A, Manosuthi W, Kantipong P, et al. Pharmacokinetics and 12 weeks efficacy of nevirapine, 400 mg vs. 600 mg per day in HIVinfected patients with active TB receiving rifampicin: a multicenter study. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections, February 25–28, 2007, Los Angeles, CA. 29. Haas DW, Bartlett JA, Andersen JW, et al. Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration. Clin Infect Dis 2006;43:783–786. 30. Ritchie MD, Haas DW, Motsinger AA, et al. Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity. Clin Infect Dis 2006;43:779–782.
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31. Autar RS, Wit FW, Sankote J, et al. Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis. Antivir Ther 2005;10:937–943. 32. Manosuthi W, Sungkanuparph S, Thakkinstian A, et al. Plasma nevirapine levels and 24-week efficacy in HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy with or without rifampicin. Clin Infect Dis 2006;43:253–255. 33. Cohen K, van Cutsem G, Boulle A, et al. Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis. J Antimicrob Chemother 2008;61:389–393. 34. Boulle A, Van Cutsem G, Cohen K, et al. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. JAMA 2008;300:530–539. 35. Burger DM, Agarwala S, Child M, et al. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents Chemother 2006;50:3336–3342. 36. La Porte CJ, Colbers EP, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother 2004;48:1553–1560. 37. Polk RE, Brophy DF, Israel DS, et al. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents Chemother 2001;45:502–508. 38. Moreno S, Podzamczer D, Blazquez R, et al. Treatment of tuberculosis in HIV-infected patients: safety and antiretroviral efficacy of the concomitant use of ritonavir and rifampin. AIDS 2001;15:1185–1187. 39. Drug-induced hepatitis with saquinavir/ritonavir + rifampin. AIDS Clin Care 2005;17(3):32. 40. Moultrie H, Meyers T. Antiretroviral and anti-TB co-therapy in children < 3 years in Soweto, South Africa: outcomes in the first 6 months. Paper presented at: XVI International AIDS Conference; August 13–18, 2006; Toronto. 41. Losso MH, Lourtau LD, Toibaro JJ, et al. The use of saquinavir/ritonavir 1000/100 mg twice daily in patients with tuberculosis receiving rifampin. Antivir Ther 2004;9:1031–1033. 42. Gallicano K, Sahai J, Shukla VK, et al. Induction of zidovudine glucuronidation and amination pathways by rifampin in HIV infected patients. Br J Clin Pharmacol 1999;48:168–179. 43. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007;46:125–133. 44. Pfizer Labs. Maraviroc package insert. http://media. pfizer.com/files/products/uspi_maraviroc.pdf. Accessed 29 August 2008. 45. Tibotec. Etravirine package insert. http://www. intelence-info.com/intelence/assets/pdf/ INTELENCE_PI.pdf. Accessed 29 August 2008. 46. McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med 1996;154:1462–1467. 47. Gonzalez-Montaner LJ, Natal S, Yonchaiyud P, et al. Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus rifampicin. Tuber Lung Dis 1994;75:341–347. 48. Schwander S, Rusch-Gerdes S, Mateega A, et al. A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis: a single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis. Tuber Lung Dis 1995;76:210–218. 49. Sun E, Heath-Chiozzi M, Cameron DW, et al. Concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse events. Paper presented at: XI International Conference on AIDS, 1996; Vancouver, Canada.
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50. Griffith DE, Brown BA, Girard WM, et al. Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium lung disease. Clin Infect Dis 1995;21:594–598. 51. Kerr BM, Daniels R, Clendeninn N. Pharmacokinetic interaction of nelfinavir with halfdose rifabutin (abstract). Can J Infect Dis 1999; 10 (Suppl B):21B. 52. Benator DA, Weiner MH, Burman WJ, et al. Clinical evaluation of the nelfinavir-rifabutin interaction in patients with tuberculosis and human immunodeficiency virus infection. Pharmacotherapy. 2007;27:793–800. 53. Gallicano K, Khaliq Y, Carignan G, et al. A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 2001;70:149–158. 54. Li J, Munsiff SS, Driver CR, et al. Relapse and acquired rifampin resistance in HIV-infected patients with tuberculosis treated with rifampin-, or rifabutinbased regimens in New York City, 1997-2000. Clin Infect Dis 2005;41:83–91. 55. Weiner M, Benator D, Burman W, et al. The association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with tuberculosis and HIV. Clin Infect Dis 2005;40:1481–1491. 56. Nettles RE, Mazo D, Alwood K, et al. Risk factors for relapse and acquired rifamycin resistance after directly observed tuberculosis treatment: a comparison by HIV serostatus and rifamycin use. Clin Infect Dis 2004;38:731–736. 57. Panomvana Na Ayudhya D, Thanompuangseree N, Tansuphaswadikul S. Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS. Clin Pharmacokinet 2004;43:725–732. 58. Doble N, Shaw R, Rowland-Hill C, et al. Pharmacokinetic study of the interaction between rifampin and ketoconazole. J Antimicrob Chemother 1988;21:633–635. 59. Jaruratanasirikul S, Sriwiriyajan S. Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients. Eur J Clin Pharmacol 1998;54:155–158. 60. Stone JA, Migoya EM, Hickey L, et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother 2004;48:4306–4314. 61. Wallace RDJ, Brown BA, Griffith DE, et al. Clarithromycin regimens for pulmonary Mycobacterium avium complex: the first 50 patients. Am J Respir Crit Care Med 1996;153:1766–1772. 62. Ribera E, Pou L, Fernandez-Sola A, et al. Rifampin reduces concentrations of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2001;45:3238–3241. 63. Sadler BM, Caldwell P, Scott JD, et al. Drug interaction between rifampin and atovaquone in HIV + asymptomatic volunteers. Paper presented at: 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1995. 64. Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clin Infect Dis 1992;14:165–174. 65. Drayton J, Dickinson G, Rinaldi MG. Coadministration of rifampin and itraconazole leads to undetectable levels of serum itraconazole. Clin Infect Dis 1994;18:266. 66. Griffith DE, Brown-Elliott BA, Wallace RJ Jr. Thrice-weekly clarithromycin-containing regimen for treatment of Mycobacterium kansasii lung disease: results of a preliminary study. Clin Infect Dis 2003;37:1178–1182. 67. Apseloff G, Foulds G, LaBoy-Garol L, et al. Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers. J Clin Pharm 1998;38:830–835. 68. El-Sadr W, Luskin-Hawk R, Yurick TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of
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Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Clin Infect Dis 1999;29:775–783. Gatti G, Merighi M, Hossein J, et al. Population pharmacokinetics of dapsone administered biweekly to human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1996;40:2743–2748. Benson CA, Williams PL, Cohn DL, et al. Clarithromycin or rifabutin alone or in combination for primary prophylaxis of Mycobacterium avium complex disease in patients with AIDS: a randomized, double-blind, placebo-controlled trial. J Infect Dis 2000;181:1289–1297. Okwera A, Whalen C, Byekwaso F, et al. Randomised trial of thiacetazone and rifampicincontaining regimens for pulmonary tuberculosis in HIV-infected Ugandans. The Makerere UniversityCase Western University Research Collaboration. Lancet 1994;344:1323–1328. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004; 364:1244–1251. van Oosterhout JJ, Kumwenda JJ, Beadsworth M, et al. Nevirapine-based antiretroviral therapy started early in the course of tuberculosis treatment in adult Malawians. Antivir Ther 2007;12:515–521. Narita M, Stambaugh JJ, Hollender ES, et al. Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis 2000;30: 779–783. Vargas A, De Wit S, Poll B, et al. Rifabutin versus rifampin in the treatment of tuberculosis in HIV patients. Paper presented at: 3rd IAS Conference on HIV Pathogenesis and Treatment; July 24–27, 2005; Rio de Janiero. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenzcontaining regimens for the initial treatment of HIV1 infection. N Engl J Med 2004;350:1850–1861. DART Virology Group and Trial Team. Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS 2006;20:1391–1399. Moyle G, Higgs C, Teague A, et al. An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy. Antivir Ther 2006;11:73–78. Panomvana Na Ayudhya D, Thanompuanseree N, Tansuphaswadikul S. Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS. Clin Pharmacokinet 2004;43:725–732. Doble N, Shaw R, Rowland-Hill C, et al. Pharmacokinetic study of the interaction between rifampin and ketoconazole. J Antimicrob Chemother 1988;21:633–635. Jaruratanasirikul S, Sriwiriyajan S. Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients. Eur J Clin Pharmacol 1998;54:155–158. Pfizer. Voriconazole package insert. 2005. Accessed 29 August 2008. Stone JA, Migoya EM, Hickey L, et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother 2004;48:4306– 4314. Wallace RDJ, Brown BA, Griffith DE, et al. Clarithromycin regimens for pulmonary Mycobacterium avium complex: the first 50 patients. Am J Respir Crit Care Med 1996;153:1766–1772. Ribera E, Pou L, Fernandez-Sola A, et al. Rifampin reduces concentrations of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2001;45:3238–3241. Sadler BM, Caldwell P, Scott JD, et al. Drug interaction between rifampin and atovaquone in HIV þ asymptomatic volunteers. Paper presented at: 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1995.
CHAPTER
61
Tuberculosis drug therapy in children H Simon Schaaf and Lisa J Nelson
INTRODUCTION
Infection with Mycobacterium tuberculosis usually results from inhalation of infected droplets into the lungs. This leads to the development of a primary parenchymal lesion (Ghon focus) in the lung with spread to the regional lymph node(s). In the majority of cases, the resultant cell-mediated immunity will contain the disease process at this stage. Disease progression does occur, especially in the very young (< 3 years old), when primary infection occurs in adolescence (> 10 years of age), and in immune-compromised children.1 Progression of disease occurs by: 1. extension of the primary focus with or without cavitation; 2. the effects of pathological processes in the draining lymph nodes; or 3. lymphatic and/or haematogenous spread of the disease.2 Children usually have paucibacillary disease (low organism numbers), as cavitating disease is relatively rare (about 6% or fewer of cases) in those less than 13 years of age.3 The majority of the bacilli in adulttype disease are found in the cavities. On the other hand, children develop extrapulmonary TB more often than adults do, and severe and disseminated TB (e.g. miliary TB and TB meningitis) occur especially in the young (< 3 years old) child. Both the bacillary load and the type of disease may influence the effectiveness of treatment regimens. Treatment outcomes in children are generally good, but treatment in young and immune-compromised children who are at higher risk of disease progression and disseminated disease should start promptly to decrease morbidity and mortality. The response of children infected with human immunodeficiency virus (HIV) to anti-TB treatment seems to be slower and mortality is generally higher.4–6 There is a low risk of adverse effects associated with use of the firstline treatment regimens recommended by the World Health Organization (WHO), which forms the basis of this chapter (permission obtained from the World Health Organization and the International Journal of Tuberculosis and Lung Disease) and will be discussed in this chapter.7–9 However, current treatment controversies and alternatives will also be discussed. Data on optimal treatment regimens are limited in children.
INCLUSION IN THE NEW STOP TB STRATEGY All children should be included in the new Stop TB Strategy 2006,10 which is based on the directly observed treatment, shortcourse (DOTS) strategy. This strategy includes elements such as:
government (political) commitment to sustained TB control activities; case detection (not only by sputum smear microscopy) of symptomatic children reporting to health services; the prescribing of efficacious standardized anti-TB regimens and monitoring adherence through direct observation of treatment; ensuring a regular uninterrupted supply of essential anti-TB drugs in paediatric dosage forms; and a standardized recording and reporting system that allows assessment of treatment results.
The main objectives of anti-TB treatment are to:7,8 1. cure the patient and decrease TB transmission to others by rapidly eliminating most of the bacilli; 2. effect permanent cure (that is, to prevent relapses by eliminating the dormant bacilli); 3. do the above with minimal adverse effects for the child; and 4. prevent the development of drug-resistant organisms by using a combination of drugs.
RECOMMENDED FIRST-LINE DRUG DOSAGES IN CHILDREN Table 61.1 shows the first-line (or essential) anti-TB drugs and their WHO/International Union against Tuberculosis and Lung Diseases (IUATLD) recommended doses.
RECOMMENDED TREATMENT REGIMENS Antituberculosis treatment is divided into two phases: an intensive phase and a continuation phase. The purpose of the initial intensive phase is to rapidly eliminate the majority of organisms and to prevent the emergence of drug resistance. This phase uses more drugs than the continuation phase. The purpose of the continuation phase is to eradicate the dormant organisms in the lesions. Fewer drugs are generally used in this phase because the risk of acquiring drug resistance is low, as most of the organisms have already been eliminated. In either phase, treatment can be given daily or three times weekly. Although twice-weekly treatment has been shown to be effective in children, mainly in studies with less severe forms of disease treated at primary level,11,12 and it is recommended and used in the United States where definite directly observed therapy is possible,13 twice-weekly treatment is not recommended by the WHO.7
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Table 61.1 Recommended doses of first-line antituberculosis drugs for children Drug
7
Recommended dose Daily
Isoniazid Rifampicin Pyrazinamide Ethambutola Streptomycinb
Three times weekly
Dose and range (mg/kg body weight)
Maximum (mg)
Dose and range (mg/kg body weight)
Daily maximum (mg)
5 (4–6) 10 (8–12) 25 (20–30) 20 (15–25) 15 (12–18)
300 600 – – –
10 (8–12) 10 (8–12) 35 (30–40) 30 (25–35) 15 (12–18)
– 600 – – –
a The recommended daily dose of ethambutol is higher in children than in adults because of lower serum concentrations with the same mg/kg dose and the recommended dose is safe with regards to optic neuritis – see text. b Streptomycin should be avoided when possible in children because the injections are painful and irreversible auditory nerve damage may occur. The use of streptomycin in children is mainly reserved for the first 2 months of treatment of TB meningitis. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. WHO, Geneva, Switzerland. WHO/HTM/TB/2006.371
Treatment of new (drug-susceptible) TB in children falls into three basic groups: 1. Treatment of uncomplicated smear-negative pulmonary/intrathoracic TB and less severe extrapulmonary TB. The majority of childhood TB should fall into this diagnostic category (category III) as long as timely diagnosis is made. 2. Treatment of smear-positive or -negative pulmonary TB with extensive parenchymal involvement/cavities and/or severe forms of extrapulmonary TB (e.g. abdominal or osteoarticular TB) other than tuberculous meningitis. This corresponds with diagnostic category I in adults. Severe concomitant HIV disease is included in this category in the WHO guidelines, but TB in HIVinfected children will be discussed in greater detail. 3. Treatment of tuberculous meningitis and miliary TB. Miliary TB should be managed similarly to TB meningitis because many children with miliary TB have meningeal tuberculous involvement.14 Although TB meningitis and miliary TB fall into diagnostic category I, these disease entities deserve special consideration (see below). Treatment of previously treated or possible drug-resistant TB in children forms a further two diagnostic categories for treatment. Previously treated cases fall into diagnostic category II although these children often do not have smear-positive pulmonary TB as defined in the adult TB diagnostic category. Category IV includes chronic and multidrug-resistant (MDR) TB. The currently recommended WHO treatment regimens for children and the respective TB diagnostic categories are summarized and defined in Table 61.2. There is a standard code for anti-TB treatment regimens. This code uses an abbreviation for each anti-TB drug, e.g. isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E). A regimen consists of two phases: the intensive and continuation phases. The number in front of each phase represents the duration of that phase in months. A subscript number (e.g. 3) following a drug abbreviation is the number of doses per week of that drug. If there is no subscript number following a drug abbreviation, treatment with that drug is daily. An alternative drug (or drugs) appears as an abbreviation (or abbreviations) in parenthesis.7 An example of this code is: 2HRZ/4H3R3. The duration of the intensive phase is 2 months and drug treatment is daily (no subscript numbers after the drug abbreviations). The continuation phase is 4H3R3: i.e. 4
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months of three times weekly isoniazid and rifampicin (subscript numbers after the abbreviations).
CORTICOSTEROIDS Corticosteroids may be used for the management of some complicated forms of TB, such as TB meningitis, complications of airway obstruction by TB lymph nodes, and pericardial TB. The drug most frequently used is prednisone in a dosage of 2 mg/kg daily, increased to 4 mg/kg daily in the most seriously ill children, with a maximum daily dose of 60 mg. Treatment is usually continued for 4 weeks, then the dose should be gradually reduced over 1–2 weeks before stopping (i.e. tapered).
CONTROVERSIES IN THE TREATMENT OF PULMONARY TUBERCULOSIS There are limited published data on the use of anti-TB medications in children. For many reasons, data from adult studies cannot always be extrapolated to children. Pharmacokinetics (what the body does with a drug) and pharmacodynamics (what the drug does to the body) vary considerably in children compared with adults, based on a number of different factors: immature renal function, altered hepatic enzyme activity and size relative to body weight, differences in drug absorption, body composition, tissue binding characteristics, and central nervous system (CNS) penetration of the various drugs. All these factors vary considerably by age. Dosing recommendations in children are age dependent, usually in the following age categories: newborn (preterm vs term), infant (0–12 or 0–24 months.), child (2–12 years), adolescent (13–17 years). There is also greater between and within child variability in drug absorption and metabolism than with adults – for this reason, some recommend therapeutic drug monitoring, where this is available. Drug dosages in children are likely to be affected by age, nutritional status, HIV status, and preparation, especially when specific paediatric drug formulations are not available. In addition to the pharmacokinetic and dynamic issues, children have greater issues with formulations (e.g. availability of liquids or other ‘child-friendly’ formulations, palatability) and adherence. Children are mostly dependent on caregivers to ensure adherence.
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Table 61.2 Recommended WHO treatment regimens for children in each TB diagnostic category TB diagnostic category
III
7 a
TB cases
61
Regimens
New smear-negative pulmonary TB (other than in category I) Less severe forms of extrapulmonary TB New smear-positive pulmonary TB New smear-negative pulmonary TB with extensive parenchymal involvement Severe forms of extrapulmonary TB (other than TB meningitis – see below) Severe concomitant HIV disease TB meningitis Previously treated smear-positive pulmonary TB: Relapse Treatment after interruption Treatment failure Chronic and MDR-TB
e
Intensive phase
Continuation phase
2HRZb
4HR or 6HE
2HRZE
4HR or 6HEc
2HRZSd 2HRZES/1HRZE
4HR 5HRE
I
I II
IV
Specially designed standardized or individualized regimens (see treatment guidelines for MDR-TB in Chapter 52)
E, ethambutol; H, isoniazid; R, rifampicin; S, streptomycin; Z, pyrazinamide. Direct observation of drug administration is recommended during the initial phase of treatment and whenever the continuation phase contains rifampicin. b In comparison with the treatment regimen for patients in category I, ethambutol may be omitted during the initial phase of treatment for patients with non-cavitary, smear-negative pulmonary TB who are known to be HIV-negative, patients known to be infected with fully drug-susceptible bacilli, and young children with primary TB. c This regimen (2HRZE/6HE) may be associated with a higher rate of treatment failure and relapse than the 6-month regimen with rifampicin in the continuation phase. d In comparison with the treatment regimen for patients in diagnostic category I, streptomycin replaces ethambutol in the treatment of TB meningitis. e Although not included in the treatment table of the WHO child TB guidance of 2006, The continuation phase can be given thrice weekly under close observation in cases of lesser forms of TB disease. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. WHO, Geneva, Switzerland. WHO/HTM/TB/2006.371 a
There is a need for better anti-TB drug pharmacokinetic knowledge in children. Several studies have shown lower serum concentrations for isoniazid, the rifamycins, pyrazinamide, and ethambutol at the same milligram/kilogram body weight dose in children than in adults. Following a recent comprehensive review on ethambutol in children, Donald for the WHO came to the conclusion that: ‘peak serum ethambutol concentrations in both children and adults increase in relation to dose, but are significantly lower in children than adults receiving the same mg/kg body weight dose.’15 Ethambutol was also shown to rarely cause optic neuritis in children at a dose of 25 mg/kg or less. The WHO recommended dose for ethambutol in children was subsequently increased to 20 mg/kg (range 15–25 mg/kg), which is higher than the recommended dose for adults. Although there has been reluctance to recommend the use of ethambutol in young children in the past, several recent comprehensive reviews of all available published data suggest that it is safe when prescribed at recommended doses.15–17 In a study on isoniazid, improved analytical technology and advanced understanding of the polymorphisms governing isoniazid metabolism were used to better understand isoniazid pharmacokinetics in children. Exposure of children to isoniazid, as reflected by the first-order elimination rate constant (k), area under the concentration versus time curve (AUC) 2–5 hours after dosing, and isoniazid concentration at different time intervals after dosing, was significantly less than that of a group of adults drawn from the same population and receiving the same milligram/kilogram body weight dose of isoniazid.18 The findings of this study, taking into account the acetylation genotype, confirm that younger children eliminate isoniazid faster than older children, and children, as a group,
faster than adults. This study suggests that children should receive an isoniazid dose closer to 10 mg/kg body weight. The WHO and IUATLD currently recommend 5 mg/kg (4–6 mg/kg) isoniazid for children and adults. However, guidelines from the American Academy of Pediatrics (AAP) and the American Thoracic Society (ATS) recommend an isoniazid dose of 10–15 mg/kg/dose.13,19 Blake et al.20 have shown that, given a comparable weightnormalized dose, rifapentine exposure estimates are lower in children than those reported in adults, suggesting that a larger weight-normalized (i.e. mg/kg) dose of rifapentine is needed in children. Rifapentine, a long-acting rifamycin, has the potential to simplify treatment regimens in children. Provisional data on rifampicin levels in a study from Cape Town, South Africa, show similar lower concentrations in children to those in adults at the same milligram/kilogram body weight dose (PR Donald, personal communication). Graham et al.21 have found poor absorption of pyrazinamide in Malawian children. Younger children (< 5 years of age) reached significantly lower serum concentrations than older (> 5 years) children and in almost all cases the maximum serum concentration failed to reach the minimal inhibitory concentration for M. tuberculosis at the three times weekly dose of 35 mg/kg body weight. A pharmacokinetic study by Zhu et al.22 also showed that incomplete or delayed absorption of pyrazinamide was more common in children than in adults. Further, the median volume of distribution and median clearance was larger in children, with a resultant median half-life 43% shorter in children. These data suggest that the currently recommended doses for several first-line anti-TB drugs in children may be too low.
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However, before these recommended doses can be changed, a thorough review of existing pharmacokinetic studies of each of these drugs needs to be done and most likely further pharmacokinetic studies will be needed. Data on the use of second-line drugs in children are extremely limited. Thiacetazone is no longer recommended as part of any first-line regimen to treat TB (and has been completely withdrawn in many countries), as it has been associated with severe reactions, such as Stevens-Johnson syndrome in adults and children with TB who were coinfected with HIV. Although optimal treatment regimens and dosages are not known for children, children in clinical trials generally have good treatment outcomes and lower death rates than adults.11,12,23 However, several recent studies have found poor treatment outcomes under routine programme conditions in developing countries,24 including high default and death rates. More research is needed to understand how to improve outcomes in these programmes.
CONTROVERSIES IN THE TREATMENT OF EXTRAPULMONARY TUBERCULOSIS IN CHILDREN MANAGEMENT OF TUBERCULOSIS MENINGITIS AND MILIARY TUBERCULOSIS Tuberculosis meningitis and miliary TB are common in young children and are associated with high rates of morbidity and mortality, particularly if diagnosis is delayed. It is therefore important to consider these diagnoses early in children, especially if there is a history of contact with an infectious TB source case. Treatment should start as soon as the diagnoses are suspected to prevent progression of disease. Miliary or haematogenously disseminated TB has a high risk (approximately 60%) of meningeal involvement and should therefore be managed similarly to TB meningitis.14 For this reason, some experts recommend that all children with miliary TB should undergo a lumbar puncture to exclude TB meningitis. In other forms of severe extrapulmonary TB and in smearpositive pulmonary TB (category I), ethambutol is recommended as the fourth drug in the intensive phase. Because of different degrees of drug penetration into the CNS, some experts recommend modifying the standard WHO antituberculous treatment for children (see Table 61.2). However, ethambutol penetrates
poorly into the cerebrospinal fluid except in the presence of inflamed meninges.25–27 Streptomycin also penetrates poorly into the cerebrospinal fluid even in the presence of meningeal inflammation and therefore probably has a role in only the first 2 months of treatment. Some experts recommend ethionamide as the fourth drug, because ethionamide crosses both healthy and inflamed meninges.28,29 Furthermore, because rifampicin does not penetrate the uninflamed meninges well and pyrazinamide does,30–32 the continuation of pyrazinamide for the full 6 months’ treatment will most likely improve eradication of most organisms from the cerebrospinal fluid and is therefore recommended by some experts. On the other hand, some experts recommend a longer duration of continuation phase treatment. Because penetration into the cerebrospinal fluid is poor with some drugs, such as rifampicin and streptomycin, treatment regimens for TB meningitis and miliary TB will most likely benefit from the upper end of the recommended dosage ranges. Table 61.3 summarizes recommended alternative treatment regimens for TB meningitis and miliary TB by different experts. Corticosteroids (usually prednisone) are recommended for all children with TB meningitis. Several studies of more severe TB meningitis have shown corticosteroids to improve survival and decrease morbidity.33–35 Prednisone dosage is 2–4 mg/kg (maximum 60 mg) daily for 4 weeks. The higher dose is recommended where higher doses of rifampicin are used, as rifampicin induces the cytochrome P450 system, causing a decrease in corticosteroid concentration. The dose should then be gradually reduced over 1–2 weeks before stopping. Drugs useful in the management of raised intracranial pressure and communicating hydrocephalus are discussed in Chapter 38. Children with TB meningitis and miliary TB should be hospitalized, preferably for at least the first 2 months or until their clinical status has stabilized. Directly observed therapy is essential, as nonadherence to treatment leads to more severe disability and death. Children with TB meningitis are at high risk of long-term disability and therefore benefit from specialist care, including occupational therapy and physiotherapy, where this is available.
OTHER TYPES OF EXTRAPULMONARY TUBERCULOSIS The majority of extrapulmonary TB types are treated with a 6-month regimen containing rifampicin. In lymph node TB, the most common form of extrapulmonary TB, the affected nodes may enlarge while patients are receiving appropriate therapy and
Table 61.3 Selected regimens for treatment of tuberculosis meningitis (and miliary tuberculosis) in children Intensive phase
Continuation phase
Source
2HRZSa 2HRZ(S or Eth)b
4HR 7–10HR or 7–10H2R2
6HRZEthc
None – remain on intensive phase drugs for full 6 months 10HR
World Health Organization (2006)7 American Academy of Pediatrics (2006)13 American Thoracic Society (2003)19 Donald et al. (1998)32
2HRZ(S or E)
British Thoracic Society (1998)69
E, ethambutol; H, isoniazid; R, rifampicin, S, streptomycin; Z, pyrazinamide, Eth, ethionamide. a For dosages see Table 61.1. b Isoniazid 10–15 mg/kg, rifampicin 10–20 mg/kg, pyrazinamide 20–40 mg/kg, streptomycin 20–40 mg/kg, and ethionamide 15–20 mg/kg (daily dosages). c Isoniazid 20 mg/kg, rifampicin 20 mg/kg, pyrazinamide 40 mg/kg, and ethionamide 20 mg/kg (daily dosages).
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even after completion of therapy without evidence of bacteriological relapse.36,37 Despite this, the recommended 6-month treatment regimen (category III, Table 61.2) is sufficient. For large lymph nodes that are fluctuant and appear to be about to drain spontaneously, aspiration (traverse through normal skin) or incision and drainage appears to be beneficial. Osteoarticular TB, and especially spinal TB, is often claimed to need longer duration of treatment.38 However, several studies have shown that osteoarticular TB including spinal TB can be treated with a 6-month regimen including rifampicin.39 Many TB specialists will prefer to treat osteoarticular TB, especially spinal TB, for 9 months or more.
RE-TREATMENT CASES In childhood TB cases when anti-TB treatment fails or a relapse occurs, every effort should be made to find the most likely cause for the failure or relapse. This could be due to incorrect regimens prescribed or non-adherence to treatment, severe immune compromise, reinfection by a new source case, drug resistance, or incorrect diagnosis, especially if not culture confirmed and especially in the HIV-infected patient. Mycobacterial culture and drug susceptibility testing (DST) should be done for all re-treatment cases where possible. Failure of treatment in children is rare. The WHO recommends these cases should be managed in the same way that failure in adults is managed, either with a category II or IV regimen, depending on what is known about the risk of MDR-TB in this group of patients, e.g. a known adult source case with MDR-TB. The standard category II regimen (Table 61.2) adds a single drug to a failing regimen if the child was previously treated with category I treatment, but two drugs if the child previously received a category III regimen. In our experience, a category II regimen is not recommended. Instead, every effort should be made to determine whether the child may have drug-resistant TB, including history of contact with an infectious drug-resistant source case and/or culture and DST on the child’s isolates. If the child has had progressive deterioration of the TB despite adherent regimen I or III treatment, it is likely that drug resistance is present and this should be taken into account when a new (category IV) regimen is considered. In all other cases of recurrent TB we recommend to restart the patient on regimen I or III, depending on the category of disease, and wait for the DST results or follow the clinical response to treatment. Category IV regimens are specially designed and may be standardized or individualized. If an adult source case with drugresistant TB is identified, the child should be treated according to the drug susceptibility pattern of the source case’s strain if an isolate from the child is not available.40,41 Two or more new drugs should be added to any re-treatment regimen in case of genuine failure of treatment and the duration of treatment should be no less than 9 months.7,8 Management of MDR-TB in children is discussed in Chapter 52.
isoniazid or rifampicin is the most important, as these drugs form the mainstay of current short-course chemotherapy. In the case where monoresistance to isoniazid is known or suspected when treatment is initiated, the addition of ethambutol to isoniazid, rifampicin, and pyrazinamide in the intensive phase is recommended. Some authorities would also recommend the addition of ethambutol in the continuation phase, the total duration of treatment lasting 9 months. For patients with more extensive disease, consideration should be given to the addition of a fluoroquinolone and to prolonging treatment to a minimum of 9 months.7 If monoresistance to isoniazid is discovered only once the child has been on treatment for a while and response is poor, the principle of never adding a single drug to a failing regimen should be adhered to. The addition of two or three new drugs, such as ethambutol, ethionamide, and/or a fluoroquinolone, should be considered. Monoresistance to rifampicin is uncommon in children. The WHO recommends that these cases should be treated with isoniazid, ethambutol, and a fluoroquinolone for at least 12–18 months, with the addition of pyrazinamide for at least the first 2 months. However, some experts recommend that these cases should be treated as MDR-TB cases. Polyresistant TB with resistance to isoniazid and other first-line drug(s) but not rifampicin should be treated with rifampicin and pyrazinamide in addition to at least two further drugs to which the organism is susceptible for a minimum duration of 9–12 months.
MULTIDRUG RESISTANCE (MDR-TB)7 Multidrug-resistant tuberculosis is resistance to both isoniazid and rifampicin with or without resistance to other anti-TB drugs. Multidrug-resistant tuberculosis in children is mainly the result of transmission of a MDR M. tuberculosis strain from an adult source case, and therefore often not suspected unless a history of contact with an adult MDR pulmonary TB case is known. Treatment is difficult and best left to a specialist. Some basic principles of treatment are as follows:
MANAGEMENT OF MONO- AND POLYDRUG RESISTANCE Monodrug resistance is defined as resistance to a single first-line drug, most commonly isoniazid, while polydrug resistance is defined as resistance to isoniazid or rifampicin (not both) with resistance to one or more other first-line drugs. Resistance to
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Do not add a single drug to a failing regimen. Treat the child according to the drug susceptibility pattern (and using the treatment history) of the source case’s strain if the child’s isolate is not available. Give at least three or more drugs to which the patient’s isolate is susceptible and/or naı¨ve (i.e. when MDR-TB is identified, a new regimen should be designed which considers what is known about the patient’s – or the source case’s – isolates as well as the patient’s previous anti-TB treatment). Use daily treatment only; directly observed therapy is essential. Counsel the caregiver at every visit, to provide support; advise about adverse effects and the importance of compliance and completion of treatment. Follow-up is essential; clinical, radiological, and with cultures. Treatment duration depends on the extent of the disease, but in most cases will be 12–18 months after the first negative culture. With correct dosing, few long-term adverse effects are seen with any of the more toxic second-line drugs in children, including ethionamide and the fluoroquinolones.
Children with MDR-TB should be treated with the first-line drugs to which their M. tuberculosis strain (or that of their source case) is susceptible. Ethambutol is bactericidal at higher doses, so daily doses up to 25 mg/kg should be used in children being
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Table 61.4 Second-line antituberculosis drugs for treatment of MDR-TB in children Second-line drug
Ethionamide or prothionamide Fluoroquinolonesb Ofloxacin Levofloxacin Moxifloxacin Gatifloxacin Ciprofloxacin Aminoglycosidesc Kanamycin Amikacin Capreomycinc Cycloserine or terizidone Para-aminosalicylic acid (PAS)d Reserve drugse Clofazamine Amoxicillin/clavulanate Clarithromycin
Mode of action
Bactericidal
7,41,70
Common adverse effects
Recommended daily dose Range (mg/kg body weight)
Maximum (mg)
15–20
1,000
15–20 7.5–10 7.5–10 7.5–10 20–40
800 – – – 1,500
Psychiatric, neurological Vomiting, gastrointestinal upset
15–30 15–22.5 15–30 10–20 150
1,000 1,000 1,000 1,000 12,000
Diarrhoea
3–5 25–45 (amoxicillin component) 15
300 2,000 1,000
a
Vomiting, gastrointestinal upset Arthralgia, arthritis
Bactericidal Bactericidal Bactericidal Bactericidal Bactericidal Ototoxicity/nephrotoxicity Bactericidal Bactericidal Bactericidal Bacteriostatic Bacteriostatic Bacteriostatic? Bacteriostatic? Bacteriostatic?
a
This can be overcome by initially dividing the daily dose and starting with a lower dose for the first week or two. Although fluoroquinolones are not approved for use in children in most countries, the benefit of treating children with MDR-TB with a fluoroquinolone may outweigh the risk in most instances. c Injectable drugs. d Divided into two or three doses daily and given in an acidic drink/food, e.g. orange juice or yoghurt. e Also called reinforcing drugs. The clinical benefit of adding these drugs has not been proven. Clofazamine is the cheapest and should be used first. Susceptibility of M. tuberculosis to clarithromycin is only approximately 15%. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. WHO, Geneva, Switzerland. WHO/HTM/TB/2006.37. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO, Geneva, Switzerland. WHO/HTM/TB/2006.361. and Partners in Health. The PIH guide to the medical management of multidrug-resistant tuberculosis. Ed. Rich ML. Partners in Health, USA 2003. b
treated for MDR-TB. Table 61.4 summarizes the second-line antiTB drugs for the treatment of MDR-TB in children. The further management and treatment of MDR-TB in children is discussed in Chapter 52.
CHILDREN WITH TUBERCULOSIS WHO ARE COINFECTED WITH HIV In high HIV prevalence settings, all children (or their parents or guardians) with TB should be routinely offered HIV testing and access to HIV-related care. Since it can be difficult to establish the diagnosis of HIV in children < 18 months of age in lowresource settings, HIV-exposed children should be managed as if they were HIV-infected, excluding antiretroviral therapy. Most current international guidelines recommend that TB in HIVinfected children should be treated with a 6-month rifampicin-based regimen as in HIV-uninfected children.7,9 However, some national guidelines recommend that HIV-infected children with pulmonary TB be treated for 9 months and those with extrapulmonary TB be treated for 12 months.42 There is a body of evidence accumulating that shows a poorer response to anti-TB treatment and a higher relapse rate in HIV-infected children (and adults) with TB.4–6,43 Where possible, HIV-infected children should be treated with rifampicin for the entire treatment duration, as higher relapse rates have been found in adults when treated with ethambutol in the continuation phase.44,45 Most children with HIV/TB coinfection
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have a good response to the 6-month rifampicin-based regimen. However, the clinical, radiological, and microbiological response to treatment should be evaluated before treatment is discontinued at the end of the 6-month treatment. If the clinical or radiological response is poor or culture for M. tuberculosis is found to be positive after the intensive treatment phase, prolonging the treatment duration to 9–12 months should be considered. Possible causes for failure, such as non-compliance with therapy, poor drug absorption, drug resistance, and alternative diagnosis, should be investigated in children who are not improving on anti-TB treatment. The optimal duration of treatment of HIV/TB coinfected children still needs to be established. As in children not infected with HIV, a trial of anti-TB treatment is not recommended in HIV-infected children. A decision to treat any child for TB should be carefully considered, and, once this is done, the child should receive a full course of treatment unless an alternative diagnosis can be established unequivocally.7
COTRIMOXAZOLE Daily or thrice-weekly cotrimoxazole chemoprophylaxis (20 mg trimethoprim (TMP) and 100 mg sulfamethoxazole (SMX) if < 6 months of age; 40 mg TMP and 200 mg SMX if 6 months to 5 years of age; 80 mg TMP and 400 mg SMX if > 5 years of age) prolongs survival in HIV-infected children not on antiretroviral therapy and reduces the incidence of respiratory infections and hospitalization. It is also recommended in HIV-exposed children
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until a diagnosis can be definitively established. Studies of cotrimoxazole prophylaxis in HIV-infected adults with TB have shown clear benefit.46 Such studies have not been done in children, but the current recommendation is that HIV-infected children with TB should receive cotrimoxazole chemoprophylaxis even when on antiretroviral therapy.47 There is currently no consensus on whether cotrimoxazole chemoprophylaxis can be stopped in children on highly active antiretroviral therapy (HAART) who have good immune reconstitution, although some experts recommend that cotrimoxazole can safely be stopped if the CD4þ cell count is more than 25%.
ANTIRETROVIRAL THERAPY HIV-infected children benefit from antiretroviral therapy (ART). Standardized recommendations for ART and when to start ART have been published by the WHO and many national guidelines exist.48 All currently recommended ART includes a minimum of three drugs from different classes, which has been named highly active antiretroviral therapy. The introduction of HAART has reduced HIV-related TB disease by up to 80% in one adult study.49 In settings with a high TB incidence many adults and children on ART still develop TB. Further, TB is often diagnosed while patients are preparing for ART or as a result of an immune reconstitution inflammatory syndrome (IRIS) after initiating ART. In HIV-infected children diagnosed with TB, however, the initiation of anti-TB treatment is the priority. Treatment of TB in HIV-infected children on ART or who are planned to start on ART needs careful consideration, as there are a number of issues that need to be taken into consideration: 1. pharmacokinetic issues, e.g. drug–drug interactions and drug malabsorption; 2. overlapping drug toxicities; 3. immune reconstitution inflammatory syndrome; 4. adherence to multiple medications; and 5. timing of initiation of (HA)ART.
Pharmacokinetic issues There is an urgent need for more pharmacokinetic data for children on TB treatment and ART, as there currently are no published studies in children. Data from adult studies are summarized below. The rifamycins induce the cytochrome P450-3A4 system in the intestinal wall and the liver, considerably decreasing the serum levels of two classes of antiretroviral drugs, the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rifampicin is the most potent of these inducers. Serum concentrations of all protease inhibitors, except ritonavir, are reduced by 75–95%, rendering them ineffective and increasing the risk of developing drug resistance.50 The serum concentration of ritonavir is decreased by only 35% and can therefore still be used in a cotreatment HAART regimen. Of the NNRTIs, the area under the curve is decreased by 22% for efavirenz and by 37–58% for nevirapine.51 These data are all obtained from adult studies, and there are large variations in hepatic clearance, especially for efavirenz. Dosage adjustment of antiretroviral drugs in TB treatment as suggested by the Centers for Disease Control and Prevention (CDC) is not generally recommended, although some clinicians routinely increase the dosage of efavirenz and/or ritonavir. Current recommendations for first-line HAART in children on rifampicinbased TB treatment are summarized in Table 61.5.
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Nevirapine at normal dosage may also be effective according to some studies,51 but causes more hepatotoxicity than efavirenz. If a patient is already on a HAART regimen that includes nevirapine and is stable, this regimen could be continued, but liver function tests should be monitored monthly while on rifampicin. Triple nucleoside reverse transcriptase inhibitor (NRTI) regimens are inferior to HAART and are no longer recommended. When lopinavir/ritonavir (Kaletra) is used, the ritonavir dose should be increased to the equivalent dose to lopinavir or, if ritonavir as a single drug is not available, a double dose of lopinavir/ ritonavir (Kaletra) should be given. Concern has been expressed that patients with HIV-related TB are more prone to malabsorption of anti-TB drugs than HIV-uninfected patients. Isoniazid concentrations were similar in HIV-infected and -uninfected children.18 Lower serum concentrations of rifampicin were found in HIV-infected patients with very low CD4þ cell counts.52 This could promote rifampicin resistance. There is concern about the relatively low doses of isoniazid (4–6 mg/kg/day) and rifampicin (8–12 mg/kg/day) currently recommended by the WHO, which are based mainly on adult studies. Given these uncertainties, in treating HIV-infected children with TB, clinicians should rather err on the side of giving the higher range of the allowed TB dosages. Where available, rifabutin offers an alternative to rifampicin and can be used with a wider range of antiretrovirals, though often with some dose adjustment. However, data on the use of rifabutin for treatment in children are scarce.
Overlapping drug toxicities Antituberculosis and antiretroviral drugs have many toxicity profiles in common. However, data in coinfected children are scarce. Adverse effects to anti-TB drugs seem to be more common in HIV-infected patients. In adult studies, most adverse effects occurred within 2 months of starting therapy.53 Because of the presence of overlapping toxicities, it is usually recommended that the initiation of HAART be delayed, either until after the completion of anti-TB treatment or until there has been time to detect and manage early adverse effects of the anti-TB drugs (approximately 2 months). In adults, peripheral neuropathy is more common when isoniazid and stavudine (d4T) are given concomitantly.53 Although peripheral neuropathy due to isoniazid is uncommon in children, pyridoxine supplementation is recommended for children on HAART. Skin rash is relatively common on anti-TB treatment, but, if not severe, treatment can be continued. An additional drug that could potentially cause severe skin rash is cotrimoxazole. Nevirapine, and to a lesser extent efavirenz and abacavir, may also cause rashes. If the rash is severe, these drugs should all be discontinued and reintroduced individually to identify the drug responsible. Both abacavir and nevirapine should not be reintroduced if a hypersensitivity reaction is suspected (fever, respiratory and gastrointestinal symptoms, elevated transaminases). Antituberculosis drugs are the most likely to cause gastrointestinal adverse effects, but this is rarely a cause for stopping therapy. Splitting the dose may reduce nausea and vomiting. This has implications for DOT, as the second dose will often not be observed. Hepatitis is not a common adverse effect in children on anti-TB treatment, but is probably the most serious. Some define hepatotoxicity as aspartate or alanine transaminase levels more than five times normal, while others look for clinical jaundice and/or
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Table 61.5 Recommendations for the timing of ART and an ART regimen following the initiation of tuberculosis treatment with a rifampicin-containing regimen in HIV-infected infants and children WHO clinical stage of child with TB (as an event indicating need for ART)
a
Timing of ART following initiation of TB treatment
WHO paediatric clinical stage 4b WHO paediatric clinical stage 3c
Start ART early: between 2 and 8 weeks following start of TB treatment With clinical management only (no CD4þ count available): Start ART early: between 2 and 8 weeks following start of TB treatment. If excellent clinical response to TB treatment in first 2– 8 weeks of TB therapy, and child is stable, initiation of ART may be delayed to after 2 months or end of TB therapy
WHO paediatric clinical stage 3
Where CD4þ count is available. Evaluate the possibility of delaying initiation of ART depending on assessment of clinical status and CD4þ, and clinical and immunological response to TB therapy: Severe and advanced immunodeficiency:f initiate ART early, between 2 and 8 weeks following start of TB treatment Mild or no immunodeficiency:g initiation of ART may be delayed until after the completion of TB therapy; closely monitor response to TB therapy and reassess need for ART after TB therapy; if no improvement, consider starting ART
Recommended ART regimen and alternatives In children < 3 years:d Triple NRTI first-line regimen (WHO) (d4T or AZT þ 3TC þ ABC) or Standard first-line regimen of 2 NRTIs þ NVP (WHO) Two NRTIs þ lopinavir/boosted ritonavir or ritonavir only57 In children > 3 years:d Triple NRTI first-line regimen (WHO 2006e) (d4T or AZT þ 3TC þ ABC) or Standard first-line regimen of 2 NRTIs þ EFVe (for many this will be first choice) Following completion of TB treatment it is preferable to remain on the ART regimen if well tolerated. Regimens as recommended above Where ART can be delayed until after completion of TB treatment, initiation with standard two NRTIs þ NNRTI first-line regimen is recommended (NVP or EFV)
Adapted from WHO (2006).48 ART, antiretroviral therapy; ABC, abacavir; NRTIs, nucleoside reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; EFV, efavirenz; NVP, nevirapine. a Administration of cotrimoxazole is important in all children coinfected with TB and HIV. b All children with paediatric WHO clinical stage 4 should be initiated on ART regardless of CD4þ criteria. c Careful clinical monitoring with laboratory support, if available, is recommended where NVP is administered concurrently with rifampicin. d Because of lack of data the ranking of preferred ARV regimens is not possible. e EFV is not currently recommended for children < 3 years of age (or < 10 kg body weight). It should also not be given to postpubertal adolescent girls who are either in the first trimester of pregnancy or are sexually active and not using adequate contraception (rifampicin also renders oral contraception inadequate) f Severe immunodeficiency – age specific.48 g Mild or non-significant immunodeficiency is assumed at age-specific CD4þ levels.48 Worlrd Health Organization. Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access. Recommendations for a public health approach 2006. WHO, Geneva Switzerland. 2006:1–163.
abdominal pain/tenderness. If liver toxicity occurs, potentially hepatotoxic TB drugs and all antiretroviral drugs should be stopped. Antituberculosis drugs take precedence over ART and should be reintroduced individually, while monitoring liver function tests. We have found a combination of ethambutol, a fluoroquinolone (ofloxacin or ciprofloxacin), and an aminoglycoside (amikacin or streptomycin) useful in the treatment of TB complicated by severe transaminitis. Efavirenz should not be used in children less than 3 years of age or during pregnancy.
Immune reconstitution inflammatory syndrome (IRIS) IRIS is characterized by clinical and/or radiological deterioration after initial improvement and has been observed in patients on anti-TB treatment who have started HAART. Immune reconstitution (or paradoxical reaction) may also occur in the absence of ART due to improved nutrition or TB treatment per se. IRIS is not the result of treatment failure or relapse, or other disease.
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Manifestations may be subtle such as temporary exacerbation of symptoms (fever) and signs (lymph node enlargement, chest radiograph appearance, enlarging or new appearance of tuberculomas). It is most commonly seen in patients on HAART and TB treatment and usually develops within days to weeks of starting treatment, but could occur up to 6 months after starting treatment.54,55 The reaction usually subsides spontaneously on continuation of anti-TB treatment and ART with the judicious use of anti-inflammatory (corticosteroid) treatment.56 Management of severe cases (e.g. IRIS resulting in a rapidly expanding CNS lesion, airway compromise, respiratory distress) should be managed in hospital.
Adherence to multiple medications Parents or caregivers should understand the importance of adherence to treatment with several drugs for both TB and HIV treatment. Consideration should be given to the number of medications the child needs to ingest (about six to eight new drugs
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if TB treatment and ART given simultaneously). The social circumstances and the family’s ability and willingness to start and cope with these treatments should be evaluated before adding antiretroviral therapy. Where possible in older children, fixed-dose combination (FDC) tablets for TB and HIV medication should be used.
When to start ART in relation to TB treatment (Table 61.5) The optimal timing for the initiation of HAART in children with TB is not known. The decision to start HAART should take into consideration the degree of immunosuppression and the child’s progress during TB treatment. Different scenarios may present:
The child is already on ART when TB is diagnosed: if the patient is stable and antiretroviral drugs are compatible with a rifampicin-based TB treatment regimen, ART may be continued and anti-TB treatment added, with close follow-up for adverse effects. The likelihood of IRIS is probably low if the patient’s immune response has already been restored. The child is known to have untreated HIV infection and is newly diagnosed with TB, or newly diagnosed with both HIV and TB: tuberculosis treatment is the priority. The decision to initiate HAART should be individualized according to existing guidelines (WHO or country-specific) for initiation of ART in children. This is based on the clinical, immunological (CD4þ lymphocyte cell count or CD4þ percentage), and/or virological (viral load) status of the child. The younger the child, the more necessary to introduce both treatments simultaneously. In children who qualify for ART, most recommendations suggest postponing ART until after the first 2 months of TB treatment, to prevent the majority of overlapping drug toxicities and IRIS. In children with severe HIV disease, ART should be started within 2–8 weeks of TB treatment, but the risk of IRIS and toxicities are high.7,9,57
ADMINISTERING ANTITUBERCULOSIS TREATMENT AND ENSURING ADHERENCE Where possible, someone other than the child’s parent or immediate family should observe or administer treatment. Treatment should be given by either the parent or the directly observed therapy supporter, depending on who is best able to get the child to take the drugs. Adherence cards are recommended for documenting treatment. All children should receive treatment free of charge, irrespective of disease severity. Fixed dose combinations should be used whenever possible to improve simplicity and adherence. Child-friendly formulations, such as soluble tablets or powder, or suspensions, should be used where available; if not available and tablets (often based on adult dosage, such as the second-line drugs) must be used, health workers need to familiarize themselves with the strength of the tablets, whether these can be split in halves or quarters and whether they may be crushed without disturbing drug stability. For ease of administration, tablets may be crushed and mixed with a vitamin syrup or water immediately prior to administration. Prolonged contact with vitamins or any other sugar-containing suspension could reduce the bioavailability of drugs, especially rifampicin. Children with severe TB disease should be hospitalized for intensive management where possible. Conditions that merit hospitalization include:
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1. TB meningitis and miliary TB, preferably for the first 2 months; 2. any child with respiratory distress; 3. spinal TB; and 4. severe adverse effects, such as hepatotoxicity. Ideally, each child should be assessed at follow-up by the national TB programme (NTP) (or those designated by the NTP to provide treatment) 2 weeks after treatment initiation, at the end of intensive phase, and every 2 months until treatment completion. The assessment should include at a minimum clinical assessment and weight. Medication dosages should be adjusted to account for any weight gain. Adherence should be assessed by reviewing the treatment card. A follow-up sputum specimen for smear and/or culture at 2 months should be obtained for children who can expectorate sputum or any child who was smear-positive at diagnosis. The NTP is responsible for ensuring treatment and recording outcome. The NTP needs to communicate with the treating clinician. Adverse effects need to be referred to the clinician, and reported to the NTP (if noted by the clinician). Outcomes of children with TB should be reported using the standard outcome definitions (cure, treatment completion, default, transfer out, death, treatment failure).
ADVERSE EFFECTS Adverse effects are much less common in children than in adults. The most important adverse effect is the development of hepatotoxicity, which can be caused by isoniazid, rifampicin, pyrazinamide, or ethionamide. Serum liver enzyme levels do not have to be monitored routinely, as an asymptomatic elevation of liver enzymes (less than five times normal values) is not an indication to stop treatment. However, the occurrence of liver tenderness, hepatomegaly, and jaundice should lead to investigation of serum liver enzyme levels and the immediate stopping of all potentially hepatotoxic drugs. Patients should be screened for other causes of hepatitis, and no attempt should be made to reintroduce these drugs until liver functions have normalized. An expert should be involved in the further management of such cases. Isoniazid may cause symptomatic pyridoxine deficiency, particularly in severely malnourished children. Supplemental pyridoxine (12.5–25 mg/day) is recommended in malnourished children, HIVinfected children, breastfeeding infants, and pregnant adolescents.7 Ethambutol has been used with much caution in children < 7 years of age where visual acuity cannot be evaluated, but recent reviews have shown that ethambutol is safe at recommended doses.15–17 Ethionamide causes gastrointestinal discomfort and vomiting in about 50% of cases. This can be overcome by initially dividing the daily dose and starting with a lower dose for the first week or two.
CHEMOPROPHYLAXIS FOR CHILDREN EXPOSED TO, OR INFECTED BY, INFECTIOUS PULMONARY TUBERCULOSIS SOURCE CASES (TREATMENT OF LATENT TUBERCULOSIS INFECTION) The paediatric indications and national and international guidelines for chemoprophylaxis (or treatment of latent TB infection) vary widely. The main reasons for the variations are the incidence of TB in different settings, and the available resources to identify
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children in need of chemoprophylaxis and to administer chemoprophylaxis. Where TB incidence is low and programmes are aiming at eradication of TB, and resources are sufficient, chemoprophylaxis becomes a priority. Where the burden of TB disease is high, the main priority remains the identification and treatment (case holding) of infectious TB cases, as well as the treatment of children with TB disease. However, even in high-TBincidence settings, certain groups of children, such as the very young (< 5 years of age) and immune-compromised children, have a much higher risk of infection and of developing disease once infected. National TB programmes need to identify the level of risk they are prepared to accept and to identify those children who need chemoprophylaxis in their specific settings (see Chapter 28).
CHEMOPROPHYLACTIC REGIMENS Only the 6-month or more isoniazid regimen for chemoprophylaxis has been prospectively evaluated in children through randomized controlled trials and these studies showed isoniazid to be very effective in preventing disease after TB infection. The optimal duration of isoniazid chemoprophylaxis was determined to be 9 months in a reanalysis of the Bethel isoniazid studies.58 Current WHO guidelines recommend that, when tuberculin skin testing is not feasible, all asymptomatic children under 5 years of age and all HIV-infected children including those more than 5 years of age in close contact with a smear-positive pulmonary TB case should receive isoniazid chemoprophylaxis 5 mg/kg daily for 6 months.7 In many developed countries treatment for latent TB infection is recommended for all high-risk cases irrespective of age and isoniazid is either given daily or intermittently for 9 months.59 Many studies have shown poor adherence to isoniazid chemoprophylaxis.60–64 Shorter regimens with more drugs may improve adherence.60 However, studies in children on regimens with combination
REFERENCES 1. Marais BJ, Gie RP, Schaaf HS, et al. The natural history of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392–402. 2. Marais BJ, Donald PR, Gie RP, et al. Diversity of disease in childhood pulmonary tuberculosis. Ann Trop Paediatr 2005;25:79–86. 3. Schaaf HS, Beyers N, Gie RP, et al. Respiratory tuberculosis in childhood: the diagnostic value of clinical features and special investigations. Pediatr Infect Dis J 1995;14:189–194. 4. Schaaf HS, Krook S, Hollemans DW, et al. Recurrent culture-confirmed tuberculosis in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2005;24:685–691. 5. Espinal MA, Reingold AL, Perez G, et al Human immunodeficiency virus infection in children with tuberculosis in Santo Domingo, Dominican Republic: prevalence, clinical findings, and response to antituberculosis treatment. J Acquir Immune Defic Syndr Hum Retrovirol 1996;13:155–159. 6. Jeena PM, Mitha T, Bamber S, et al. Effects of human immunodeficiency virus on tuberculosis in children. Tuber Lung Dis 1996;77:437–443. 7. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children (WHO/HTM/TB/ 2006.371). Geneva: World Health Organization, 2006.
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therapy are few. Retrospective observational cohort studies showed equal benefit in reduction of disease in infected children by a 3-month daily isoniazid and rifampicin regimen compared with longer duration chemoprophylaxis with the same combination regimen.65 Further, a study in adults with silicoses showed equal efficacy of 3HR and 6H in preventing TB disease compared with placebo. In the latter study there was no difference in hepatotoxicity between the treatment groups.66 A 2- or 3-month regimen of rifampicin plus pyrazinamide (2–3RZ) has been shown to be as effective in preventing TB as isoniazid alone for 6–12 months in adults with or without HIV infection. Mortality in these groups was the same, but severe adverse effects (mainly hepatotoxicity) were more common with the 2–3RZ regimen.67 The 2RZ regimen is therefore no longer recommended for routine chemoprophylaxis in contacts of drug-susceptible infectious TB cases. In 1992 the AAP recommended treating children infected with an INH-resistant strain with rifampicin for 9 months.68 Since then a study in adults with silicoses showed a 3-month course of rifampicin to be as effective as 6H.66 Current ATS and AAP guidelines recommend a treatment regimen of 4–6 or more months of rifampicin only in INH-resistant cases of latent TB infection or when children cannot tolerate isoniazid.13,59 Optimal chemoprophylaxis for contacts of MDR-TB cases is currently not known. No randomized controlled trials have been done in adults or children to establish a treatment regimen for contacts exposed to MDR strains. WHO currently recommends isoniazid chemoprophylaxis in case the source case who infected the child may have been an isoniazid-susceptible patient and close follow-up of the asymptomatic exposed child for a minimum of 2 years.41 A non-randomized prospective study of child contacts of adults with MDR pulmonary TB showed a significant reduction in TB cases when contacts were given two anti-TB drugs to which the source case’s strain was susceptible for a period 6 months.40 For further management of MDR TB contacts see Chapter 52.
8. Stop TB Partnership Childhood TB Subgroup, World Health Organization. Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Chapter 2: Anti-tuberculosis treatment in children. Int J Tuberc Lung Dis 2006;10:1205–1211. 9. Stop TB Partnership Childhood TB Subgroup, World Health Organization. Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Chapter 3: Management of TB in the HIV-infected child. Int J Tuberc Lung Dis 2006;10:1331–1336. 10. Stop TB Strategy. WHO/HTM/TB/2006.368. Geneva: WHO, 2006. 11. Te Water Naude JM, Donald PR, Hussey GD, et al. Twice weekly vs. daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 2000;19:405–410. 12. Al-Dossary FS, Ong LT, Correa AG, et al. Treatment of childhood tuberculosis with a six month directly observed regimen of only two weeks of daily therapy. Pediatr Infect Dis J 2002;21:91–97. 13. American Academy of Pediatrics. Tuberculosis. In: Pickering LJ, Baker CJ, Long SS, et al. (eds). Red Book: 2006 Report of the Committee on infectious Diseases, 27th edn. Elk Grove Village, IL: American Academy of Pediatrics, 2006: 678–704. 14. Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and miliary tuberculosis in: the Rich focus revisited. J Infect 2005;50:193–195. 15. World Health Organization. Ethambutol efficacy and toxicity: literature review and recommendations for daily and intermittent dosage in children (WHO/
16.
17.
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19.
20.
21.
22.
23. 24.
HTM/TB/2006.365). Geneva: World Health Organization, 2006. Graham SM, Daley HM, Banerjee A, et al. Ethambutol in tuberculosis: time to reconsider? Arch Dis Child 1998;79:274–278. Tre´bucq A. Should ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature. Int J Tuberc Lung Dis 1997; 1:12–15. Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child 2005;90:614–618. American Thoracic Society. American Thoracic Society/Centers for Disease Control and Prevention/ Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603–662. Blake MJ, Abdel-Rahman SM, Jacobs RF, et al. Pharmacokinetics of rifapentine in children. Pediatr Infect Dis J 2006;25:405–408. Graham SM, Bell DJ, Nyirongo S, et al. Low levels of pyrazinamide and ethambutol in children with tuberculosis and impact of age, nutritional status, and human immunodeficiency virus infection. Antimicrob Agents Chemother 2006;50:407–413. Zhu M, Starke JR, Burman WJ, et al. Population pharmacokinetic modeling of pyrazinamide in children and adults with tuberculosis. Pharmacotherapy 2002;22:686–695. Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9:794–801. Harries AD, Hargreaves NJ, Graham SM, et al. Childhood tuberculosis in Malawi: nationwide
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25.
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41.
case-finding and treatment outcomes. Int J Tuberc Lung Dis 2002;6:424–431. Erratum in: Int J Tuberc Lung Dis 2002;6:556. Place VA, Pyle MM, De la Huerga J. Ethambutol in tuberculous meningitis. Am Rev Respir Dis 1969; 99:783–785. Bobrowitz ID. Ethambutol in tuberculous meningitis. Chest 1972;61:629–632. Gundert-Remy U, Klett M, Weber E. Concentration of ethambutol in cerebrospinal fluid in man as a function of the non-protein-bound drug fraction in serum. Eur J Clin Pharmacol 1973;6:133–136. Donald PR, Seifart HI. Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis. J Pediatr 1989;115:483–486. Hughes IE, Smith H, Kane PO. Ethionamide: its passage into the cerebrospinal fluid of man. Lancet 1962;1:616–617. Ellard GA, Humphries MJ, Gabriel M, et al. Penetration of pyrazinamide into the cerebrospinal fluid in tuberculous meningitis. BMJ 1987;294(6567):284–285. Woo J, Humphries M, Chan K, et al. Cerebrospinal fluid and serum levels of pyrazinamide and rifampicin in patients with tuberculous meningitis. Curr Therapeutic Res 1987;42:235–242. Donald PR, Schoeman JF, Van Zyl LE, et al. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998;2:704–711. Schoeman JF, Van Zyl LE, Laubscher JA, et al. Effect of corticosteroidson intracranial pressure, computed tomographic findings and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226–231. Escobar JA, Belsey MA, Duenas A, et al. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975;56:1050–1055. Girgis NI, Farid Z, Kilpatrick ME, et al. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179–183. British Thoracic Society Research Committee. Six months versus nine months chemotherapy for tuberculosis of lymph nodes: preliminary results. Respir Med 1992;86:15–19. Campbell IA, Ormerod LP, Friend PA, et al. Six months versus nine months chemotherapy for tuberculosis of lymph nodes: final results. Respir Med 1993;87:621–623. Ramachandran S, Clifton IJ, Collyns TA, et al. The treatment of spinal tuberculosis: a retrospective study. Int J Tuberc Lung Dis 2005;9:541–544. Van Loenhout-Rooyackers JH, Verbeek AL, Jutte PC. Chemotherapeutic treatment for spinal tuberculosis. Int J Tuberc Lung Dis 2002;6:259–265. Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young children in contact with adult multidrugresistant pulmonary tuberculosis: a 30-month followup. Pediatrics 2002;109:765–771. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis (WHO/HTM/TB/2006.361). Geneva: World Health Organization, 2006.
42. Centers for Disease Control and Prevention, National Institutes of Health, and Infectious Diseases Society of America. Treating opportunistic infections among HIVexposed and infected children. Recommendations from CDC, NIH, and IDSA. MMWR Morb Mortal Wkly Rep 2004;53(RR-14):1–63. 43. Driver CR, Munsiff SS, Li J, et al. Relapse in persons treated for drug-susceptible tuberculosis in a population with high coinfection with human immunodeficiency virus in New York City. Clin Infect Dis 2001;33:1762–1769. 44. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Unit, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;3:S231–S279. 45. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004; 364:1244–1251. 46. Zachariah R, Spielmann MP, Chinji C, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS 2003; 17:1053–1061. 47. World Health Organization. Guidelines on Cotrimoxazole Prophylaxis for HIV-related Infections in Children, Adolescents and Adults. Recommendations for a Public Health Approach. Geneva: World Health Organization, 2006. 48. World Health Organization. Antiretroviral Therapy of HIV Infection in Infants and Children in Resource-limited Settings: Towards Universal Access. Recommendations for a Public Health Approach 2006. Geneva: World Health Organization, 2006: 1–163. 49. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002; 359:2059–2064. 50. Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001;164:7–12. 51. Centers for Disease Control and Prevention, National Center for HIV, STD and TB Prevention, and Division Tuberculosis Elimination. Updated guidelines for the use of rifamycins for the treatment of tuberculosis in HIV-infected patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. [online]. Available at: http:// www.cdc.gov/tb/TB_HIV_Drugs/default.htm 52. Sahai J, Gallicano K, Swick L, et al. Reduced plasma concentrations of antituberculous drugs in patients with HIV infection. Ann Intern Med 1997; 127:289–293. 53. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16:75–83. 54. Shelburne SA 3rd, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67–79.
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55. Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIVinfected persons. Chest 2001;120:193–197. 56. Puthanakit T, Oberdorfer P, Akarathum N, et al. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis J 2006;25:53–58. 57. Schaaf HS, Cotton MF. The diagnosis and management of tuberculosis in HIV-infected children. S Afr J Infect Epidemiol 2006;21(1):9–13. 58. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 1999;3:847–850. 59. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221–S247. 60. Van Zyl S, Marais BJ, Hesseling AC, et al. Adherence to antituberculosis chemoprophylaxis and treatment in children. Int J Tuberc Lung Dis 2006;10(1):13–18. 61. Marais BJ, van Zyl S, Schaaf HS, et al. Adherence to isoniazid preventive chemotherapy in children: a prospective community-based study. Arch Dis Child 2006;91:762–765. 62. Alperstein G, Morgan KR, Mills K, et al. Compliance with anti-tuberculosis preventive therapy among 6-year-old children. Aust N Z J Public Health 1998;22:210–213. 63. Reichler MR, Reves R, Bur S, et al. Treatment of latent tuberculosis infection in contacts of new tuberculosis cases in the United States. South Med J 2002;95:414–420. 64. Bock CK, Metzger BS, Tapia JR, et al. A tuberculin screening and isoniazid preventive therapy program in an inner-city population. Am J Respir Crit Care Med 1999;159:295–300. 65. Ormerod LP. Rifampicin and isoniazid prophylactic chemotherapy for tuberculosis. Arch Dis Child 1998;78:169–171. 66. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicoses in Hong Kong. Am Rev Respir Dis 1992;145:36–41. 67. Gao X-F, Wang L, Liu G-J, et al. Rifampicin and pyrazinamide versus isoniazid for treating latent tuberculosis infection: a meta-analysis. Int J Tuberc Lung Dis 2006;10:1080–1090. 68. American Academy of Pediatrics, Committee on Infectious Diseases. Chemotherapy for tuberculosis in infants and children. Pediatrics 1992;89:161–165. 69. British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998;53:536–548. 70. Rich ML (ed.). PIH Guide to the Medical Management of Multidrug-Resistant Tuberculosis. Boston: Partners in Health, 2003.
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Tuberculosis drug therapy in adults Malgorzata Grzemska
INTRODUCTION Tuberculosis is one of the very few diseases for which the standards of treatment have been so rigorously defined and recommendations so universally accepted. Numerous randomized, controlled clinical trials established the effectiveness of chemotherapy and then refined regimens to what is known as ‘short-course’ chemotherapy, the modern standard used throughout the world.1 Effective chemotherapy for TB, apart from curing the infected individual, is also the most important means of preventing transmission of Mycobacterium tuberculosis.2 There is virtual international consensus concerning appropriate therapy, so that treatment guidelines have been issued by expert groups in developed countries with low rates of TB such as the United States and the United Kingdom.3,4 The World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (the Union) are targeting their recommendations towards developing countries where TB is most prevalent. However, the same principles apply for both developed and developing countries: 1. the use of multiple drugs to which the tubercle bacilli are susceptible; 2. continuation of treatment for a period of time sufficient to control and usually eradicate the disease, and 3. regular ingestion of medication by the patient. The International Standards of TB Care issued in 2006 described the widely accepted level of care that all practitioners, public and private, should follow when managing a patient with TB.5
PRINCIPLES OF CHEMOTHERAPY Modern TB chemotherapy started in 1944 with the introduction of streptomycin, which was the first effective anti-TB drug and used alone resulted in clinical and bacteriological response. Unfortunately, it was soon observed that therapy with streptomycin alone, while giving some initial relief of symptoms, leads to deterioration, selection of resistant organisms, and consequently failure of treatment.6,7 The same phenomenon was observed with monotherapy with even the most potent bactericidal drug (e.g. isoniazid), which led to treatment failure with the development of acquired drug resistance due to the spontaneous emergence of resistance in a small number of tubercle bacilli.8 After the introduction of para-aminosalicylic acid (PAS) and isoniazid, the first major
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principle of TB chemotherapy, that successful therapy requires the administration of a minimum of two drugs to which the organisms are susceptible, was acknowledged. The effectiveness of multipledrug chemotherapy was demonstrated by the British Medical Research Council in studies in which two-drug combinations consisting of streptomycin and PAS, isoniazid and streptomycin, or isoniazid and PAS were used.9,10 These classic studies are recognized as the first controlled clinical trials, techniques of proving regimen efficacy in most diseases that are used to this day. The second principle of therapy is that treatment of TB requires continuation of chemotherapy well after improvement in clinical disease and disappearance of symptoms. Prolonged drug therapy is required to eliminate ‘persistent’ bacilli composed of a small population of metabolically inactive organisms. Early interrupted treatment may lead to the increased possibility of relapse months to years after initial cure. With the treatment regimens used in the 1950s and 1960s, 18–24 months of therapy were required to ensure cure.11,12 The introduction of rifampicin into TB chemotherapy in the late 1960s/early 1970s substantially shortened the therapy, allowing for treatment of 6–9 months (short-course chemotherapy). Studies in the 1980s that evaluated regimens with a treatment duration of less than 6 months demonstrated high relapse rates (11– 40%) in patients with sputum smear-positive pulmonary TB.13,14 With the multidrug therapy currently used, the vast majority of TB patients successfully complete treatment within 6 months. Antituberculosis drugs can be divided into three groups in terms of their activity, as described by Mitchison.15 These are prevention of drug resistance, early bactericidal activity, and sterilizing activity. Drugs active in the prevention of drug resistance are able to prevent growth of the entire bacterial population in the lesions, preventing development of resistance to other drugs. Early bactericidal activity allows a reduction in the number of bacilli in the initial part of therapy.16 Sterilizing activity is the ability to kill all, or almost all, bacilli in the lesion. The sterilizing activity of a drug indicates its suitability for incorporation into the short-course regimen. Based on the above principles, treatment of TB is divided into two phases. The initial phase with the combination of bactericidal drugs killing rapidly multiplying populations of bacilli and preventing the emergence of drug resistance. This period should end with culture conversion and is followed by the subsequent continuation phase. However, not every combination of drugs will have this effect. At least two bactericidal drugs, such as isoniazid and rifampicin or isoniazid and streptomycin, are required in the initial phase.17 Pyrazinamide given in the initial phase allows a reduction in treatment
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duration from 9 to 6 months.18 Ethambutol or streptomycin is added to the initial phase to prevent development of rifampicin resistance in case of unrecognized primary isoniazid resistance. During the continuation phase, the sterilizing drugs kill less active, intermittently multiplying bacilli. More detailed description on drugs action could be found in Chapter 59. For anti-TB therapy to be effective, it must be prescribed as well as ingested properly with the use of appropriate drugs in appropriate doses for appropriate durations. Non-adherence has been recognized as the major cause of unsuccessful outcomes, such as treatment failure, relapse, and the emergence of drug resistance.19,20 The reasons for poor adherence to treatment are numerous, complex, and unpredictable.21–23 Services for TB care should identify and address factors that may make patients interrupt or stop treatment. Supervised treatment, which may include direct observation of therapy (DOT), helps patients take their drugs regularly and complete treatment consequently, leading to reduction of drug resistance and relapse.24–26 There is no single approach to management that is effective for all patients, conditions, and settings.3 Therefore, supervision of treatment must be carried out in a context-specific and patient-sensitive manner to ensure adherence of both the providers and the patients. Depending on the local conditions, supervision may be undertaken at a health facility, in the workplace, in the community, at a pharmacy, or at home. Setting clinic hours to suit the patient’s schedule and offering incentives and enablers, such as transportation reimbursements and provision of food and hygienic packages, were used by different programmes and settings.27 Using treatment supporters acceptable to the patient and properly trained by the health services is also recommended.28 Fixed-dose drug combinations (FDCs) have advantages over individual drugs as the prescription errors are likely to be less frequent, the number of tablets to ingest is smaller and may encourage adherence, and, finally, if treatment is not observed, patients cannot select the drugs to ingest.29,30 However, fixed-dose combinations also have some disadvantages. If prescription errors occur, excess dosage with higher risk of toxicity or subinhibitory concentrations favouring development of drug resistance may result. In addition, poor rifampicin bioavailability has been found in some FDCs. Therefore, use of quality-assured combinations is essential.31 Developing and middle-income countries may benefit from the Global Drug Facility (GDF) grants and direct procurement to ensure quality-assured products are used in TB treatment.32 Patient-centred approaches using the full range of accepted measures to ensure drug intake and completion of therapy are the cornerstone of the WHO’s Stop TB Strategy33,34 described in more detail in Chapter 58.
TREATMENT REGIMENS RECOMMENDED BY WHO The ‘first-line’ anti-TB drugs used commonly for treatment of susceptible disease include isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S). The first-line anti-TB drugs, their dosing, action, adverse reactions, etc. are described in detail in Chapter 59.
NEW CASES The basic treatment regimen recommended by the WHO for previously untreated (new) cases with either pulmonary or extrapulmonary TB consists of an initial (or intensive) phase lasting 2 months and a continuation phase lasting 4 (or 6) months. The
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Table 62.1 Recommended treatment regimens for new cases Patient diagnostic category
TB patients
I
New smear-positive patients, new smearnegative patients with extensive parenchymal involvement, concomitant HIV diseases or severe forms of extrapulmonary TB New smear-negative pulmonary TB (other than in category I) and less severe forms of extrapulmonary TB
III
a
TB treatment regimens Initial phase
Continuation phase
Preferred 2HRZEb
Preferred 4HR 4(HR)3 Optional 6HE Optional 4(HR)3
Optional 2HRZE Optional 2(HRZE)3 Preferred 2HRZEc Optional 2HRZE Optional 2(HRZE)3
Preferred 4HR 4(HR)3 Optional 6HE Optional 4(HR)3
Adapted from 37. World Health Organization. Treatment of tuberculosis: guidelines for national programmes, third edition. WHO/CDS/TB/ 2003.313. Chapter 4 revised 2004. a Numbers preceding regimens indicate length of treatment in months. Subscripts following regimens indicate frequency of administration per week. When no subscripts are given, the regimen is daily. b Streptomycin may be used instead of ethambutol and it should replace ethambutol in tuberculous meningitis. c Ethambutol in the initial phase may be omitted for patients with limited, non-cavitary, smear-negative pulmonary TB who are known to be HIV-negative, patients with less severe forms of extrapulmonary TB, and patients with known susceptible strains.
initial phase consists of four drugs: rifampicin, isoniazid, pyrazinamide, and ethambutol and is followed by a continuation phase with two drugs, rifampicin and isoniazid, for 4 months (or exceptionally rifampicin asnd ethambutol for 6 months). Table 62.1 shows several variations in the administration of this basic standardized category I regimen. Patients with a large bacillary load (sputum smear-positive pulmonary TB and many human immunodeficiency virus (HIV) infected patients with a smear-negative pulmonary TB) have an increased risk of selecting resistant bacilli. Short-course chemotherapy regimens with four drugs in the intensive phase reduce this risk. Such regimens are highly effective in patients with susceptible bacilli and almost as effective in patients with initial resistance to isoniazid.35 Patients negative for HIV, with smear-negative or extrapulmonary TB that is fully drug-susceptible, have little risk of selecting resistant bacilli because their lesions generally harbour fewer bacilli, and could be treated with a three-drug regimen (R, H, Z). However, initial resistance to isoniazid is common in many areas.36 HIV testing of TB patients is not commonly practised; therefore, it is recommended that the same four-drug regimen, including ethambutol, is used during the initial phase of treatment for patients with smear-negative pulmonary and extrapulmonary TB. Daily administration of drugs in the initial phase of treatment of all new cases is recommended as a preferred option.37 After the first 2 months of treatment with four drugs, the continuation phase of treatment with two drugs is administered. The
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SECTION
7
CLINICAL MANAGEMENT OF TUBERCULOSIS
preferred continuation regimen is 4 months of rifampicin and isoniazid (4RH) administered daily or three times weekly. The primary advantage of this regimen is the low rate of treatment failure and relapse for patients with a fully susceptible TB or TB with initial isoniazid resistance. The use of rifampicin requires patient-oriented measures to ensure adherence to treatment and to prevent development of rifampicin resistance. Daily treatment may be appropriate if the patient is hospitalized or the treatment supporter is closely available (neighbour, community, or family member). Thrice-weekly therapy always requires direct observation and, if taken regularly, its effectiveness is similar to that of daily therapy. In both daily and intermittent therapy, the use of FDCs is recommended. The WHO does not recommend the twice-weekly regimen. A self-administered, daily treatment consisting of 6 months of isoniazid and ethambutol (6HE) is an option where and when adherence to treatment with HR cannot be ensured, for example in mobile populations and patients with very limited access to healthcare. However, in a comparative international multicentre clinical trial, the 6HE continuation phase was found to be inferior to the 4RH continuation phase regimen, with a significantly higher unfavourable outcome (failure or relapse) at 12 months after the end of chemotherapy.38
PREVIOUSLY TREATED CASES Previously treated patients include patients treated for more than 1 month who continued to be or became sputum smear (or culture) positive. These patients could be relapse cases, failure cases, or
default cases (patients who have interrupted previous treatment). Previously treated cases have a much higher likelihood of drug resistance, which could have been acquired through the course of inadequate previous therapy. Ideally, all previously treated patients should be assessed for drug susceptibility prior to initiating chemotherapy. However, in most developing countries, access to qualityassured culture and susceptibility testing is limited and, therefore, a standardized regimen for previously treated cases is recommended by the WHO. Table 62.2 shows possible options of therapy for previously treated patients (category II regimen). The standard re-treatment regimen consists of five drugs in the initial phase (rifampicin, isoniazid, pyrazinamide, ethambutol, and streptomycin) and three drugs in the continuation phase (rifampicin, isoniazid, and ethambutol). The initial phase is administered for 3 months, of which the first 2 months include all five drugs. Streptomycin is discontinued after 2 months and the four remaining drugs are given in the third month. Daily administration of drugs in the initial phase is strongly preferred. The continuation phase with three drugs is administered for 5 months, daily or intermittently, thrice weekly. This standardized regimen can cure patients excreting bacilli fully susceptible or resistant to isoniazid and/or streptomycin. It should not be used in failures of the category I regimen who have higher probability of multidrug-resistant (MDR) TB, particularly if the treatment was directly observed and included rifampicin in the continuation phase. The category II standardized regimen has poor results in MDR-TB cases (less than 50% cure rate),39 and, of most concern, may result in the amplification of drug resistance.40,41
Table 62.2 Recommended treatment regimens for previously treated patients Treatment category
TB patients
II
Relapses Treatment after default
II
Treatment failure of category I In settings where: Representative DRS data show low rates of MDR-TB or individualized DST show drug-susceptible disease Or In settings of: Poor programme performance Absence of representative DRS data Insufficient resources to implement category IV treatment Treatment failure of category I In settings with: Adequate programme performance Representative DRS data showing high rates of MDR-TB and/or capacity for DST of cases Availability of second-line drugs Chronic (still smear-positive after supervised re-treatment regimen) proven or suspect MDR-TB casesa
II
IV
TB treatment regimens Initial phase
Continuation phase
Preferred 2HRZES/1HRZE Optional 2(HRZES)3/1(HRZE)3 Preferred 2HRZES/1HRZE Optional 2(HRZES)3/1(HRZE)3
Preferred 5HRE Optional 5(HRE)3 Preferred 5HRE Optional 5(HRE)3
Specially designed standardized or individualized regimens with the use of second-line drugs
Specially designed standardized or individualized regimens with the use of second-line drugs
Adapted from 37. World Health Organization. Treatment of tuberculosis: guidelines for national programmes, third edition. WHO/CDS/TB/2003.313. Chapter 4 revised 2004. DRS, drug resistance surveillance; DST, drug susceptibility testing. a Drug susceptibility testing is recommended for patients who are contacts of known MDR-TB cases.
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For this reason, countries with a high proportion of MDR-TB among failures of the category I regimen should consider treating such failures with a regimen consisting of second-line drugs (category IV regimen). However, introduction of category IV regimens require either individual drug susceptibility testing (DST) or representative drug resistance surveillance (DRS) data in such patients. Culture and DST should be quality assured and all the conditions for the programmatic management of MDR-TB patients should be in place.43 In principle, category IV regimens should be introduced in well-performing TB control programmes and be tailored to a local situation (drug-resistance problem, history of drug use, laboratory capacity, human and financial resources). The use of category IV regimen is not recommended in settings where relevant programmatic and DRS data are lacking, nor in programmes where most of the failure to category I regimens are due to poor programme performance.
HIV-INFECTED TUBERCULOSIS PATIENTS The recommended treatment regimen for HIV-infected patients with TB consists of the same 6-month regimen as for non-HIVinfected patients. However, there are several important areas for consideration, in which therapy of patients with both TB and HIV infection differs. The 8-month regimen with a 6-month continuation phase of isoniazid and ethambutol is not recommended for TB patients who are coinfected with HIV.37,38,43 There is also an association between HIV infection and acquired drug resistance.44,45 Rifamycin resistance may develop during the treatment of HIV-infected TB patients and has been particularly associated with the use of increased intermittent treatment intervals with drug administration once or twice weekly in the continuation phase.46 An important consideration for treatment of TB in patients with HIV infection is the potential for interaction, especially rifampicin, with the antiretroviral therapy (ART).47 For patients with active TB in whom HIV infection is diagnosed and ART is required, the first priority is to initiate standard anti-TB treatment. The optimal time to initiate ART is not known. Case fatality rates in TB patients during the first 2 months of TB treatment are especially high in settings with high prevalence of HIV, suggesting that ART should begin early.48 On the other hand, consideration of pill burden, drug–drug interactions, toxicity and immune reconstitution inflammatory syndrome (IRIS) support deferred initiation of ART.49 The WHO recommends that, in persons with CD4þ cell counts < 200 cells/mm3, ART should be started between 2 and 8 weeks after the start of TB therapy, when the patient is still taking the initial four-drug intensive phase regimen. For patients with CD4þ cell counts > 200 cells/mm3 the commencement of ART may be delayed until after the initial phase of TB treatment has been completed. In patients with CD4þ cell counts > 350 cells/mm3, ART can be delayed until after the completion of a 6-month TB regimen. In circumstances where CD4þ cells counts cannot be obtained, the WHO recommends that ART be initiated 2–8 weeks after the start of the TB treatment. Table 62.3 shows the relationship between ART and the TB chemotherapy. Drug interactions between rifampicin and ART, especially nonnucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), may compromise the co-management of two infections. However, accumulating data support the use of first-line NNRTI-containing regimens in patients receiving a rifampicincontaining regimen for TB. The efavirenz (EFV)-containing
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Table 62.3 Initiating first-line ART in relation to starting antituberculosis chemotherapy CD4þ cell count
ART recommendations
Timing of ART in relation to start of TB treatment
CD4þ < 200 cells/mm3 CD4þ between 200 and 350 cells/mm3 CD4þ > 350 cells/mm3
Recommend ART
Between 2 and 8 weeks
Recommend ART
After 8 weeks
Defer ART
Not available
Recommend ART
Re-evaluate patient at 8 weeks and at the end of TB treatment Between 2 and 8 weeks
ART, antiretroviral therapy. Adapted from World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a public health approach. 2006 revision. ISBN 92 4 159467 5.49
regimen is an option of choice, except for use in pregnant women or in women of child-bearing age. Alternative first-line ART regimens include nevirapine (NVP) and triple NRTI (based on tenofovir disoproxil fumarate (TDF) or abacavir (ABC)). Monitoring of serum drug concentrations may be useful in avoiding the adverse consequences of the interactions.50 Another feature of TB treatment in persons with HIV infection is the immune reconstitution inflammatory syndrome, which may present worsening of TB symptoms after the initiation of ART.51–53 It may occur in up to 30% of TB patients who initiate ART. This paradoxical reaction can also happen in patients without HIV infection, but the frequency is much lower. Tuberculosis-associated IRIS typically presents with fever and worsening of pre-existing TB disease. Several reports suggest that IRIS is more common if ART is started early in the course of TB treatment and in patients with low CD4þ counts. Presumably this reaction is a result of reconstitution of the immune response to mycobacteria. However, TB treatment failure should be ruled out as well as presence of other opportunistic diseases. Most cases resolve without any intervention or with a symptomatic treatment with anti-inflammatory agents and ART can be safely continued. Serious reactions such as tracheal compression caused by massive adenopathy or breathing difficulties may require the use of corticosteroids.51,54 Finally, because of high death rates early in the course of treatment of HIV-infected persons with TB, rates of treatment success are much lower than in patients without HIV infection. In addition, the increased rates of treatment failure and relapse requires DOT to safeguard and ensure the high level of adherence.55,56
TREATMENT IN SPECIAL SITUATIONS Pregnancy and breastfeeding Of the first-line drugs, isoniazid, rifampicin, and ethambutol can be given safely in pregnancy. Streptomycin may cause ototoxicity in the fetus and is contraindicated. Although there are no data indicating that pyrazinamide is teratogenic, it has not been recommended in the United States. However, both the Union and the WHO recommend that pyrazinamide be included in the treatment regimen given to pregnant women.37,57 Most anti-TB drugs appear in small concentrations in breast milk at levels not producing toxicity in infants. Therefore, breastfeeding is not contraindicated.58
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However, the levels of these drugs in breast milk do not provide adequate therapy or preventive therapy of TB infection for infants. The baby should be given prophylactic isoniazid for at least 3 months beyond the time the mother is considered to be non-infectious.37 Bacillus Calmette–Gue´rin (BCG) vaccination of the newborn should be postponed until the end of isoniazid prophylaxis.
Renal failure Of the first-line anti-TB drugs, isoniazid, rifampicin, and pyrazinamide may be given at the usual dosages in mild to moderate renal failure. In severe renal failure, both isoniazid and pyrazinamide should be given at slightly reduced dosages unless maintenance haemodialysis is being given.59,60 In addition, patients with severe renal failure should receive pyridoxine with isoniazid to prevent peripheral neuropathy. The renal clearance of both ethambutol and streptomycin is reduced in renal failure, and potentially toxic serum levels of ethambutol occur with standard doses.61 Thus, when either drug is required for the treatment of TB in patients with renal failure, it is mandatory to reduce the drug dose and closely monitor serum levels. The safest regimen for patients with renal failure is 2HRZ/4HR. Hepatic disease If the patients requiring treatment for TB have underlying liver disease, it may increase the risk of hepatotoxicity from isoniazid, rifampin, and/or pyrazinamide. This is especially common among alcoholic patients and injecting drug users. Furthermore, isoniazid and rifampicin depend on hepatic mechanisms for metabolism and clearance, so increased drug levels may occur when these drugs are given to patients with severe hepatic impairment.62 In such cases, the severity of TB and the degree of hepatic impairment must be considered in deciding what drugs to give. Patients with relatively mild forms of TB and severe hepatic disease may be treated with ethambutol and streptomycin until the hepatic dysfunction is lessened. In those with more severe forms of TB requiring more aggressive therapy, rifampicin and/or isoniazid may be included, with careful monitoring of hepatic function. In severe hepatic insufficiency, the dosages of both drugs may be reduced. Pyrazinamide is best avoided in these cases, as serum levels and half-life are markedly increased in the presence of hepatic insufficiency,63 and the drug’s contribution to the bactericidal phase of therapy is modest. Finally one must consider that in TB/HIV patients or patients with extrapulmonary TB, hepatic TB can cause biochemical findings that may mimic TB drug hepatotoxicity. Consequently, judgements as to whether disease or drug toxicity is causing the findings are very difficult.
Table 62.4 Recommended treatment strategies for multidrug-resistant tuberculosis Standardized treatment
Standardized treatment followed by individualized treatment
Empirical treatment followed by individualized treatment
Adapted from World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/ TB/2006.361.
programmes, like Peru, India, and China. Once MDR-TB strains are established in a population, short-course chemotherapy will fail to cure a certain proportion of TB cases. The WHO standardized category II regimen recommended for previously treated cases, when used in MDR-TB cases, has been documented to be successful in a very low proportion of patients (on average, 29% in data from six different countries39). The frequency of TB recurrence among MDR-TB patients declared ‘cured’ after short-course chemotherapy is close to 30%.67 Furthermore, there is evidence that short-course chemotherapy with first-line drugs may inadvertently amplify pre-existing resistance and lead to MDR-TB.40,41 Good TB control programmes should treat MDR-TB patients regardless of the rates and numbers. For MDR-TB, a regimen based on a reliable DST and a review of treatment history is the gold standard of care. Programmes have different options for treatment strategies which may include the following:
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS The emergence of resistant to first-line anti-TB drugs, and, particularly, MDR-TB has become a significant public health problem in a number of countries.36 The WHO estimates that 424,203 MDR-TB cases occurred world-wide in 2004, and in the same year 181,408 MDR-TB cases were estimated to have occurred among previously treated TB cases alone.64 In addition, the emergence of extensively drug-resistant TB (XDR-TB), especially combined with high death rates in HIV-infected patients, shows how important treatment of drug-resistant TB is not only for the individual patient but also for public health.65,66 MDR-TB is already endemic and threatening to undermine TB control gains even in settings with excellent national TB control
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Representative DRS data in welldefined patient populations are used to design the regimen. All patients in the same category receive an identical regimen Initially, all patients in a certain group receive the same regimen based on DST survey data from representative populations. The regimen is adjusted when DST results of an individual patient become available (DST often to a limited number of drugs) Each regimen is individually designed based on patient history and adjusted when DST results become available (often DST available for all first-line and major second-line drugs)
Standardized treatment regimens based on representative DRS data of specific treatment categories. All patients in a defined group or category receive the same treatment regimen. Empirical treatment in which each regimen is individually designed based on the history of previously taken anti-TB drugs and with the help of representative DRS survey data. Once DST results of the patient become available, the empirical treatment regimen is adjusted accordingly. Individualized treatment designed on the bases of previous history of treatment and individual DST results.
Table 62.4 illustrates treatment strategies recommended by WHO guidelines for programmatic management of drug-resistant TB.42
PRINCIPLES OF TREATMENT AND REGIMEN DESIGN Second-line drugs used for treatment of MDR-TB are defined as second line because they are more toxic, are not as efficacious, and must be administered for much longer periods than standardized chemotherapy for susceptible cases. In order to enhance the
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probability of successful outcome, the treatment needs to be supervised by a trained health worker (doctor, nurse), although successful community-based treatment programmes have been reported.68,69 Patients with MDR-TB are more likely to have had problems with non-adherence in the past.20 Adherence to a MDR-TB regimen is particularly difficult because of its prolonged treatment regimens with larger numbers of drugs and more severe side effects.70 However, MDR-TB treatment can be successful when adequate support to patients is being provided.68 These measures include incentives and enablers for delivery of treatment and may include the following: nutritional supplementation, emotional and psychological support, education of patients and their families, and early and effective management of adverse effects. Whether standardized, empirical, or individualized regimens are administered, certain principles for the choice of an appropriate therapy need to be taken into account. Early detection and initiation of treatment are crucial factors in ensuring successful outcomes. Regimens should be based on the history of drugs previously taken by the patient.
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Drugs and regimens commonly used in the country or setting and prevalence to first- and second-line drugs should be considered. Regimen should contain at least four drugs with either certain (or almost certain) effectiveness. The regimen can be started with more drugs when the susceptibility pattern is unknown, drug effectiveness is unclear, and/or extensive, bilateral, pulmonary disease is present. Drugs should be administered at least six times per week, possibly once daily, especially pyrazinamide, ethambutol, and fluoroquinolones (because high peaks attained in once-a-day dosing is more efficacious). Other drugs should also be administered once per day depending on patient tolerance. However, traditionally ethionamide/prothionamide, cycloserine, and PAS have been administered in split doses. Bedtime doses of these drugs are also efficacious and may promote adherence. They could be more acceptable to the patients because any gastrointestinal intolerance would occur during sleep. The second-line anti-TB drugs, their dosing, adverse reactions, etc. are described in detail in Chapter 59. Drugs dosage should be determined by patient’s weight (see Table 62.5).
Table 62.5 Weight-based dosing of antituberculosis drugs in treatment of drug-resistant tuberculosis (daily doses) Medication
Weight class < 33 kg
33–50 kg
51–70 kg
> 70 kg (also maximum dose)
4–6 mg/kg 10–20 mg/kg 25 mg/kg 30–40 mg/kg
200–300 mg 450–600 mg 800–1200 mg 1000–1750 mg
300 mg 600 mg 1200–1600 mg 1750–2000 mg
300 mg 600 mg 1600–2000 mg 2000–2500 mg
15–20 15–20 15–20 15–20
500–750 500–750 500–750 500–750
1000 1000 1000 1000
1000 1000 1000 1000
Group 1: First-line oral anti-TB drugs Isoniazid (H) Rifampicin (R) Ethambutol (E) Pyrazinamide (Z) Group 2: Injectable anti-TB drugs Streptomycin (S) Kanamycin (K) Amikacin (Am) Capreomycin (Cm)
mg/kg mg/kg mg/kg mg/kg
mg mg mg mg
mg mg mg mg
mg mg mg mg
Group 3: Fluoroquinolones Ciprofloxacin (Cfx) Ofloxacin (Ofx) Levofloxacin (Lfx) Moxifloxacin (Mfx) Gatifloxacin (Gfx)
20–30 mg/kg Adult dose for Adult dose for Adult dose for Adult dose for
MDR-TB MDR-TB MDR-TB MDR-TB
is is is is
800 mg 750 mg 400 mg 400 mg
1500 mg 800 mg 750 mg 400 mg 400 mg
1500 mg 800 mg 750 mg 400 mg 400 mg
1500 mg 800 mg 750 mg 400 mg 400 mg
Group 4: Oral bacteriostatic second-line anti-TB drugs Ethionamide (Eto) 15–20 mg/kg 500 mg 750 mg Protionamide (Pto) 15–20 mg/kg 500 mg 750 mg Cycloserine (Cs) 15–20 mg/kg 500 mg 750 mg Terizidone (Trd) 15–20 mg/kg 500 mg 750 mg Para-aminosalicylic acid (PAS) 150 mg/kg 8g 8g Sodium PAS Dosing can vary with manufacturer and preparation: check dose recommended by the Thiacetazone Usual dose is 150 mg for adults Group 5: Agents with unclear efficacy (not recommended by the WHO for routine use in MDR-TB patients) Clofazimine (Cfz), Amoxicillin/Clavulonate (Amx/Clv), Clarithromycin (Clr), Linezolid (Lzd). Efficacy and dosing in the treatment of drug-resistant TB is not fully determined.
750–1000 mg 750–1000 mg 750–1000 mg 750–1000 mg 8g manufacturer
Adapted from World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. WHO/HTM/TB/2006.361.
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If available, pharmacokinetic studies (drug serum level testing) for determining the optimal dosing for maximum serum concentrations in the therapeutic range can be performed. An injectable agent (an aminoglycoside or capreomycin) should be used for a minimum of 6 months. The treatment should last for at least 18 months after culture conversion. Extension to 24 months may be indicated in patients classified as ‘chronic cases’ with extensive pulmonary damage. Each dose of each drug should be given under DOT for the entire duration of treatment. DST, when available from a reliable laboratory, should be guiding the selection of drugs for the regimen. DST does not predict the effectiveness or ineffectiveness of drugs with complete certainty.71 Nonetheless, the regimen should include at least four drugs highly likely to be susceptible, based on DST and/or drug history of the patient. The newer rifamycins have a high level of cross resistance to rifampicin and should be considered ineffective if DST indicates rifampicin resistance. Amikacin should be considered ineffective if kanamycin tests resistant and vice versa. Pyrazinamide can be used for the entire treatment if it is judged to be effective. Many MDR-TB patients have chronically inflamed lungs, which theoretically produce the acid environment in which pyrazinamide is active. Analysis of patients’ outcomes should follow internationally recommended case registration and outcome definitions.72
CHOICE OF REGIMEN Standardized treatment regimens Certain groups of patients could be treated with standardized regimens that do not depend on individualized DST, especially in resource-poor settings without laboratory capacity. However, the representative DRS data for such groups should be available. The survey data in each group will help design the regimen. Some previously treated patients, defined as ‘relapse’ or ‘treatment default’, can safely use the standard category II regimen with all five first-line drugs (see Table 62.2). Other previously treated groups, such as ‘failure cases’ and ‘chronic cases’, would require a specially designed category IV regimen consisting of a combination of firstand second-line drugs.73,74 Once enrolled on a category IV regimen, it is strongly recommended that MDR-TB be confirmed (or excluded) in all patients. Experience in the use of standardized regimens for large cohorts is limited. Data from three reports (Peru, Korea, and Bangladesh) show relatively low cure rates: 48%, 44.1%, and 69%, respectively.74–76 The low rate of successful outcomes in Peru and Korea could have been attributed to some programmatic issues. In Peru there was heavy reliance on pyrazinamide and ethambutol, drugs used in the first-line treatment, low doses of ciprofloxacin, and use of injectable only for 3 months.74 The Korean study assessed a self-administered regimen, without DOT, which resulted in a relatively high default rate of 28.9%.75 The Bangladesh study documented the highest success rate of all three and it would be interesting to observe further development in this setting.76 More data are being obtained from numerous settings in developing countries applying standardized regimens approved by the Green Light Committee (GLC),77 and there is no reason to doubt that carefully designed and well-supported standardized
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treatment regimens will obtain results similar to those from individualized regimens, if and when appropriate patient support, including treatment of adverse events, is available.
Empirical treatment regimen Patients with a high probability of MDR-TB (such as close contact of known MDR-TB cases) should be started on an empirical treatment regimen pending availability of DST results in order to prevent clinical deterioration and transmission to contacts. The empirical regimen could be standardized for the same group of patients (as described earlier) or tailored for each individual patient. The individualized empirical regimens should be based on a patient’s treatment history, local patterns of drug resistance, and DST results of any known contacts. In circumstances where rapid culture and DST methods are not available, most patients will necessarily start their treatment on an empirical regimen. If the laboratory uses a rapid method with a turnaround of 1–2 weeks and the patient is in a stable clinical condition, it may be appropriate to wait for DST results before the start of therapy. In addition, in a patient with a chronic disease, treated several times with second-line drugs, waiting for DST results is wise as long as the patient is clinically stable and appropriate infection control measures are in place. Every effort should be made to obtain detailed clinical and treatment history, especially of specific TB drugs taken, to help eliminate most likely ineffective drugs. The longer the patient was previously treated, the higher probability of acquired resistance to previously used drugs. In particular, evidence of clinical or bacteriological treatment during the period of regular drug administration is highly suggestive of drug resistance. In many TB control programmes, category I regimen failures that use isoniazid and rifampicin in the continuation phase have high MDR-TB rates, ranging from 63% to 88% in published studies.78–80 A study from Vietnam reported an 80% rate of MDR-TB in category I failures treated with the regimen containing a 6-month ethambutol and isoniazid continuation phase.81 It is very important to note, however, that resistance can develop in some cases in less than 1 month of treatment.82 The result of DST should complement rather than rule out other sources of information about the likely effectiveness of a specific drug. If a history of previous treatment indicates that certain drugs could be ineffective, they should not be relied upon as a basis for designing the regimen. In other words, if the patient has used a drug for a month or longer and had consistently positive smear or culture results, the strain should be considered ‘probably resistant’, even if it is reported as susceptible by DST. In contrast, if the strain is resistant to a drug in the laboratory, but the patient has never taken it and resistance to this drug is extremely rare in the community, this particular drug could be used in the empirical regimen. Individualized treatment regimens The design of an individualized treatment regimen uses the resistance pattern of the infecting strain of the individual patient, in addition to the patient’s treatment history and prevailing resistance patterns in the community. Heavy dependence on DST requires a high level of confidence in the laboratory performing the test, participation of the laboratory in continuous external quality control through the International Supranational Laboratory Network,83 and appropriate training of doctors in proper interpretation of DST results. The same caution as when designing the empirical regimen should be exercised when a treating clinician decides on the regimen, particularly when DST results to second-line drugs are guiding the choice of drugs to be used.71
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In addition, the patient in question may have already received several months of the standardized or empirical regimens after the specimen was collected and before the DST results became available. In such situations, development of further acquired resistance is possible and should be taken into account when tailoring the regimen. Some laboratories may report that a strain has a low or intermediate level of resistance to a specific drug. There is very little clinical evidence to support this type of designation, particularly if the drug in question was part of a regimen provided under uninterrupted DOT.
MULTIDRUG-RESISTANT TUBERCULOSIS TREATMENT IN SPECIAL SITUATIONS Pregnancy and breastfeeding Pregnancy is not a contraindication for treatment of MDR-TB, which poses a great risk to the lives of both mother and child.91,92 Pregnant patients should be carefully evaluated, taking into consideration the stage of pregnancy and severity of the TB disease. The risks and benefits of treatment should be carefully assessed and the following principles should be considered:
DURATION OF TREATMENT The intensive phase of treatment with the use of an injectable agent should be administered for at least 6 months. Treatment should be continued for at least 4 months after the patient first becomes and remains sputum smear or culture negative. The recommended duration of treatment is guided by smear and culture conversion. The minimal recommendation is that treatment should last for at least 18 months after culture conversion. In addition to bacteriological results, clinical and radiographic data could be used. Extension to 24 months may be indicated in patients defined as ‘chronic cases’ with extensive pulmonary damage.42 The newer generation fluoroquinolones may allow shorter regimens, but, as evidence to date is still lacking, chemotherapy regimens shorter than 18 months are not currently recommended.
MULTIDRUG-RESISTANT TUBERCULOSIS AND HIV Unrecognized MDR-TB in an HIV patient carries a very high risk of mortality. The devastating coinfection of HIV and MDR-TB or HIV and XDR-TB was reported in terms of extremely poor outcomes for coinfected patients.66 The recommended treatment of MDR-TB is the same for HIV-infected and non-HIV-infected patients, except for the use of thiacetazone, which should not be administered to HIVinfected patients.87 However, treatment is much more difficult, adverse events and drug malabsorption are more common. Death during MDR-TB treatment is more frequent in HIVinfected patients, particularly in the advanced stages of immunodeficiency. In general, HIV-infected MDR-TB patients have a higher rate of adverse drug reactions to TB and non-TB medications.88,89 The concomitant use of second-line anti-TB drugs and ART, given the large amount of pills to be ingested, is often associated with adverse events that may lead to the interruption of TB and/ or HIV therapy. Joint administration of fluoroquinolones and didanosine may result in decreased fluoroquinolone absorption. Clarithromycin, the drug used by some MDR-TB treatment programmes, if used jointly with ritonavir, may result in increased blood levels of clarithromycin, but, when jointly used with efavirenz or nevirapine, clarithromycin’s metabolism is induced with its decreased plasma concentration.90 MDR-TB outbreaks have overwhelmingly involved HIVinfected patients in overcrowded wards or outpatient facilities where TB and HIV patients were hospitalized or treated.66,84–86 Implementation of adequate infection control measures may reduce nosocomial transmission. More details on infection control can be found in Chapter 68.
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Start treatment of MDR-TB in the second trimester if the condition of the patient is not severe, to avert teratogenic effects of anti-TB drugs. When therapy is started, three or four oral drugs with demonstrated efficacy against the infecting strain should be used and an injectable agent should be added after the delivery.93 Aminoglycosides should not be used during the pregnancy as they can be particularly ototoxic to the fetus.94 If injectable agents must be used, capreomycin is the drug of choice. Ethionamide should be avoided as it can increase the nausea and vomiting and teratogenic effects have been observed in animal studies.95
A woman who is breastfeeding and has an active MDR-TB should receive a full course of MDR-TB therapy. Most anti-TB drugs used in the regimen will be found in the breast milk in minimal concentrations. However, any effects on infants of such exposure during the full course of MDR-TB treatment have not been established. Therefore, when available, infant formula should be used rather than breast milk.42
Renal failure Renal insufficiency resulting from previous treatment with nephrotoxic drugs (for example, aminoglycosides) or caused by TB itself is not rare. Therefore, the dose and the frequency of administered second-line drugs should be adjusted (as shown on Table 62.6). Hepatic disease Among the second-line drugs, ethionamide, protionamide, and PAS can be hepatotoxic, although to a lesser extent than the first-line drugs. Patients with chronic liver disease should not receive pyrazinamide. All other drugs can be used, but the liver enzymes should be closely monitored. If there is a significant increase in liver enzymes, the responsible drugs should be stopped. Patients with a history of liver disease can receive the usual MDRTB regimen provided that there is no clinical evidence of chronic hepatitis, excessive alcohol abuse, presence of hepatitis virus, or past history of acute hepatitis. However, hepatotoxic reactions to the prescribed drugs may be more common. If acute hepatitis occurs, all drugs should be stopped until the acute hepatitis has been resolved. In some severe MDR-TB cases when treatment with second-line drugs needs to be continued during acute hepatitis, a combination of four non-hepatotoxic drugs (although usually demonstrably weaker) should be used. In summary, MDR-TB treatment is a complex intervention and no single approach will fit all situations. It is often stated that individualized regimens have better results than standardized ones. However, if the standardized regimens are well designed, there is no reason to doubt that both approaches can achieve comparable results. Both strategies experience similar levels of drug toxicity, and require an extended patient support system to limit the level of default. Standardized regimens may not be possible in areas or
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Table 62.6 Adjustment of drugs dosage and frequency of administration of second-line antituberculosis drugs in renal insufficiency Drug
Change in frequency?
a Recommended dose and frequency for patients with creatinine clearance < 30 mL/min or for patients on haemodialysis
Isoniazid Rifampicin Pyrazinamide Ethambutol Ciprofloxacin Ofloxacin Levofloxacin Moxifloxacin Gatifloxacin Cycloserine Protionamide Ethionamide PASc Streptomycin Capreomycin Kanamycin Amikacin
No change No change Yes Yes Yes Yes Yes No change Yes Yes No change No change No change Yes Yes Yes Yes
300 mg once daily or 900 mg three times per week 600 mg once daily or 600 mg three times per week 25–35 mg/kg per dose three times per week (not daily) 15–25 mg/kg per dose three times per week (not daily) 1000–1500 mg per dose three times per week (not daily) 600–800 mg per dose three times per week (not daily) 750–1000 mg per dose three times per week (not daily) 400 mg once daily 400 mg per dose three times per week (not daily) 250 mg once daily or 500 mg/dose three times per weekb 250–500 mg per dose daily 250–500 mg per dose daily 4 g/dose, twice daily 12–15 mg/kg per dose two or three times per week (not daily)d 12–15 mg/kg per dose two or three times per week (not daily)d 12–15 mg/kg per dose two or three times per week (not daily)d 12–15 mg/kg per dose two or three times per week (not daily)d
Adapted from American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:604–661. Official publication of the American Thoracic Society. a To take advantage of the concentration-dependent bactericidal effect of many anti-TB drugs, standard doses are given unless there is intolerance. b The appropriateness of 250-mg daily doses has not been established. There should be careful monitoring of neurotoxicity (if possible measure serum concentration and adjust accordingly). c Sodium salt formulation of PAS may result in an excessive sodium load and should be avoided. Formulations of PAS without sodium salt can be safely used. d Caution should be used with all injectable agents because of the increased risk of ototoxicity and nephrotoxicity.
countries with a wide use of second-line drugs and with large proportions of MDR-TB cases harbouring strains with extensive drug resistance.96 Therefore, epidemiological, financial, and operational factors should be taken into account in deciding which approach to use. Furthermore, and extremely important, is the consideration that almost all cases of MDR-TB have occurred through lack of patient or programme adherence, so, to properly treat these patients, the programme must ensure proper treatment conditions, especially assured treatment delivery including DOT and infection control.42 Treatment of MDR-TB is difficult, long, and toxic, not to mention expensive, and therefore requires extensive treatment support
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pulmonary tuberculosis. Am Rev Respir Dis 1980;121:939–949. British Thoracic Society and Tuberculosis Association. Short-course chemotherapy in pulmonary tuberculosis. Lancet 1976;115:3–8. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of six- month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1979;119:579–585. Fox W. The problem of self-administration of drugs; with particular reference to pulmonary tuberculosis. Tubercle 1958;39:269–274. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998;2(1):10–15. World Health Organization. Adherence to Long-term Therapies. Evidence for Action. Geneva: World Health Organization, 2003. Fox W. Self-administration of medicaments. A review of published work and a study of the problems. Bull Int Union Tuberc 1962;32:307–331. Sbarbaro JA. The patient–physician relationship: compliance revisited. Ann Allergy 1990;64:325–332. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995;345: 1545–1548. Jin BW, Kim SC, Mori T, et al. The impact of intensified supervisory activities on tuberculosis treatment. Tuber Lung Dis 1993;74:267–272. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179–1184. Sumartojo E. When tuberculosis treatment fails. A social behavioural account of patient adherence. Am Rev Respir Dis 1993;147:1311–1320. World Health Organization. A guide for tuberculosis treatment supporters (WHO/CDS/TB/2002.300). Geneva: World Health Organization, 2002. World Health Organization. Operational guide for National Tuberculosis Control Programmes on the introduction and use of fixed-dose combination drugs (WHO/CDS/TB/2002.308 – WHO/EDM/PAR/ 2002.6). Geneva: World Health Organization, 2002. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995; 122:951–954. Acocella G, Luisetti M, Gialdroni Grassi G, et al. Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed triple formulation) in intermittent anituberculous chemotherapy. Monaldi Arch Chest Dis 1993;48: 205–209. Stop TB Partnership Secretariat. Global TB Drug Facility: A global mechanism to ensure uninterrupted access to quality TB drugs for DOTS implementation (WHO/CDS/STB/2001.10a). Geneva: World Health Organization, 2001. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952–955. World Health Organization, Stop TB Partnership. The Stop TB Strategy (WHO/HTM/TB/2006.368). Geneva: World Health Organization, 2006. Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423–430. World Health Organization. Anti-tuberculosis drug resistance in the world. Report No.3, The WHO/ IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance (WHO/HTM/TB/ 2004.343). Geneva: World Health Organization, 2004. World Health Organization. Treatment of tuberculosis: guidelines for national programmes, third edn (WHO/CDS/TB/2003.313), Chap 4, rev 2004. [online]. Availabe at URL:http://www.who. int/tb/publications/tb_2003_313_chap4_rev.pdf Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly
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diagnosed pulmonary tuberculosis: international multicentre randomized trial. Lancet 2004;364: 1244–1251. Espinal MA, Kim SJ, Suarez PG, et al. Standard shortcourse chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 200;283:2537–2545. Farmer PE, Bayona J, Furin J, et al. The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis 1998;2(11):869–876. Farmer PE. Managerial success, clinical failures. Int J Tuberc Lung Dis 1999;3(5):365–367. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis (WHO/HTM/TB/2006.361). Geneva: World Health Organization, 2006. Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003;37:101–112. Bradford WZ, Martin JN, Reingold AL, et al. The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 1996; 348(9032):928–931. Centers for Disease Control and Prevention. Notice to Readers: Acquired rifamycin resistance in person with advanced HIV disease being treated for active tuberculosis with intermittent ryfamicin-based regimen. MMWR Morb Mortal Wkly Rep 2002;51:214–215. Vernon A, Burman W, Benator D, et al. Acquired rifamycin monoresistance in patients with HIVrelated tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999;353:1843–1847. Kwara A, Flanigan TP, Carter EJ. HIghly active antiretroviral therapy (HAART) in adults with tuberculosis: current status. Int J Tuberc Lung Dis 2005;9(3):248–257. Corbett EL, Watt C, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163(9):1009–1021. World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach. Geneva: World Health Organization, 2006 rev. Burman W, Gallicano K, Peloquin C. Therapeutic implications of drug interactions in the treatment of HIV-related tuberculosis. Clin Infect Dis 1999;28: 419–430. Narita M, Ashkin D, Hollander ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157–161. Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIVinfected persons. Chest 2001;120:193–197. Ramos A, Asensio A, Perales I, et al. Prolonged paradoxical reaction of tuberculosis in an HIV infected patient after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2003;22:374–376. Lawn SD, Bekker L, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;(6):361–373. Mukadi YD, Maher D, Harries A. Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa. AIDS 2001;15:143–152. Harries AD, Hargreaves NJ, Kemp J, et al. Deaths from tuberculosis in sub-Saharan African countries with a high prevalence of HIV-1. Lancet 2001;357:1519–1523. Enarson DA, Rieder HL, Arnadottir T, et al. Management of Tuberculosis. A Guide for Low Income Countries, 5th edn. Paris: International Union against Tuberculosis and Lung Diseases, 2000. Snider DE, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984;144:589–590. Bowersox DW, Winterbauer RH, Stewart GL, et al. Isoniazid dosage in patients with renal failure. N Engl J Med 1973;289:84–87.
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60. Stamatakis G, Montes C, Trouvin JH, et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clin Nephrol 1988;30:230–234. 61. Varughese A, Brater DC, Benet LZ, et al. Ethambutol kinetics in patients with impaired renal function. Am Rev Respir Dis 1986;134:34–38. 62. Acocella G, Bonollo L, Garimoldi M, et al. Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease. Gut 1972;13:47–53. 63. Lacroix C, Tranvouez JL, Phan Hoang T, et al. Pharmacokinetics of pyrazinamide and its metabolites in patients with hepatic cirrhotic insufficiency. Drugs Res 1990;40:76–79. 64. Zignol M, Hosseini MS, Wright A, et al. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 2006;194:479–485. 65. Shah NS, Wright A, Bai GH, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007;13:380–387. 66. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368: 1575–1580. 67. Migliori GB, Espinal M, Danilova ID, et al. Frequency of recurrence among MDR-TB cases ‘successfully’ treated with standardized short-course chemotherapy. Int J Tuberc Lung Dis 2002;6(10): 858–864. 68. Mitnick C, Bayona J, Palacios E, et al. Communitybased therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003;348(2):119–128. 69. Farmer PE, Kim JY. Community-based approaches to the control of multidrug-resistant tuberculosis: introducing DOTS-Plus. BMJ 1998;317(7159): 671– 674. 70. Chaulk CP, Chaisson RE, Lewis JN, et al. Treating multidrug-resistant tuberculosis: compliance and side effects. JAMA 1994;271(2):103–104. 71. Kim SJ. Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur Respir J 2005;25(3): 564–569. 72. Laserson KF, Thorpe LE, Leimane V, et al. Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2005;9(6):640–645. 73. Heldal E, Arnadottir T, Chacon L, et al. Low failure rate in standardized retreatment of tuberculosis in Nicaragua: patient category, drug resistance and survival of ‘chronic’ patients. Int J Tuberc Lung Dis 2001;5(2):129–136. 74. Suarez PG, Floyd K, Portocarrero J, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002; 359(9322):1980–1989. 75. Park SK, Lee WC, Lee DH, et al. Self-administered, standardised regimens for multidrug-resistant tuberculosis in South Korea. Int J Tuberc Lung Dis 2004;8(3):361–368. 76. Van Deun A, Bastian I, Portaels F, et al. Results of a standardized regimen for multidrug-resistant tuberculosis in Bangladesh. Int J Tuberc Lung Dis 2004;8(5):560–567. 77. World Health Organization. Instructions for applying to the Green Light Committee for Access to SecondLine Antituberculosis Drugs (WHO/HTM/TB/ 2006.369). Geneva: World Health Organization, 2006. 78. Tuberculosis Research Centre, Chennai, India. Low rate of emergence of drug resistance in sputum positive patients treated with short-course chemotherapy. Int J Tuberc Lung Dis 2001;5(1):40–45. 79. Yoshiyama T, Yanai H, Rhiengtong D, et al. Development of acquired drug resistance in recurrent tuberculosis patients with various previous treatment outcomes. Int J Tuberc Lung Dis 2004;8(1):31–38. 80. Saravia JC, Appleton SC, Rich ML, et al. Retreatment management strategies when first-line tuberculosis therapy fails. Int J Tuberc Lung Dis 2005; 9(4):421–429.
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81. Quy HTW, Lan NTN, Borgdorff MW, et al. Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment regimen adequate? Int J Tuberc Lung Dis 2003;7(7):631–636. 82. Horne NW, Grant IW. Development of drug resistance to isoniazid during desensitization: a report of two cases. Tubercle 1963;44:180–182. 83. Laszlo A, Rahman M, Espinal M, et al. Quality assurance programme for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994-1998. Int J Tuberc Lung Dis 2002;6(9):748–756. 84. Centers for Disease Control and Prevention. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons – Florida and New York, 1988-1991. JAMA 1991;266(11): 1483–1485. 85. Centers for Disease Control and Prevention. Multidrug-resistant outbreak on an HIV ward – Madrid, Spain, 1991-1995. MMWR Morb Mortal Wkly Rep 1996;45(16):330–333. 86. Moro ML, Gori A, Errante I, et al. An outbreak of multidrug-resistant tuberculosis involving HIV-
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infected patients of two hospitals in Milan, Italy. AIDS 1998;12(9):1095–1102. Nunn P, Kibuga D, Gathusa S, et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV1 seropositive patients treated for tuberculosis. Lancet 1991;337:627–630. Chaisson RE, Schecter GF, Theuer CP, et al. Tuberculosis in patients with the acquired immunodeficiency syndrome. Clinical features, response to therapy, and survival. Am Rev Respir Dis 1987;136(3):570–574. Soriano E, Mallolas J, Gatell JM, et al. Characteristics of tuberculosis in HIV-infected patients: case-control study. AIDS 1988;2(6):429–432. Rich ML (ed.). PIH Guide to the Medical Management of Multidrug-Resistant Tuberculosis. Boston: Partners in Health, 2003. Figueroa-Damian R, Arredondo-Garcia JL. Neonatal outcome of children born to women with tuberculosis. Arch Med Res 2001;32(1):66–69. Brost BC, Newman RB. The maternal and fetal effects of tuberculosis therapy. Obstet Gynecol Clin North Am 1997;24(3):659–673.
93. Duff P. Antibiotic selection in obstetric patients. Inf Dis Clin N Am 1997;11(1):1–12. 94. Nishimura H, Tanimura T. Clinical Aspects of Teratogenicity of Drug. Amsterdam: Excerpta Medica, 1976:131. 95. Fujimora H, Yamada F, Shibukawa N, et al. The effect of tuberculostatics on the fetus: an experimental production of congenital anomaly in rats by ethionamide. Proc Congenital Anom Res Assoc Jpn 1965;5:34–35. 96. Leimane V, Riekstina V, Holtz TH, et al. Clinical outcome of individualised treatment of multidrugresistant tueberculosis in Latvia: a retrospective cohort study. Lancet 2005;365:318–326. 97. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis. We can’t afford not to try it. N Engl J Med 1993;328(8):576–578. 98. Raviglione MC, Smith IM. XDR tuberculosis – implications for global public health. N Engl J Med 2007;356(7):656–659.
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International standards for tuberculosis care Philip C Hopewell, Elizabeth L Fair, and Madhukar Pai
INTRODUCTION Tuberculosis care, a clinical function intended to cure individual patients, is the core element of TB control, a public health function, the goal of which is to protect the health of the public by reducing and, ultimately, eliminating TB.1 Consequently, any provider of healthcare, public or private, who undertakes to deliver TB services is responsible both to the community and to the individual patient. To fulfil these responsibilities effectively, the care provided must meet certain essential standards that apply regardless of who is delivering the care or where it is provided. These standards are embodied in the International Standards for Tuberculosis Care (ISTC) described in this chapter.2 The basic principles of care for persons with, or suspected of having, TB are the same world-wide and are included in the internationally recommended directly observed treatment, shortcourse (DOTS) strategy:3 a diagnosis should be established promptly and accurately; standardized treatment regimens of proven efficacy should be used together with appropriate treatment support and supervision; and the response to treatment should be monitored. In addition to these basic care elements, cases must be reported to public health authorities and persons exposed to infectious cases must be evaluated.4 Generally, in the public sector TB control programmes provide substantial guidance to their clinicians in the application of these principles, and there usually is ongoing monitoring and evaluation that identifies both individual and programmatic shortcomings. Such is not the case in the private sector. Unfortunately, studies of the performance of the private sector conducted in several different parts of the world suggest that poor quality care is common.3,5–12 Clinicians, particularly those who work in the private healthcare sector, often deviate from internationally accepted practices.3,12 These deviations include under-utilization of sputum smear microscopy and other microbiological evaluations for diagnosis, generally associated with over-reliance on chest radiography. Additionally, unproven diagnostic tests such as serological studies are heavily promoted and used in many developing countries where they can be least afforded. The use of non-recommended drug regimens with incorrect combinations of drugs and mistakes in both drug dosage and duration of treatment results in both underand over-treatment. Moreover, failure to supervise and ensure adherence to treatment results in erratic or incomplete treatment, often with the patient continuing to be infectious and perhaps
developing drug resistance.3,6–12 Each of these errors in management carries risks for both the patient and the community. The emergence of extensively drug-resistant (XDR) TB serves as a frightening example of the failure to adhere to the fundamental principles of TB care.13 As was editorialized in Lancet Infectious Diseases, adherence to the ISTC will prevent the occurrence of XDRTB as well as other negative outcomes.14 Although an important purpose of the ISTC is to provide guidance to the private sector, adherence to the standards by the public sector is equally important. Moreover, collaboration between the public and private sectors is essential for adherence to the ISTC. For example, private providers may not have free access to quality-assured microbiological services or drugs. Such services and drugs can be made available through local public health programmes. Commonly, private providers have no means of assessing treatment adherence or of addressing poor adherence. Co-management with the local TB clinic can provide the necessary supervision. Thus, public health programmes may need to make accommodations that enable private providers to comply with the standards. Full engagement of all care providers through various forms of public–private and public–public partnerships is an important component of both the World Health Organization’s (WHO) expanded strategy for TB control and the Global Plan to Stop TB, 2006–2015.15 Although there have been several approaches developed for involvement of the private sector (as well as for government-employed providers who are not affiliated with a TB control programme) there has been no generally agreed upon set of standards describing the essential actions that should be taken by all practitioners in providing TB services. To address this shortcoming, the ISTC was developed through a year-long inclusive process guided by a 28-member steering committee. The steering committee included individuals who represented a wide variety of relevant perspectives on TB care and control. In addition the document was presented at a number of public forums with an open invitation for comments. A number of individuals and organizations had substantive comments that were included in the document. The result was agreement on a group of 17 standards: six addressing diagnosis, nine addressing treatment and two addressing public health responsibilities. The ISTC describes a widely endorsed level of care that all practitioners, public and private, should seek to achieve in managing patients who have, or are suspected of having, TB. The ISTC applies to patients of all ages, including those with smear-positive, smear-negative and extrapulmonary TB, TB caused by drug-resistant
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Mycobacterium tuberculosis complex organisms and TB combined with human immunodeficiency virus (HIV) infection. For all forms of TB a high standard of care is essential to restore the health of individuals, to prevent the disease in their families and others with whom they come into contact and to protect the health of communities.5 The ISTC focuses on the contribution that good clinical care makes to TB control. A balanced approach emphasizing both individual patient care and public health principles of disease control is essential to reduce the human suffering and economic losses from TB. The ISTC is not intended to replace either WHO or local guidelines and was written to accommodate local differences in practice. It is anticipated that it will be used as a tool to unify approaches to TB care between public (at least government TB control programmes) and private providers. Although the standards themselves should not be modified based on local circumstances, clearly there will need to be local approaches to their use and implementation. It is anticipated that, as new information emerges, these standards will change. The ISTC is envisioned as a living document that will be undergoing regular review and revision. In tandem with the development of the ISTC, a group of patient activists and advocates developed the ‘Patients’ Charter for Tuberculosis Care’ (available at http://www.who.int/tb/publications/ 2006/istc_charter.pdf), describing a patient’s rights and responsibilities. There was considerable interaction between the two groups during the course of drafting the documents.
STANDARDS FOR DIAGNOSIS Standard 1: All persons with otherwise unexplained productive cough lasting 2–3 weeks or more should be evaluated for TB The most common symptom of pulmonary TB is persistent productive cough, often accompanied by systemic symptoms, such as fever, night sweats and weight loss. In a survey of primary healthcare services of nine low- and middle-income countries conducted by the WHO, respiratory complaints, including cough, constituted on average 18.4% of symptoms that prompted a visit to a health centre for persons older than 5 years of age. Of this group 5% of patients, overall, were categorized as possibly having TB because they had an unexplained cough for more than 2–3 weeks.16 Other studies have shown that 4–10% of adults attending outpatient health facilities in developing countries complain of a persistent cough lasting more than 2–3 weeks.17 This percentage varies somewhat depending on whether there is active questioning concerning the presence of cough. Data from India, Algeria and Chile generally show that the percentage of patients with positive sputum smears increases with increasing duration of cough from 1–2 weeks, to 3–4, and to > 4 weeks.18 However, in these studies even patients with shorter duration of cough had an appreciable prevalence of TB. A more recent assessment from India demonstrated that by using a threshold of > 2 weeks to prompt collection of sputum specimens the number of patients with suspected TB increased by 61%, but, more importantly, the number of TB cases identified increased by 46% compared with a threshold of > 3 weeks.19 The results also suggested that actively enquiring as to the presence of cough in all adult clinic attendees increases the yield of cases.19
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Choosing a threshold of 2–3 weeks is an obvious compromise. Cough is a very non-specific symptom, and, in countries with a low prevalence of TB, it is highly likely that cough of this duration is due to conditions other than TB. Conversely, in high-prevalence countries, TB will be one of the leading diagnoses to consider, together with other conditions, such as asthma, bronchitis and bronchiectasis. Unfortunately, several studies suggest that, commonly, patients with subacute or chronic respiratory symptoms receive an inadequate evaluation for TB because of the assumption that the cough is due to another cause.6,8–12,20
Standard 2: All patients (adults, adolescents and children who are capable of producing sputum) suspected of having pulmonary TB should have at least two and, preferably, three sputum specimens obtained for microscopic examination. When possible at least one early morning specimen should be obtained A confirmed diagnosis of TB can only be established by culturing M. tuberculosis complex (or, in appropriate circumstances, identifying specific nucleic acid sequences in a clinical specimen) from any suspected site of disease. In practice, however, there are many settings in which culture is not feasible currently. Fortunately, microscopic examination of stained sputum is feasible in nearly all settings, and the diagnosis of TB can be strongly inferred by finding acid-fast bacilli (AFB) by microscopic examination. In nearly all clinical circumstances in high-prevalence areas, finding AFB in stained sputum is highly specific and, thus, is accepted as the equivalent of a confirmed diagnosis. Failure to perform a proper diagnostic evaluation before initiating treatment potentially exposes the patient to the risks of unnecessary or wrong treatment with no benefit. Moreover, such an approach may delay accurate diagnosis and proper treatment. This standard applies to adults, adolescents and children. With proper instruction and supervision many children 5 years of age and older can generate a specimen. Thus, age alone is not sufficient justification for failing to attempt to obtain a sputum specimen from a child or adolescent. The optimum number of sputum specimens to establish a diagnosis has been examined in a number of studies. A rigorously conducted systematic review of 41 studies on this topic found that, on average, the second smear detected about 13% of smear-positive cases, and the third smear detected 4% of all smear-positive cases.21 In studies that used culture as the reference standard, the mean incremental yield in sensitivity of the second smear was 9% and that of the third smear was 4%.21 A reanalysis of data from a study involving 42 laboratories in four high-burden countries showed that the incremental yield from a third sequential smear ranged from 0.7% to 7.2%.22 The timing of specimen collection is also important. The yield appears to be greatest from early morning (overnight) specimens.21,23–25 Thus, at least one specimen should be obtained from an early morning collection. A variety of methods have been used to improve the performance of sputum smear microscopy.26 In general the sensitivity of microscopy (as compared with culture) is higher with concentration by centrifugation (usually after pre-treatment with chemicals such as NALC-NaOH) and/or sedimentation (usually after pre-treatment with bleach), as compared with direct smear microscopy. A systematic review of 83 studies describing the effects of various physical and/or chemical methods for concentrating and processing sputum prior to microscopy found that concentration
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resulted in a higher sensitivity (15–20% increase) and smear-positivity rate, when compared with direct smears.26 Although there are demonstrable advantages to concentration of sputum, there are also disadvantages. Centrifugation is more complex, requires electrical power and may be associated with increased infection risk to laboratory personnel. Consequently, it is not clear that the advantages offset the disadvantages in low-resource settings. A systematic review of 43 studies in which the performance of direct sputum smear microscopy with fluorescence staining was compared with Ziehl–Neelsen (ZN) staining using culture as the gold standard showed that fluorescence microscopy is on average 10% more sensitive than conventional light microscopy and has comparable specificity.27 The combination of increased sensitivity with little or no loss of specificity makes fluorescence microscopy a more accurate test, although the increased cost and complexity might make it less applicable in many areas. For this reason fluorescence staining is probably best used in centres with specifically trained and proficient microscopists, in which a large number of specimens are processed daily, and in which there is an appropriate quality assurance programme.
Standard 3: For all patients (adults, adolescents and children) suspected of having extrapulmonary TB, appropriate specimens from the suspected sites of involvement should be obtained for microscopy and, where facilities and resources are available, for culture and histopathological examination Bacteriological confirmation of extrapulmonary TB is often more difficult than for pulmonary TB. Given the low yield of microscopy, both culture and histopathological examination of tissue specimens, such as may be obtained by needle biopsy of lymph nodes, are important. In addition to the collection of specimens from the sites of suspected TB, sputum should be examined and a chest radiograph obtained, especially in patients with HIV infection, in whom there is an appreciable frequency of subclinical pulmonary TB.28 Standard 4: All persons with chest radiographic findings suggestive of TB should have sputum specimens submitted for microbiological examination Chest radiography is a sensitive but non-specific test for detecting TB.29 Radiographic examination of the thorax or other suspected sites of involvement may be useful for identifying persons for further evaluation; however, a diagnosis of TB cannot be established by radiography alone. Reliance on the chest radiograph as the only diagnostic test for TB will result in both over-diagnosis of TB and missed diagnoses of TB and other diseases. As summarized in a study from India in which 2,229 outpatients were examined by photofluorography, 227 were classified as having TB by radiographic criteria.30,31 Of the 227, 81 (36%) had negative sputum cultures, whereas of the remaining 2,002 patients 31 (1.5%) had positive cultures. Looking at these results in terms of the sensitivity of chest radiography 32 (20%) out of 162 culture-positive cases would have been missed by radiography. Chest radiography is useful for evaluating persons who have negative sputum smears to attempt to find evidence for pulmonary TB and to identify other abnormalities that may be responsible for the symptoms. With regard to TB, radiographic examination is most useful when applied as part of a systematic approach in the evaluation of persons whose symptoms and/or findings suggest TB, but who have negative sputum smears (see Standard 5).
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Standard 5: The diagnosis of sputum smear-negative pulmonary TB should be based on the following criteria: at least three negative sputum smears (including at least one early morning specimen); chest radiography findings consistent with TB; and lack of response to a trial of broad-spectrum antimicrobial agents. (Note: Because the fluoroquinolones are active against M. tuberculosis complex and, thus, may cause transient improvement in persons with TB, they should be avoided.) For such patients if facilities for culture are available, sputum cultures should be obtained. In persons with known or suspected HIV infection the diagnostic evaluation should be expedited Given the non-specific nature of the symptoms of TB and the multiplicity of other diseases that could be the cause of the patient’s illness, it is important that a rigorous approach be taken in diagnosing TB in a patient in whom at least three adequate sputum smears are negative. Because patients with HIV infection and TB frequently have negative sputum smears and because of the broad differential diagnosis in this group, such a systematic approach is crucial. It is important, however, to balance the need for a systematic approach, in order to avoid both over- and under-diagnosis of TB, with the need for prompt treatment in a patient with an illness progressing rapidly. A presumptive diagnosis of TB when the illness has another cause will delay correct diagnosis and treatment, whereas under-diagnosis will lead to more severe consequences of TB, as well as ongoing transmission of M. tuberculosis. A number of algorithms have been developed as a means to diagnose smear-negative TB. Although none of the algorithms has been adequately validated under field conditions, they generally provide a useful framework for systematizing the approach to diagnosis.32,33 Of particular concern, however, is the lack of evidence on which to base approaches to the diagnosis of smear-negative TB in persons with HIV infection. There are several pitfalls in using algorithms. First, strict adherence to the sequential steps of the algorithm may delay appropriate treatment in patients with an illness worsening rapidly. Second, several studies have shown that patients with TB may respond, at least transiently, to empiric broad-spectrum antimicrobial treatment, a frequent element of diagnostic algorithms.34–37 Obviously, such a response will lead one to delay a diagnosis of TB. Fluoroquinolones, in particular, are bactericidal for M. tuberculosis complex. Empiric fluoroquinolone monotherapy for respiratory tract infections has been associated with delays in initiation of appropriate anti-TB therapy and acquired resistance to the fluoroquinolones.38 Third, the approach outlined in an algorithm may be quite costly to patients and deter them from continuing with the diagnostic evaluation. Although sputum microscopy is the first bacteriological diagnostic test of choice, where resources permit and adequate, qualityassured laboratory facilities are available, culture should be included in the evaluation of patients suspected of having TB, but who have negative sputum smears. Properly done, culture increases diagnostic sensitivity, which should result in earlier case detection.39,40 The disadvantages of culture are its cost, technical complexity and the time required to obtain a result, thereby imposing a diagnostic delay if there is less reliance on sputum smear microscopy. In addition, ongoing quality assessment is essential for culture results to be credible. Such quality assurance measures are not available widely in most low-resource settings.
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Nucleic acid amplification tests (NAATs), although widely distributed, do not offer major advantages over culture at this time. Although a positive result can be obtained more quickly than with any of the culture methods, the NAATs are not sufficiently sensitive for a negative result to exclude TB.4,41–43 In addition, NAATs are not of proven value in identifying M. tuberculosis in specimens from extrapulmonary sites of disease.4,43 Other approaches to establishing a diagnosis of TB, such as serological tests, are not of proven value and should not be used in routine practice at this time.4,41
Standard 6: The diagnosis of intrathoracic (i.e. pulmonary, pleural, and mediastinal or hilar lymph node) TB in symptomatic children with negative sputum smears should be based on the finding of chest radiographic abnormalities consistent with TB, and either a history of exposure to an infectious case or evidence of TB infection (positive tuberculin skin test or interferon gamma release assay). For such patients, if facilities for culture are available, sputum specimens should be obtained (by expectoration, gastric washings or induced sputum) for culture Compared with adults, sputum smears from children are more likely to be negative, and cultures of sputum or other specimens, radiographic examination of the chest and tests to detect tuberculous infection (generally, a tuberculin skin test) are of relatively greater importance. Because many children less than 5 years of age do not cough and produce sputum effectively, culture of gastric aspirates/washings or induced sputum has a higher yield than spontaneous sputum.44 Several recent reviews have examined the effectiveness of various diagnostic tools, scoring systems and algorithms for diagnosing TB in children.44–47 Many of these approaches lack standardization and validation, and, thus, are of limited applicability. Table 63.1
Table 63.1 Clinical features suggestive of tuberculosis recommended by the Integrated Management of Childhood Illness (IMCI) programme of the WHO The risk of TB is increased when there is an active case (infectious, smear-positive TB) in the same house, or when the child is malnourished, is HIV-infected or has had measles in the past few months. Consider TB in any child with: A history of: ○ Unexplained weight loss or failure to grow normally ○ Unexplained fever, especially when it continues for more than 2 weeks ○ Chronic cough ○ Exposure to an adult with probable or definite pulmonary infectious TB On examination: ○ Fluid on one side of the chest (reduced air entry, stony dullness to percussion) ○ Enlarged non-tender lymph nodes or a lymph node abscess, especially in the neck ○ Signs of meningitis, especially when these develop over several days and the spinal fluid contains mostly lymphocytes and elevated protein ○ Abdominal swelling, with or without palpable lumps ○ Progressive swelling or deformity in the bone or a joint, including the spine Source: Reproduced from WHO/FCH/CAH/00.1.48
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provides a list of clinical features suggestive of TB recommended by the Integrated Management of Childhood Illness (IMCI) programme of the WHO, which is widely used in first-level facilities in low- and middle-income countries.48 A systematic approach to assessing all the available diagnostic evidence is particularly important where HIV infection is common because HIV infection compounds the diagnostic difficulties.45,49
STANDARDS FOR TREATMENT Standard 7: Any practitioner treating a patient for TB is assuming an important public health responsibility. To fulfil this responsibility the practitioner must not only prescribe an appropriate regimen, but also be capable of assessing the adherence of the patient to the regimen and addressing poor adherence when it occurs. By so doing, the provider will be able to ensure adherence to the regimen until treatment is completed All providers who undertake to treat a patient with TB must have the knowledge to prescribe a standard treatment regimen and the means to assess adherence to the regimen and address poor adherence to ensure that treatment is completed.50 National TB programmes commonly possess approaches and tools for ensuring adherence with treatment and, when properly organized, can offer these to non-programme providers. Failure of a provider to ensure adherence could be equated with, for example, failure to ensure that a child receives the full set of immunizations. Standard 8: All patients (including those with HIV infection) who have not been treated previously should receive an internationally accepted first-line treatment regimen using drugs of known bioavailability. The initial phase should consist of 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol. (Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, do not have extensive pulmonary TB or severe forms of extrapulmonary disease and who are known to be HIV-uninfected.) The preferred continuation phase consists of isoniazid and rifampicin given for 4 months. Isoniazid and ethambutol given for 6 months is an alternative continuation phase regimen that may be used when adherence cannot be assessed but is associated with a higher rate of failure and relapse, especially in patients with HIV infection The doses of anti-TB drugs used should conform to international recommendations. Fixed-dose combinations of two (isoniazid and rifampicin), three (isoniazid, rifampicin and pyrazinamide) and four (isoniazid, rifampicin, pyrazinamide and ethambutol) drugs are highly recommended, especially when medication ingestion is not observed A large number of well-designed clinical trials have provided the evidence base for this standard and several sets of treatment recommendations based on these studies have been written during the past few years.50–52 All these data indicate that a rifampicin-containing
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regimen is the backbone of anti-TB chemotherapy and is highly effective in treating TB caused by drug-susceptible M. tuberculosis. It is also clear from these studies that the minimum duration of treatment for smear- and/or culture-positive TB is 6 months. For the 6-month treatment duration to be maximally effective, the regimen must include pyrazinamide during the initial 2-month phase and rifampicin, together with isoniazid, must be included throughout the full 6 months. There are several variations in the frequency of drug administration that have been shown to produce acceptable results.50–52 Two systematic reviews of regimens of less than 6 months have found that shorter durations of treatment have an unacceptably high rate of relapse.53,54 Thus, the current international standard for smear- or culture-positive TB is a regimen administered for a minimum of 6 months.50,52 Although the 6-month regimen is the preferred option, an alternative continuation phase regimen, consisting of isoniazid and ethambutol given for 6 months, making the total duration of treatment 8 months, may also be used. It should be recognized, however, that this regimen, presumably because of the shorter duration of rifampicin administration, is associated with a higher rate of failure and relapse, especially in patients with HIV infection.55–57 Nevertheless the 8-month regimen may be used when adherence to treatment throughout the continuation phase cannot be assessed.52 The rationale for this approach is that if the patient is non-adherent, the emergence of resistance to rifampicin will be minimized. A retrospective review of the outcomes of treatment of TB in patients with HIV infection shows that TB relapse is minimized by the use of a regimen containing rifampicin throughout a 6-month course.55 However, the patient’s HIV stage, the need for and availability of antiretroviral drugs and the quality of treatment supervision/support must be considered in choosing an appropriate continuation phase of therapy. Intermittent administration of anti-TB drugs enables supervision to be provided more efficiently and economically with no reduction in efficacy. The evidence on effectiveness of intermittent regimens was reviewed recently.58,59 These reviews, based on several trials,60–65 suggest that anti-TB treatment may be given intermittently thrice weekly throughout the full course of therapy or twice weekly in the continuation phase without apparent loss of effectiveness. However, the WHO and the International Union against Tuberculosis and Lung Disease (IUATLD) do not recommend the use of twice-weekly intermittent regimens because of the potentially greater consequences of missing one of the two doses.51,52,66 A simplified version of the current WHO recommendations for treating persons who have not been treated previously is shown in Table 63.2.52 The evidence on drug dosages and safety and the biological basis for dosage recommendations have been extensively reviewed elsewhere.50–52,66–68 The recommended doses for daily and thrice-weekly administration are shown in Table 63.3. Treatment of TB in special clinical situations such as the presence of liver disease, renal disease, pregnancy and HIV infection may require modification of the standard regimen or alterations in dosage or frequency of drug administration. Guidelines for these situations can be found elsewhere.50,52 Although there is no evidence that fixed-dose combinations (FDCs) are superior to individual drugs, expert opinion suggests that they minimize inadvertent monotherapy and may decrease the frequency of acquired drug resistance and medication errors.50,52 Fixed-dose combinations also reduce the number of tablets to be consumed and may thereby increase patient adherence to recommended treatment regimens.69,70
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Table 63.2 WHO recommended tuberculosis treatment for persons not treated previously Ranking Preferred Optional
Initial phase
Continuation phase a, b
daily or INH, RIF, PZA, EMB 3/week for 2 months INH, RIF, PZA, EMBb daily for 2 months
INH, RIF daily or 3/ week for 4 months INH, EMB daily for 6 monthsc
INH, isoniazid; RIF, rifampicin; PZA, pyrazinamide; EMB ethambutol. a Streptomycin may be substituted for EMB. b Ethambutol may be omitted in the initial phase of treatment for adults and children who have negative sputum smears, do not have extensive pulmonary TB or severe forms of extrapulmonary disease and who are known to be HIV-uninfected. c Associated with higher rate of treatment failure and relapse; should generally not be used in patients with HIV infection. Source: WHO52
Table 63.3 Doses of first-line antituberculosis drugs in adults and children Drug
Recommended dose in mg/kg body weight (range) Daily
Isoniazid
5 (4–6), maximum 300 daily Rifampicin 10 (8–12), maximum 600 daily Pyrazinamide 25 (20–30) Ethambutol Children: 20 (15–25)a Adults: 15 (15–20) Streptomycin 15 (12–18)
Thrice weekly 10 10 (8–12), maximum 600 daily 35 (30–40) 30 (25–35) 15 (12–18)
a
The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults (15 mg/kg), because the pharmacokinetics are different (peak serum ethambutol concentrations are lower in children than in adults receiving the same mg/kg dose). Source: WHO52
Standard 9: To foster and assess adherence, a patient-centred approach to administration of drug treatment, based on the patient’s needs and mutual respect between the patient and the provider, should be developed for all patients. Supervision and support should be gender-sensitive and age-specific and should draw on the full range of recommended interventions and available support services, including patient counselling and education. A central element of the patient-centred strategy is the use of measures to assess and promote adherence to the treatment regimen and to address poor adherence when it occurs. These measures should be tailored to the individual patient’s circumstances and be mutually acceptable to the patient and the provider. Such measures may include direct observation of medication ingestion (directly observed therapy) by a treatment supporter who is acceptable and accountable to the patient and to the health system The approach described in the standard is designed to encourage and facilitate a positive partnership between providers and patients,
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working together to improve adherence. Assuming an appropriate drug regimen is prescribed, adherence to treatment is the critical factor in determining treatment success.71 This partnership between patients and providers is embodied in the ‘Patients’ Charter for Tuberculosis Care’ (http://www.who.int/tb/publications/ 2006/istc_charter.pdf), developed as a companion to the ISTC. Achieving adherence is not an easy task, for either the patient or the provider. Yet, failure to complete treatment for TB leads to prolonged infectivity, poor outcomes and drug resistance.72 Adherence is a multidimensional phenomenon determined by the interplay of five categories of factors: health system, socioeconomic, therapy-related, condition-related and patient-related.71 Despite evidence to the contrary, there is a widespread tendency to focus on patient-related factors as the main cause of poor adherence.71 Less attention is paid to provider- and health system-related factors. Sociological and behavioural research during the past 40 years has shown that patients need to be supported, not blamed.71 Several studies have evaluated various interventions for improving adherence to TB therapy. There are a number of reviews that examine the evidence on the effectiveness of these interventions.50,71,73–79 Among the interventions evaluated, DOT has generated the most debate and controversy. The third component of the global DOTS strategy, now widely recommended as the most effective strategy for controlling TB world-wide, is the administration of a standardized, rifampicin-based regimen using case management interventions appropriate to the individual and the circumstances.50,52,80,81 These interventions should include DOT as one of a range of measures for promoting and assessing adherence to treatment. The main advantage of DOT is that treatment is carried out entirely under close observation.76 This provides both an accurate assessment of the degree of adherence and greater assurance that the medications have actually been ingested. When a second individual observes a patient swallowing medications, there is greater certainty that the patient is actually receiving the prescribed medications. This approach, therefore, results in a high cure rate and a reduction in the risk of drug resistance. Also, because there is a close contact between the patient and the treatment supporter, adverse drug effects and other complications can be identified quickly and managed appropriately.76 Moreover, such case management can also serve to identify and assist in addressing the myriad other problems experienced by patients with TB such as undernutrition, poor housing and loss of income, to name a few. In a Cochrane systematic review that synthesized the evidence from six controlled trials comparing DOT with self-administered therapy,73,74 the authors found that patients allocated to DOT and those allocated to self-administered therapy had similar cure rates (relative risk (RR) 1.06, 95% confidence interval (CI) 0.98, 1.14) and rates of cure plus treatment completion (RR 1.06; 95% CI 1.00, 1.13). They concluded that direct observation of medication ingestion did not improve outcomes.73,74 In contrast, other reviews have found DOT to be associated with high cure and treatment completion rates.50,52,75,76,82 Also, programmatic studies on the effectiveness of the DOTS strategy have shown high rates of treatment success in several countries.71 It is likely that these inconsistencies across reviews are due to the fact that primary studies are often unable to separate the effect of DOT alone from the overall DOTS strategy.71,78 In a retrospective review of programmatic results, the highest rates of success were achieved with ‘enhanced DOT’ which consisted of ‘supervised swallowing’ plus social supports, incentives and enablers as part of a larger programme to encourage adherence to treatment.75 Such
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complex interventions are not easily evaluated within the conventional randomized controlled trial framework.71 Interventions other than DOT have also shown promise.71,79 For example, interventions that used incentives, peer assistance, repeated motivation of patients and staff training and motivation all have been shown to improve adherence significantly.79 In addition adherence may be enhanced by provision of more comprehensive primary care, as described in the Integrated Management of Adolescent and Adult Illness,83–85 as well as by provision of specialized services such as opiate substitution for injection drug users. Interventions that target adherence must be tailored or customized to the particular situation and cultural context of a given patient.71 Such an approach must be developed in concert with the patient to achieve optimum adherence. This patient-centred, individualized approach to treatment support is now a core element of all TB care and control efforts. It is important to note that treatment support measures, and not the treatment regimen itself, must be individualized to suit the unique needs of the patient.
Standard 10: All patients should be monitored for response to therapy, best judged in patients with pulmonary TB by follow-up sputum microscopy (two specimens) at least at the time of completion of the initial phase of treatment (2 months), at 5 months and at the end of treatment. Patients who have positive smears during the 5th month of treatment should be considered as treatment failures and have therapy modified appropriately (see standards 14 and 15). In patients with extrapulmonary TB and in children, the response to treatment is best assessed clinically. Follow-up radiographic examinations are usually unnecessary and may be misleading Patient monitoring is necessary to evaluate the response of the disease to treatment and to identify adverse drug reactions. To judge response of pulmonary TB to treatment, the most expeditious method is sputum smear microscopy. Ideally, where qualityassured laboratories are available, sputum cultures, as well as smears, should be performed for monitoring. Having a positive sputum smear at completion of 5 months of treatment defines treatment failure, indicating the need for determination of drug susceptibility and initiation of a re-treatment regimen.80,86,87 Radiographic assessments, although used commonly, have been shown to be unreliable for evaluating response to treatment.88 Similarly, clinical assessment can be unreliable and misleading in the monitoring of patients with pulmonary TB.88 In patients with extrapulmonary TB and in children, clinical evaluations may be the only available means of assessing the response to treatment. Standard 11: A written record of all medications given, bacteriological response and adverse reactions should be maintained for all patients A recording and reporting system enables targeted, individualized follow-up to identify patients who are failing therapy.89 It also helps in facilitating continuity of care, particularly in settings where the same practitioner might not be seeing the patient during every visit. A good record of medications given, results of investigations such as smears, cultures and chest radiographs, and progress notes on clinical improvement, adverse events and adherence will provide for more uniform monitoring and ensure a high standard of care. Records are important for providing continuity when patients move from one care provider to another and enable tracing of patients who miss appointments. In patients who default and then
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return for treatment, and patients who relapse after treatment completion, it is critical to review previous records in order to assess the likelihood of drug resistance. Lastly, management of complicated cases (e.g. multidrug-resistant (MDR) TB) is not possible without an adequate record of previous care. It should be noted that, wherever patient records are concerned, care must be taken to ensure confidentiality of the information.
Standard 12: In areas with a high prevalence of HIV infection in the general population where TB and HIV infection are likely to coexist, HIV counselling and testing is indicated for all TB patients as part of their routine management. In areas with lower prevalence rates of HIV, HIV counselling and testing is indicated for TB patients with symptoms and/or signs of HIV-related conditions, and in TB patients having a history suggestive of high risk of HIV exposure Infection with HIV changes the clinical manifestations of TB.49,90,91 In comparison with non-HIV-infected patients, patients with HIV infection who have pulmonary TB have a lower likelihood of having AFB detected by sputum smear microscopy.49,90,91 Moreover, the chest radiographic features are atypical and the proportion of extrapulmonary TB is greater in patients with advanced HIV infection than in those who do not have HIV infection. Consequently, knowledge of a person’s HIV status would influence the approach to a diagnostic evaluation for TB. For this reason it is important, particularly in areas where there is a high prevalence of HIV infection, that the history and physical examination include a search for indicators that suggest the presence of HIV infection.49,92,93 Even though in low-HIV-prevalence countries few TB patients will be HIV-infected, the connection is sufficiently strong and the impact on the patient sufficiently great that the test should always be considered in managing individual patients, especially among groups in which the prevalence of HIV is higher, such as injecting drug users. In countries having a high prevalence of HIV infection, the yield of positive results will be high and, again, the impact of a positive result on the patient will be great. Thus, the indication for HIV testing is strong; coinfected patients may benefit from access to antiretroviral therapy as HIV treatment programmes expand or through administration of cotrimoxazole for prevention of opportunistic infections, even when antiretroviral drugs are not available locally.49,94,95 Standard 13: All patients with TB and HIV infection should be evaluated to determine whether antiretroviral therapy is indicated during the course of treatment for TB. Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment. Given the complexity of co-administration of anti-TB treatment and antiretroviral therapy, consultation with a physician who is expert in this area is recommended before initiation of concurrent treatment for TB and HIV infection, regardless of which disease appeared first. However, initiation of treatment for TB should not be delayed. Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infections All patients with TB and HIV infection either currently are or will be candidates for antiretroviral therapy. Antiretroviral therapy results in remarkable reductions in morbidity and mortality in HIV-infected persons and may improve the outcomes of treatment for TB. Highly active antiretroviral therapy (HAART) is the
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internationally accepted standard of care for persons with advanced HIV infection. In patients with HIV-related TB, treating TB is the first priority. In the setting of advanced HIV infection, untreated TB can progress rapidly to death. However, antiretroviral treatment may be lifesaving for patients with advanced HIV infection. Consequently, concurrent treatment may be necessary in patients with advanced HIV disease (e.g. CD4þ count < 200/mL in adults). It should be emphasized, however, that treatment for TB should not be interrupted in order to initiate antiretroviral therapy, and, in patients who do not have advanced HIV infection, it may be safer to defer antiretroviral treatment until at least the completion of the initial phase of TB treatment.49 There are a number of problems associated with concomitant therapy for TB and HIV infection. These include overlapping drug toxicity profiles, drug–drug interactions (especially with rifamycins and protease inhibitors), potential problems with adherence to multiple medications and immune reconstitution reactions.49,50 Consequently, consultation with an expert in HIV management in deciding when to start antiretroviral drugs, the agents to use, and plan for monitoring for adverse reactions and response to both therapies is needed. Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infections. Several studies have demonstrated the benefits of cotrimoxazole prophylaxis, and this intervention is currently recommended by the WHO as part of the TB–HIV management package.49,95–101
Standard 14: An assessment of the likelihood of drug resistance, based on history of prior treatment, exposure to a possible source case having drugresistant organisms and the community prevalence of drug resistance, should be obtained for all patients. Patients who fail treatment and chronic cases should always be assessed for possible drug resistance. For patients in whom drug resistance is considered to be likely, culture and drug susceptibility testing for isoniazid, rifampicin and ethambutol should be performed promptly Drug resistance is largely man-made and is a consequence of suboptimal regimens and treatment interruptions. Clinical errors that commonly lead to the emergence of drug resistance include failure to provide effective treatment support and assurance of adherence; failure to recognize and address patient non-adherence; inadequate drug regimens; adding a single new drug to a failing regimen; and failure to recognize existing drug resistance.102 Programmatic causes of drug resistance include drug shortages and stock-outs, administration of poor-quality drugs and lack of appropriate supervision to prevent erratic drug intake.102 The strongest factor associated with drug resistance is previous anti-TB treatment.102,103 In previously treated patients, the odds of any resistance are at least four fold higher and that of MDR at least 10-fold higher than in new (untreated) patients.103 Patients with chronic TB (sputum positive after re-treatment) and those who fail treatment (sputum positive after 5 months of treatment) are at highest risk of having MDR-TB, especially if rifampicin was used throughout the course of treatment.87,103 Persons, especially children and HIV-infected individuals, in close contact with confirmed MDR-TB patients are also at high risk of being infected with MDR strains. In some closed settings prisoners, persons staying in homeless shelters and certain categories of immigrants and migrants are at increased risk of MDR-TB.102–107
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Drug susceptibility testing (DST) for first-line anti-TB drugs should be performed in specialized reference laboratories that participate in an ongoing, rigorous quality assurance programme. DST for first-line drugs is currently recommended for all patients with a history of previous anti-TB treatment: patients who have failed treatment, especially those who have failed a standardized re-treatment regimen, and chronic cases are the highest priority.102 Patients who develop TB and are known to have been in close contact with persons known to have MDR-TB should also have DST performed on an initial isolate. Although HIV infection has not been conclusively shown to be an independent risk factor for drug resistance, MDR-TB outbreaks in HIV settings and high mortality rates in persons with MDR-TB and HIV infection justify routine DST in all HIV-infected TB patients, resources permitting.102
Standard 15: Patients with TB caused by drug-resistant (especially MDR) organisms should be treated with specialized regimens containing second-line anti-TB drugs. At least four drugs to which the organisms are known or presumed to be susceptible should be used and treatment should be given for at least 18 months. Patient-centred measures are required to ensure adherence. Consultation with a provider experienced in treatment of patients with MDR-TB should be obtained Current recommendations for treatment of MDR-TB are based on observational studies, general microbiological and therapeutic principles, extrapolation from available evidence from pilot MDR-TB treatment projects and expert opinion.102,108,109 Three strategic options for treatment of MDR-TB are currently recommended by the WHO: standardized, empiric and individualized treatment regimens.102 The choice among these should be based on availability of second-line drugs and DST for first- and second-line drugs, local drug resistance patterns and the history of use of second-line drugs. Basic principles involved in the design of any regimen include the use of at least four drugs with either certain or highly likely effectiveness, drug administration at least 6 days a week, drug dosage determined by patient’s weight, the use of an injectable agent (an aminoglycoside or capreomycin) for at least 6 months, treatment duration of 18–24 months and DOT throughout the treatment course. Standardized treatment regimens are based on representative drug-resistance surveillance data or on the history of drug usage in the country. Based on these assessments regimens that will have a high likelihood of success can be designed. Advantages include less dependency on highly technical laboratories, less reliance on highly specialized clinical expertise required to interpret DST results, simplified drug ordering and easier operational implementation. A standardized approach is useful in settings where secondline drugs have not been used extensively and where resistance levels to these drugs are consequently low or absent. Empiric treatment regimens are commonly used in specific groups of patients while the DST results are pending. Unfortunately, most of the available DST methods have a turnaround time of several months. Empiric regimens are strongly recommended to avoid clinical deterioration and to prevent transmission of MDR strains of M. tuberculosis to contacts while awaiting the DST results.102 Once the results of DST are known, an empiric regimen may be changed to an individualized regimen. Ongoing global efforts to address the problem of MDR-TB will probably result in broader access to laboratories performing DST and a faster return of results.
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Individualized treatment regimens (based on DST profiles and previous drug history of individual patients, or on local patterns of drug utilization) have the advantage of avoiding toxic and expensive drugs to which the MDR strain is resistant. However, an individualized approach requires access to substantial human, financial and technical capacity. DST for second-line drugs is notoriously difficult to perform.110 Also, laboratory proficiency testing results are not yet available for second-line drugs; as a result little can be said about the reliability of DST for these drugs.103,110 Clinicians treating MDR-TB patients must be aware of these limitations and interpret DST results with this in mind. MDR-TB treatment is a complex health intervention and medical practitioners are strongly advised to consult colleagues experienced in the management of these patients.
STANDARDS FOR PUBLIC HEALTH RESPONSIBILITIES Standard 16: All providers of care for patients with TB should ensure that persons (especially children under 5 years of age and persons with HIV infection) in close contact with patients who have infectious TB are evaluated and managed in line with international recommendations. Children under 5 years of age and persons with HIV infection who have been in contact with an infectious case should be evaluated for both latent infection with M. tuberculosis and active TB Close contacts of patients with TB are at high risk of acquiring the infection; thus, contact investigation is an important activity, to find both persons with previously undetected TB and persons who are candidates for treatment of latent TB infection.111,112 The potential yield of contact investigation in high- and lowincidence settings has been reviewed previously.111,112 In lowincidence settings (e.g. USA), it has been found that, on average, 5–10 contacts are identified for each incident TB case. Of these, about 30% are found to have latent TB infection, and another 1–4% have active TB.111,113,114 Much higher rates of both latent infection and active disease have been reported in high-prevalence countries, where about 50% of household contacts have latent infection, and about 10–20% have active TB at the time of initial investigation.112 A recent systematic review of more than 50 studies on household contact investigations in high-incidence settings showed that, on average, about 6% (range 0.5–29%; n ¼ 40 studies) of the contacts were found to have active TB.115 The median number of household contacts evaluated to find one case of active TB was 19 (range 14–300).115 The median proportion of contacts found to have latent infection was 49% (range 7–90%; n ¼ 34 studies).115 The median number of contacts evaluated to find one person with latent TB infection was two (range 1–14).115 Evidence from this review suggests that contact investigation in high-incidence settings is a high-yield strategy for case finding. Among close contacts, there are certain subgroups particularly at high risk for acquiring the infection with M. tuberculosis and progressing rapidly to active disease – children and persons with HIV infection. Children (particularly those under the age of 5 years) are a vulnerable group because of the high likelihood of progressing from latent infection to active disease. Children are also more likely to develop disseminated and serious forms of TB.
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Standard 17: All providers must report both new and re-treatment TB cases and their treatment outcomes to local public health authorities, in conformance with applicable legal requirements and policies Reporting TB cases to the local TB control programme is an essential public health function, and in many countries is legally mandated. An effective reporting system enables a determination of the overall effectiveness of TB control programmes, of resource needs and of the true distribution and dynamics of the disease within the population as a whole, not just the population served by the government TB control programme. A system of recording and reporting information on TB cases and their treatment outcomes is one of the key elements of the DOTS strategy.89 The recording and reporting system allows for targeted, individualized follow-up to help patients not making adequate progress (i.e. failing therapy).89 The system also allows for evaluation of the performance of the practitioner, the hospital or institution, local health system and the country as a whole. Although reporting to public health authorities is essential, it is also essential that patient confidentiality be maintained. Thus, reporting must follow predefined channels using standard procedures that guarantee that only authorized persons see the information.
POTENTIAL USES OF THE ISTC Supported by a broad international consensus and based on rigorous systematic review of the existing evidence, the ISTC can be used in many ways to facilitate and unite public and private sectors to provide a uniformly accepted level of care for patients with or suspected of having TB. Generally, the ISTC can be used as a focus for a global campaign to improve TB care and as a powerful advocacy tool to ensure that essential elements of TB care (diagnosis, treatment and public health) are available. After its publication in 2006, many countries adopted and endorsed the ISTC and have used the ISTC to assess their programmes, to mobilize their private and professional societies and to educate their pre-service and in-service healthcare providers.
REFERENCES 1. Hopewell PC, Migliori GB, Raviglione MC. Tuberculosis care and control. Bull World Health Organ 2006;84(6):428. 2. Tuberculosis Coalition for Technical Assistance (TBTCA). International Standards for Tuberculosis Care. The Hague: Tuberculosis Coalition for Technical Assistance, 2006. 3. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367(9514):952–955. 4. Fair E, Hopewell PC, Pai M. International Standards for Tuberculosis Care: revisiting the cornerstones of tuberculosis care and control. Expert Rev Anti Infect Ther 2007;5(1):61–65. 5. Hopewell PC, Pai M. Tuberculosis, vulnerability, and access to quality care. JAMA 2005;293(22): 2790–2793. 6. Lonnroth K, Thuong LM, Linh PD, et al. Delay and discontinuity--a survey of TB patients’ search of a diagnosis in a diversified health care system. Int J Tuberc Lung Dis 1999;3(11):992–1000. 7. Olle-Goig JE, Cullity JE, Vargas R. A survey of prescribing patterns for tuberculosis treatment amongst doctors in a Bolivian city. Int J Tuberc Lung Dis 1999;3(1):74–78.
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THE ISTC AS A SITUATIONAL ASSESSMENT TOOL A partner document to the ISTC is an ‘Implementation Guide’ that describes ways countries can use the ISTC. The Implementation Guide includes a situation analysis tool based on the ISTC. The tool provides a framework for healthcare providers and policy makers to review each of the 17 standards and to assess which standards are being met and which are not being met and why. This exercise allows providers from all sectors to take stock of their current situation and decide how to best approach strengthening their gaps in TB care. A situation analysis based on the ISTC allows programme managers to advocate for additional resources, such as increased laboratory capacity or more field staff, targeted at addressing the gaps.
THE ISTC FOR MOBILIZATION A second potential use of the ISTC is to facilitate mobilization of the private sector and professional societies involved in TB. Many professional societies have endorsed the ISTC and used the materials and evidence as a focal point for further training and as a vehicle for applying peer pressure to raise awareness about and to improve TB care.
THE ISTC AS A FOCAL POINT FOR TRAINING AND EDUCATIONAL ACTIVITIES Finally, the ISTC can be used for training and educational purposes. A set of basic training materials based on the ISTC and easily adaptable to different country contexts was developed. The ISTC can be used as a core for medical and nursing school criteria and curricula, and as a focus of continuing medical education programmes. A brief version of ISTC was published in Lancet Infectious Diseases (Hopewell PC, Pai M, Maher D, et al. International standards for tuberculosis care. Lancet Infect Dis 2006;6(11):710–725.) The ISTC are available in multiple languages. For further information please refer to http://www.nationaltbcenter.edu/international/.
8. Prasad R, Nautiyal RG, Mukherji PK, et al. Diagnostic evaluation of pulmonary tuberculosis: what do doctors of modern medicine do in India? Int J Tuberc Lung Dis 2003;7(1):52–57. 9. Shah SK, Sadiq H, Khalil M, et al. Do private doctors follow national guidelines for managing pulmonary tuberculosis in Pakistan? East Mediterr Health J 2003; 9(4):776–88. 10. Singla N, Sharma PP, Singla R, et al. Survey of knowledge, attitudes and practices for tuberculosis among general practitioners in Delhi, India. Int J Tuberc Lung Dis 1998;2(5): 384–389. 11. Suleiman BA, Houssein AI, Mehta F, et al. Do doctors in north-western Somalia follow the national guidelines for tuberculosis management? East Mediterr Health J 2003;9(4):789–795. 12. World Health Organization. Geneva: Involving Private Practitioners in Tuberculosis Control: Issues, Interventions, and Emerging Policy Framework. Geneva: World Health Organization, 2001: 1–81. 13. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368(9547): 1575–1580. 14. The tuberculosis X factor. Lancet Infect Dis 2006; 6(11):679.
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22. Rieder HL, Chiang CY, Rusen ID. A method to determine the utility of the third diagnostic and the second follow-up sputum smear examinations to diagnose tuberculosis cases and failures. Int J Tuberc Lung Dis 2005;9(4):384–391. 23. Gopi PG, Subramani R, Selvakumar N, et al. Smear examination of two specimens for diagnosis of pulmonary tuberculosis in Tiruvallur District, south India. Int J Tuberc Lung Dis 2004;8(7):824–828. 24. Van Deun A, Salim AH, Cooreman E, et al. Optimal tuberculosis case detection by direct sputum smear microscopy: how much better is more? Int J Tuberc Lung Dis 2002;6(3):222–230. 25. Sarin R, Mukerjee S, Singla N, et al. Diagnosis of tuberculosis under RNTCP: examination of two or three sputum specimens. Indian J Tuberc 2001; 48:13–16. 26. Steingart KR, Ng N, Henry M, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006;7:664–674. 27. Steingart KR, Henry M, Ng N, et al. Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006;6:568–579. 28. Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among HIVinfected ambulatory subjects in Tanzania. Clin Infect Dis 2005;40(10):1500–1507. 29. Koppaka R, Bock N. How reliable is chest radiography? In: Frieden TR (ed.). Toman’s Tuberculosis. Case Detection, Treatment and Monitoring, 2nd edn. Geneva: World Health Organization, 2004: 51–60. 30. Harries A. What are the relative merits of chest radiography and sputum examination (smear microscopy and culture) in case detection among new outpatients with prolonged chest symptoms? In: Frieden TR (ed.). Toman’s Tuberculosis. Case Detection, Treatment and Monitoring, 2nd edn. Geneva: World Health Organization, 2004: 61–65. 31. Nagpaul DR, Naganathan N, Prakash M. Diagnostic photofluorography and sputum microscopy in tuberculosis case findings. Proceedings of the 9th Eastern Region Tuberculosis Conference and 29th National Conference on Tuberculosis and Chest Diseases, 1974, Delhi. 32. Colebunders R, Bastian I. A review of the diagnosis and treatment of smear-negative pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4(2):97–107. 33. Siddiqi K, Lambert ML, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in lowincome countries: the current evidence. Lancet Infect Dis 2003;3(5):288–296. 34. Bah B, Massari V, Sow O, et al. Useful clues to the presence of smear-negative pulmonary tuberculosis in a West African city. Int J Tuberc Lung Dis 2002; 6(7):592–598. 35. Oyewo TA, Talbot EA, Moeti TL. Non-response to antibiotics predicts tuberculosis in AFB-smearnegative TB suspects, Botswana, 1997–1999 (abstract). Int J Tuberc Lung Dis 2001;5(Suppl 1):S126. 36. Somi GR, O’Brien RJ, Mfinanga GS, et al. Evaluation of the MycoDot test in patients with suspected tuberculosis in a field setting in Tanzania. Int J Tuberc Lung Dis 1999;3(3):231–238. 37. Wilkinson D, De Cock KM, Sturm AW. Diagnosing tuberculosis in a resource-poor setting: the value of a trial of antibiotics. Trans R Soc Trop Med Hyg 1997; 91(4):422–424. 38. Sterling TR. The WHO/IUATLD diagnostic algorithm for tuberculosis and empiric fluoroquinolone use: potential pitfalls. Int J Tuberc Lung Dis 2004;8(12):1396–1400. 39. van Deun A. What is the role of mycobacterial culture in diagnosis and case finding? In: Frieden TR (ed.). Toman’s Tuberculosis. Case Detection, Treatment and Monitoring, 2nd edn. Geneva: World Health Organization, 2004: 35–43. 40. Kim TC, Blackman RS, Heatwole KM, et al. Acidfast bacilli in sputum smears of patients with pulmonary tuberculosis. Prevalence and significance of negative smears pretreatment and positive smears
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Role of communities in tuberculosis care and prevention Giuliano Gargioni
INTRODUCTION The involvement of people affected by TB and, in general, of communities and civil society organizations is one of the essential elements of the Stop TB Strategy launched by the World Health Organization (WHO) in 2006. Tuberculosis is often defined as a disease of poverty: poor living conditions and inadequate housing and hygiene may favour the transmission of the TB infection or its progression to active disease; furthermore, a poor socioeconomic status and limited access to both health services and correct information can make the establishment of effective TB control measures particularly problematic. The condition of illness experienced by TB patients is often made worse by social stigmatization, which leads to isolation by their family and community. The involvement of TB patients and communities in design, planning, implementation and evaluation of TB control initiatives is extremely important in order to remove prejudices and discriminations, improve access to health services, ensure adequate adherence to treatment and encourage early referral for screening of family members or neighbours with symptoms that may suggest an active disease. The collaboration with community members in a patient’s care places the whole human person with its complexity, and not just a disease, at the centre of health interventions. The participation of society in these interventions encourages people’s assumption of responsibility for their own health and fosters a partnership between the health services and the communities they serve.
PRIMARY HEALTH CARE, THE INVOLVEMENT OF COMMUNITIES. . . The International Conference on Primary Health Care (PHC) held in Alma Ata (Kazakhstan, then Soviet Union) in 1978 made a decisive contribution in promoting a new approach to the organization of health services, centred on the involvement of the general population in activities of disease prevention and health promotion. In particular, health policy makers and planners from countries with poor health infrastructure and a very limited health budget realized that the mere construction of hospitals and rural health centres was not enough to enhance people’s access to medical care and to improve significantly the quality of life and the health status of the population. Only generalized public health interventions with active people’s participation promised to improve general hygiene and living conditions and to reduce morbidity and
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mortality related to the high burden of infectious diseases in children and in the adult population. In PHC interventions information and health education play a key role in increasing families’ and communities’ awareness of their health problems and in facilitating a discussion on how to put in place remedies that are effective and appropriate to the specific sociocultural context. Active involvement prompts communities to recognize that people are not just passive beneficiaries of services supplied by the government and that health is part of a common good that must be protected and towards which people need to direct their efforts. As a part of a post-Alma Ata PHC movement, a participatory process has promoted countless ‘community-based’ health programmes which over the years have made an important contribution to making essential health services more accessible to people who live in poor or remote areas. Following the 1978 Alma Ata Declaration, people’s participation and contribution to the health systems has been recognized as central to primary healthcare and accepted as an essential element of many public health interventions. The health reforms in the 1990s somehow gave less attention to community participation and social values, focusing more on technical, economic and management factors in health systems. However, initiatives taken by civil society to address the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic have been a remarkable exception to this situation. The challenges posed by major epidemics, such as HIV/AIDS, TB and malaria, and the role that civil society has played in helping individuals and families to cope with them, have certainly contributed to making people and policy makers more aware of some limitations of public and private health services, particularly in terms of inequalities in coverage and access for people with the lowest income or living in remote areas. The mere existence of services in a certain administrative area does not prove that they are used, and used correctly. In order to be used, services must be accessible. This implies the organized supply of care that is geographically, financially and culturally accessible. The literature provides abundant evidence about benefits and risks, for both the state and society, related to a greater involvement of communities and civil society organizations (CSOs) in various functions traditionally exercised by health systems.
. . .AND TUBERCULOSIS CONTROL PROGRAMMES The Stop TB Strategy launched in 2006 is the result of an evolutionary process (see Chapter 106) that had a fundamental milestone
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in the development, in the 1960s and 1970s, of a TB control model based on the sound epidemiological principles of case-finding among symptomatic patients and the application of chemotherapy and was delivered using the existing district-based general health services infrastructure. The TB control model, integrated into the PHC system, has provided a comprehensive organizational and managerial approach, combining the key elements of an effective public health response with those of good patient care. Starting from 1995, the WHO recommended the implementation of this model under the acronym of DOTS (directly observed treatment, short course) strategy. The formulation, implementation and rapid scale-up of the DOTS strategy built on the existence of functional PHC services and contributed to strengthening the efficiency and effectiveness of such services (Box 64.1). The development of the WHO Stop TB Strategy (see Chapter 106) has been based on the experience of health professionals, people affected by TB and their communities in addressing these challenges.
STOP TB STRATEGY AND COMMUNITY EMPOWERMENT The empowerment of people affected by TB and communities is an essential element of the WHO Stop TB Strategy which specifically focuses on the human and social dimension of the TB epidemic. Fostering community involvement and partnership from healthcare settings to households, TB patients can be supported and treated effectively, with dignity and respect, and people most directly affected by TB are involved in shaping the response to the pandemic. By being fully aware that TB is a serious transmissible but curable disease and that diagnostic and treatment services are freely available to all, the general population can effectively contribute by early referral to the health services of every person with respiratory symptoms and, thus, curb the disease transmission. Community involvement means sharing with communities responsibilities and functions that the community can exercise more effectively than the health services (e.g. personal home-based support to people directly affected by TB), while health staff can use their time, resources and facilities more efficiently for medical functions.
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The challenges posed by TB care and prevention highlight, once more, that medicine and public health cannot just take care of a disease, but need to consider holistically every person who, without question, faces, through illness, one of the most difficult events in personal life. Promoting people’s involvement and responsibility for their own health and giving consideration to the human and social environment in which a person lives is one key aspect of such a holistic approach.
COMMUNITY INVOLVEMENT IN HEALTHCARE: ESSENTIAL TERMINOLOGY A more active promotion of community involvement in various aspects of TB control programmes, recommended by the WHO Stop TB Strategy, poses huge opportunities for a synergistic effort with similar initiatives by other health programmes. Joint efforts require a shared, consistent, language and terminology: there is urgent need for greater clarity about terms and definitions used to describe the wide range of people’s contributions to the health system. For almost three decades ‘community-based healthcare programmes’ have used concepts and terminology drawn from the Primary Health Care and Health for All literature, from the Universal Declaration of Human Rights and from documents on social justice.1–5 From the mid-1980s, a similar terminology with sometimes different meanings has been used by civil society organizations that have played a most important role in supporting people living with HIV/AIDS and in advocating for their rights. A common understanding of terms and issues is essential to realize the richness of experience documented in ‘good practices’ described in the literature and to analyse their social relevance. It is, therefore, necessary to recall this terminology and the meaning of some expressions consistently used by the international health authorities.3–5 Health, defined by the WHO as a state of complete physical, mental and social well-being and not merely the absence of disease and infirmity, is a fundamental human right and a social goal, whose attainment requires a concerted action by the health sector with all other
Box 64.1 Challenges faced by integrated tuberculosis control and PHC services during the past three decades 1. In rural settings PHC services did not achieve the desired level of quality and access to the package of essential health services for all people, raising serious concerns about an equitable distribution of human and financial resources and the unmet health needs of entire populations. 2. Often as a consequence of underfunded and underperforming public healthcare, the private healthcare sector has flourished in many countries. Inadequate regulation has contributed to disintegrated healthcare delivery and to extremely weak quality control, leading to rampant misuse of medical technologies in general and irrational use of medicines, including anti-TB drugs, in particular. 3. PHC services had a particularly weak development in urban settings, where more public and private health facilities are available but health services are often not organized within a rational referral system which can effectively support and orient patients at their first contact with health services. This may prove problematic also for the follow-up of chronic conditions or for the adherence to prolonged treatments. 4. The urbanization process has worsened this problem, compounding it with a different and more difficult social context in which health
promotion is not supported by an often more conducive community environment. 5. The HIV/AIDS epidemic has had a devastating impact in many countries, especially in sub-Saharan Africa, reversing the gains in life expectancy of previous decades and affecting significantly also the health workforce. HIV has dramatically fuelled TB in populations with high HIV prevalence. The TB/HIV collaborative activities which address this challenge are, again, delivered through the PHC system and are often an important test of the system’s capability to deliver quality care. 6. Recognition of the extent of the global problem of drug-resistant TB led to the adaptation of the DOTS strategy as ‘DOTS-Plus’ to counter multidrugresistant (MDR) TB. The DOTS strategy is the starting point for managing drug-resistant TB, which also involves quality-assured drug-susceptibility testing and the use of second-line drugs in recommended treatment regimens. 7. Widespread poverty and insecurity continued to fuel the TB epidemic, through its links with malnutrition, poor housing and urban migration as well as through poor access to available services.
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sectors of the society. Health is also a social and relational phenomenon. Social goals, such as improved quality of life and better health status, are achieved through social means, including the acceptance of greater responsibility for health by communities and individual persons and their active participation in attaining them. At the core of the ‘right to health’ is the dignity of each and every person. The recognition of the dignity of every man and woman provides the most important reason for planning and implementing patient-centred services. Social services (of which health services are an important component) can contribute to safeguarding and promoting human dignity by addressing persistent situations of serious disparity and inequality. The commitment to provide universal access to essential healthcare is, therefore, not only central to the social and economic development of a community but also an important aspect of social justice; hence, the fundamental principles of social justice (see the section ‘Defining Core Elements of Community Involvement and of a Right-Based Approach’) should inform the way healthcare is planned and delivered. The first and fundamental community to which most persons naturally belong is the family. Family members, women in particular, are often the main providers of healthcare and have an important role in health promotion. The sphere of close friends and neighbours is also extremely important for every person’s daily life as it constitutes an immediate point of reference for mutual help and advice. A community consists of people living together in some form of social organization and cohesion. Though it may vary significantly in size and socioeconomic profile, its members usually share social, cultural and economic characteristics as well as common interests, including health. Therefore, health can also be defined as part of the common good (see ‘Defining Core Elements of Community Involvement’ below) and therefore all people have the right and responsibility to participate individually and as a community in activities aimed at the improvement and maintenance of their health. Further, the achievement of an improved health status is linked with and helps the promotion of development in general. The expression community involvement means obviously much more than simply responding to services planned and designed from the outside. The community should be an active part of the process from the very beginning: it can contribute to defining health problems and needs, to discussing available solutions and to being involved in planning, implementation and evaluation of health interventions. Building an operational partnership with the community with the goal of improving the health status of the population is a step beyond participation and involvement. The institution (the central or the local government), which has a mandate to provide services to address at least the essential health needs of the population, intervenes through its normative role and through professional expertise to support the community in its own endeavour to achieve a better health status. Essential to the creation of a formal or informal partnership is the commitment of each partner, with clear definition of roles and responsibilities, to contribute to this common goal with its professional or social specificity. The starting point of such initiatives is, often, the recognition that each partner alone may not be able to achieve the goal without the synergistic contribution of the other. The establishment of partnerships between an institution and the society requires that people be empowered to assume such responsibility.
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Community self-reliance and social awareness are among the key factors in human development. By being empowered through access to relevant information, literacy and adequate institutional arrangements, individuals, families, communities and CSOs can assume responsibility for their health and enhance their capacity and determination to address and possibly solve their own health problems. Communication and social mobilization play a decisive role in facilitating the empowerment of communities. One of the fundamental principles of PHC states that everyone in the community should be involved with and have access to PHC services. Having access denotes a potential to utilize a service, if required. The proof of access is use of service, not simply the presence of a facility, as potential access may not be realized.6 There may be personal, organizational and financial barriers to service utilization: such barriers reflect actual or perceived obstacles to access. Society is made up of families and communities. Provided with knowledge about health and interacting with the health services, families usually act in their best interest. Society, as a broad term, should be distinguished from civil society, which is usually defined as the social environment that exists between the state and the individual person or family. Civil society does not have the coercive and regulatory power of the state, but provides the social power or influence of ordinary people. All institutions and organizations outside of government can be defined as part of civil society which therefore includes, for example, non-governmental organizations (NGOs), community-based organizations (CBOs), faith-based organizations (FBOs) and private practitioners. Individuals and communities may organize themselves to pursue their collective interest and engage in activities of public utility. Civil society organizations draw from the community, neighbourhood, working environment or any other social context beyond the immediate family, in order to collectively relate to the state, or to another lower institution. The role of CSOs is increasingly becoming more prominent thanks to a renewed public awareness and concern over the right to participate in policies and processes that affect people’s lives. The organization of national and global networks is providing a valuable support to local CSOs which, however, remain the most important collaborators and counterparts of political leaders and administrators in as much as they are rooted in and responsive to the local population they serve, rather than to the agencies that may fund them. A health system consists of all organizations, people and actions whose primary intent is to promote, restore or maintain health. This includes efforts to influence determinants of health as well as more direct health-improving activities. A health system is therefore more than the pyramid of publicly owned facilities that deliver personal health services. It includes, for example, parents caring for a sick child at home, private providers, behaviour change programmes, public health campaigns and health insurance organizations. It also includes actions by other sectors – for example, work place safety legislation. The health system is responsible for ensuring access to quality health services, for providing clear information and advice on the benefits of health measures/interventions proposed to the community and for facilitating its early involvement in assessing the situation, defining the problem, planning and managing the action. A partnership for health between the government, or an institution, and the community is based on the commitment of both actors to actively collaborate in order, for example, to support the quality of health services or to make public health programmes
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more effective. This collaboration can be established only if political leaders and administrators take on a specific commitment to social development and if the society, adequately empowered, is ready to assume its part of responsibility. The seriousness of political commitment is confirmed by the decision to avail human and financial resources and by the determination to start a dialogue with the society at the level where problems occur, so that communities can contribute to shape the response to their practical problems and needs. When a partnership is successful the health services maintain all their technical and professional responsibilities, but they also effectively support what the community, which is directly affected by a health problem, can do by its own endeavour. Health personnel are people who have undergone a formal medical or public health training; they are part of the community and should maintain active contact with it. When health staff are involved in community activities their training should be complemented by education in essential communication and social mobilization skills. The private health sector plays an important role through the services of private practitioners, pharmacists and traditional healers. Public–private partnerships constitute an opportunity to establish and recognize the collaboration of the private health sector with services of public utility. Community health workers are generally people with a basic education who are given elementary training to contribute to some specific health activities. Their profile, role and responsibilities vary greatly from one country, or one community, to the other. Their activity, which may take several of their working hours every day, is often supported through incentives in kind or in cash provided either by the community they serve or by the health services. Community volunteers are community members who, having been sensitized about a specific and often time-bound service necessary to benefit their family or wider community, volunteer their time and energies to render such service without any monetary compensation. Voluntary work, rather than being a matter of personal generosity, should be based on a clear understanding of the benefits that come to one’s family or community. The service rendered by community health workers and community volunteers unfolds its full potential in the presence of adequate support from the health system and if an effective two-way communication is in place between health facilities, public health services and the community. Regular contacts between public health workers and community leaders often constitutes an efficient interface between the health services and the community.
COMMUNITY INVOLVEMENT IN TUBERCULOSIS CONTROL: A REVIEW OF EXPERIENCES AT COUNTRY LEVEL A review conducted in 1995 by the WHO in several sub-Saharan African countries highlighted the possibility of a greater involvement of communities and CSOs in TB control programmes.7 Notwithstanding the integration of TB control within general PHC services available in rural health facilities, case detection and treatment success were alarmingly low as a result of several constraints: inadequate geographical access to services, costs incurred by patients to travel to the health centres for regular follow-up, consequences on the family’s daily subsistence economy of prolonged or recurrent absence and costs to the health services for
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the initial several weeks’ hospitalization. Further, the high HIV prevalence in many countries stretched the capacity of health services, multiplying the TB caseload and threatening the performance of national TB programmes. On the other hand, the impressive experience of communities and CSOs supporting people living with HIV/AIDS (PLWHA) set a paradigm that could be applied also to TB care. The potential for community contribution to TB control programmes ranges from support and motivation of patients in treatment adherence, to earlier referral to health facilities of people with respiratory symptoms, to improved access to anti-TB drugs after diagnosis and during the treatment follow-up. In 2000 the WHO commissioned a review of community contribution to TB care in Asia, comprising a literature search and visits to selected community TB care projects in Bangladesh and India.8 Historically, TB control efforts in much of Asia were centred on curative services delivered through specialized institutions in urban centres. This approach was associated with limited success and this gradually led to the integration of TB control activities with general health services. The potential for community contribution to TB care in Asia is high because of the long history of community involvement in primary healthcare. Areas of interest investigated during this review included type and extent of community involvement, components of care provided in various programmes by the community, process of selection of community health workers, their training and supervision and, finally, the issue of different motivation and incentives across different programmes. The WHO report published in 2002 described a high level of community involvement in TB care in India and Bangladesh. This seemed to be built upon the high level of direct community involvement in community development initiatives and primary healthcare services. The extension of this activity into TB control looked a logical development. A similar review was conducted by the WHO in Latin America in 2001 and comprised a literature search and visits to selected community TB care projects in Bolivia and Colombia.9 Methods used to collect data in the sites visited included observation, interviews with key informants (community project leaders and health officers in charge of TB programmes) using a semi-structured interview guide and review of National TB Control Programme (NTP) records. The report published in 2002 illustrated the substantial variations of the healthcare system infrastructure across Latin American countries. Many countries have relatively good public healthcare infrastructure and modern healthcare technology, at least in major towns and cities, while others have a relatively poorly developed system. HIV prevalence, compared with that in Africa, was low and had not led to a significant increase in TB caseload. Substantial evidence of effective community participation in healthcare was reported in general, and in particular in some disease control programmes based on vector control at community level. Community involvement was driven both by the need to supplement relatively weak governmental responses to diseases and by the promotion of community participation within health projects supported by foreign-supported NGOs. The main findings of the review confirmed that there was a strong foundation of community involvement in primary healthcare, often through NGOs. Community participation in TB programmes included referral of symptomatic people, community-based support to treatment adherence, contact tracing, social support and advocating TB control with local governments.
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Box 64.2 Conclusions and policy recommendations drawn from the findings of the WHO’s multinational project to evaluate community contribution to tuberculosis care in eight sites in six sub-Saharan African countries between 1997 and 2000 1. Community-based TB care is a feasible, acceptable, effective and costeffective way to deliver TB services. However, it must be implemented as an integral component of a NTP. 2. While community care is cheaper and more cost-effective than hospitalbased care, new resources are often required in its implementation. This is mainly for training of care providers, strengthening of health delivery systems such as laboratory, monitoring and evaluation services, and patient follow-up. 3. Successful community contribution to TB care requires close collaboration between the NTP and the community, in order to provide technical and other support to the community initiatives and ensure high-quality services. It should therefore only be pursued where essential elements of a national control programme are in place and decentralization of health facility provision of TB services has been maximized. 4. Managerial expertise is necessary to linking the TB programme, general health services and community care providers. Training of community
Given the limited published experience available in the late 1990s and the prospect for community contribution to TB control efforts highlighted by several reviews, between 1997 and 2000 the WHO coordinated a multinational project to evaluate community contributions to TB care in eight sites in six sub-Saharan African countries:10,11 Machakos in Kenya,12,13 Lilongwe in Malawi,14–16 Guguletu and Hlabisa in South Africa,17–19 Kiboga and Kawempe in Uganda,20,21 Francis-Town in Botswana,22 and Ndola in Zambia.23 The aim of the project was to evaluate the effect on NTP performance of community involvement in the provision of TB care beyond fixed health facilities. The most important outcomes of interest were effectiveness, acceptability, affordability and cost-effectiveness (Box 64.2). Over the past 5 years community involvement in TB and TB–HIV care has attracted ever-increasing interest in many countries. Experiences and lessons learned have been published for Ethiopia,24 Burkina Faso,25 Malawi,26 South Africa,27,28 Swaziland,29 Tanzania,30,31 Uganda,32 Bangladesh,33 India,34 Pakistan,35–37 Peru,38,39 and several other countries. The abundant information and documentation available in 2006 on this subject led to the inclusion of community involvement among the essential elements of the WHO Stop TB Strategy. However, published experience also points to the need for further operational research in at least two areas: 1. improved understanding of challenges posed by scaling-up community care to national level and managing it under routine (rather than ‘research’) conditions; and 2. better realization of effective approaches for maintaining community and volunteer care providers’ motivation over time.
DEFINING CORE ELEMENTS OF COMMUNITY INVOLVEMENT AND OF A RIGHT-BASED APPROACH The WHO and the Stop TB Partnership conducted between 2005 and 2006 specific reviews in seven countries in four WHO regions and engaged in wide consultations with NTPs, CSOs and community representatives in order to provide guidance for the policy formulation process at country level.40
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care providers is essential and should focus on a limited number of tasks. Supervision should be regular, frequent and supportive; and community TB care should be designed to complement and extend NTP capacity, not to replace it. 5. Sustainability of community involvement is very important and must be planned from the start. A good situation analysis is necessary to understand the social context and to identify appropriate community care providers. These are likely to be motivated individuals close to the patient or to belong to a well-established and experienced community group. It is crucial to identify the context-specific motivation of community care providers and ensure ongoing motivation to sustain their activities. 6. Effective community contribution to TB care requires strong referral, recording and reporting systems, easy access to laboratory services, and a secure drug supply. These should therefore be developed as part of general healthcare delivery system strengthening in order to ensure smooth delivery of services and efficient support for activities at all levels.
The main challenges that national programmes encounter in fostering the involvement of communities in TB care and prevention are often related to the adaptation of published experience to their local context and to the identification of the core elements that, across different contexts, have emerged as essential for the promotion of such involvement. Steps to be taken in planning and implementation become clearer once these elements are defined. In addition, the opportunity of establishing a partnership with communities and CSOs, based on a human rights approach to the global epidemics of TB and HIV/AIDS, demands a serious commitment to the principles of social justice. These principles also enlighten some of the most important factors sustaining people’s motivation in the collaboration with health services, as observed in all country reviews. The objective of this appraisal was to study different aspects of community involvement in TB control activities, utilizing a combined qualitative and quantitative research method, in order to: 1. define what is meant across different contexts by ‘communitybased initiative’ and encourage the use of a consistent terminology (see the section ‘Community Involvement in Healthcare: Essential Terminology’ above); 2. explore motivational aspects of community/civil society involvement in different settings and relate them to broader principles of social justice that should shape how social services are delivered; and 3. learn lessons on good practices in order to better define key elements and methods for implementation. Hence, the selection of countries was based not only on different geographical contexts (Uganda, Kenya and Malawi in Africa; Bangladesh, Indonesia and The Philippines in Asia; Mexico in Latin America), but also on each country’s several-year experience in implementation and scale-up of community initiatives at national level. The following paragraphs summarize the overarching principles of social justice at stake in planning and implementation of community healthcare, and key to sustaining people’s motivation, and identify constitutive elements which successful experiences have in common, notwithstanding very different contexts.
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COMMUNITY INVOLVEMENT AND SOCIAL JUSTICE Social justice and its principles should inform the way healthcare is designed, planned and delivered. The engagement of communities and civil society with healthcare providers is not the result of a mere organizational process and is not just the final step of decentralization of health services. Building this engagement as a partnership entails a vision of the relation between state (often embodied by the local government) and the society as well as of the relationships within society and communities.41–45 Giving due attention to the principles that should inform these relationships is a decision of an ethical and political nature which affects the very possibility of establishing such a partnership and its effectiveness and duration over time. The recognition of universal access to essential health services as a human rights is based on the acknowledgement of the absolute value and dignity of each individual person in determining political choices, resource allocation, design of health services and so on. The motivation to provide care most consistently reported by people committed to support TB patients is the value of the person they assist. The awareness that public and individual health are part of a common good demands that everyone take on his/her part of responsibility: rights and responsibilities are complementary to each other. The right to health is a consequence of the natural right to life and to its preservation. Health as a common good is a concrete good, for each person, which can be achieved only through the cooperative interaction of the many. If such good is preserved, for example by providing adequate support measures and medical care to prevent spreading of an infectious disease, all members of the society benefit from it. The increased awareness of this responsibility is a powerful factor of development of the society, as it counters both passive fatalism in facing problems and an excess of welfarism. Not all solutions come from a higher institutional authority: much can be done, often better done (e.g. family care and support), at the level where a problem occurs. Equity demands that all members of a community have an equal right and opportunity of access to healthcare, and all communities have equal rights to access to health information and resources. Solidarity is the moral responsibility to share the needs and problems of others and to recognize and defend the dignity of each individual. Furthermore, several people referred that fostering solidarity reduces stigma and discriminations. Finally, an important factor of successful initiatives is the recognition of the priority of families, groups and associations, local realities to which people spontaneously give life and which enable them to achieve an effective personal and social growth. This is known as the principle of subsidiarity; it is based on the natural order of the society and it requires that a higher institution or level of the society should support and promote what a lesser form of social organization can do. Medical functions such as diagnosis, prescription of treatment and follow-up are clearly part of the professional competence of health personnel; other functions, such as psycho-social support, are, in fact, better played by community or family members. There is not confusion but, rather, complementarity of roles.
CORE ELEMENTS OF COMMUNITY INVOLVEMENT IN TUBERCULOSIS CONTROL The WHO recommendations on community involvement identify eight specific areas that should be considered in order to promote
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the role of community in TB care and prevention and to contribute to fostering its empowerment in health interventions.40
Policy guidance Countries need to establish at national level a multisectoral core working group with the participation of community leaders and CSOs, whose work will help the national health authorities to revise the existing NTP policy and adapt it to the new Stop TB strategy. If a ‘partnership vision’ is supported and promoted, it should influence the way interventions are designed, implemented and evaluated: it is, therefore, necessary to agree on the fundamental principles of a right-based approach. Policy formulation requires designing a flexible framework for community involvement, which clarifies different stakeholders’ role in the context of the existing TB control services and is adaptable to various local contexts (urban vs rural areas, vulnerable groups, emergency situations). Based on an initial analysis of the situation of TB services and of the community, this model can be developed first in demonstration areas, further adapted to address pitfalls and then implemented at national level, ensuring enough in-field support for capacity building and community mobilization. Advocacy, communication and social mobilization (ACSM)46 Advocacy indicates activities designed to place TB control high on the political and development agenda, build and maintain political commitment, including commitment to mobilize resources, and obtain support at community level. Programme communication aims at informing and creating awareness about TB among the general public, specific communities or patients with TB, in an open and respectful way. It is essential for creating mutual respect and understanding. Dialogue will most often focus on simple messages about the disease, the available services, how people can take action, challenges, roles and responsibilities. Social mobilization is the process of bringing together all feasible and practical intersectoral allies to raise awareness of and demand for a particular intervention, to assist in the delivery of resources and services and to strengthen community participation. Dialogue and consensus, building on existing development and social initiatives, can engage in complementary efforts of local authorities, opinion leaders, NGOs and FBOs, and the private sector, and strengthen a bottom-up approach involving people with TB and communities. Capacity building Developing and implementing a training plan, which includes a clear analysis of all tasks and identification of resources, is key to enabling all partners involved to exercise effectively their functions. Training of health personnel should include ACSM skills. Capacity building activities are tailored on the framework for community involvement developed at national level. The preparation and adaptation of flowcharts with sequence of events and checklists of activities is an extremely helpful tool to understand the general model and individual roles. Conducting and following up training is often challenging in developing countries stricken by scarcity of human resources, but several governments are addressing this constraint by establishing agreements focused on partial devolution of responsibility for supervision, with NGOs already operating in hard-to-reach areas, urban settings or other specific situations, as deemed necessary.
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Monitoring and evaluation This element should be built in every strategic component not only to assess performance but also to identify new needs or take corrective actions. All relevant stakeholders need to be involved in identifying indicators to measure levels of representation and involvement of communities and people affected by TB. National recording and reporting systems may need revision to reflect new indicators. A new area that requires attention is the development of a community’s capacity to assess service delivery as well as its own contribution.
Specific challenges Fostering involvement also demands taking into account specific challenges (e.g. TB–HIV coinfection, multidrug resistant TB, access to indigenous populations, care of refugees, internally displaced people, prisoners). In many countries with high HIV prevalence, for example, these initiatives can build on the wellestablished experience of HIV/AIDS civil society initiatives and provide a strong basis for advocating for synergistic efforts and for improved TB–HIV services.
Budgeting and financing Budgeting for community involvement is based on a clear definition of all the activities required by the framework’s implementation and on the estimation of their related costs. The expenditures relevant to the involvement of different stakeholders (e.g. training, transportation, barriers for patients such as hunger) should be considered at both national and subnational levels. Securing funds for primary healthcare activities at community level to facilitate the work of public health staff and community health workers (CHWs) is sometimes problematic; the complex issues around adequate remuneration of health staff and enablers or incentives of CHWs, based on functions and time spent, needs to be carefully addressed. Costs specific to community involvement will usually include:
Operational research Additional operational research is highly needed to answer general or context-specific questions. Communities can contribute to suggest problematic areas for further investigation and should participate in planning, implementation and analysis of results. Operational research issues that require more attention include documentation of good practices and innovative schemes, particularly in integrating with other existing community initiatives, potential contribution of (ex-)patients, problematic access to services related to gender and identification of indicators for routine monitoring and evaluation of the community contribution to TB control, level of community involvement and, finally, quality of care as perceived by people who are directly affected by TB.
all up-front expenditures for situation analysis, ACSM activities, training and preparation of training tools, and regular visits to the communities involved in initial demonstration areas; and recurrent costs of support supervision at all levels, re-training or new training related to staff turnover and, depending on circumstances, the implementation of incentive schemes for CHWs.
Dialogue with all relevant stakeholders/partners on each one’s contribution towards community involvement is more effective if the issue is discussed as a general development opportunity and not an exclusive health initiative.
Ensuring quality Ensuring the quality, and therefore ongoing support, of the range of services provided at community level is essential for building trust and long-term commitment. Quality in community services implies not only adequate professional skills, but also that services are patient-oriented and tailored to local culture. An empowered community requires knowledge of the nature of TB as an infectious curable disease, of symptoms, of the availability of free treatment, etc. Lastly, a critical aspect of quality is maintaining adequate communication and linkage between all levels of health services and people (public health staff and local leaders) who most often represent the ‘interface’ between health services and community, ensuring enough resources to make this function effective.
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PARTNERSHIP FOR HEALTH: A WORK IN PROGRESS Promoting community involvement in TB care and prevention provides an opportunity for building an operational partnership with the community. The central or local government, which has the mandate to provide health and social services and address the essential health needs of the population, intervenes through its normative role and professional expertise to support the community in its own endeavour to achieve a better health status. Participation of individuals and communities, contributing to the life of the society to which they belong, is an essential condition for a subsidiary approach to the delivery of services. Involvement in activities that contribute to the common good is a right and a responsibility for everyone. A partnership approach, even in its less structured forms, is an opportunity for contributing to public ethics based on solidarity and cooperation. Partnership between health services, civil society and communities is based on a paradigm of mutual support and collaboration, open also to the constructive critical function of all partners involved. Such a partnership is a benefit per se: there is a value in strengthening both partners and building a social capital that goes beyond any immediate operational return. Giving due consideration to these principles is a decision of ethical and political nature, which affects the possibility of establishing a partnership for health, its effectiveness and its long-term sustainability.
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tuberculosis in Bangladesh. Health Policy Plan 2006;21:143–155. Singh AA, Parasher D, Shekhavat GS, et al. Effectiveness of urban community volunteers in directly observed treatment of tuberculosis patients: a field report from Haryana, North India. Int J Tuberc Lung Dis 2004;8:800–802. Khan MA, Walley JD, Witter SN, et al. Cost and cost-effectiveness of different DOT strategies for the treatment of tuberculosis in Pakistan. Health Policy Plan 2002;17:178–186. Mumtaz Z, Salway S, Waseem M, et al. Genderbased barriers to primary health care provision in Pakistan: the experience of female providers. Health Policy Plan 2003;18:261–269. Khan MA, Walley JD, Witter SN, et al. Tuberculosis patient adherence to direct observation: results of a social study in Pakistan. Health Policy Plan 2005;20:354–365. Bowyer T. Popular participation and the State: democratizing the health sector in rural Peru. Int J Health Plann Manage 2004;19:131–161. Shin S, Furin J, Bayona J, et al. Community-based treatment of multidrug-resistant tuberculosis in Lima, Peru: 7 years of experience. Soc Sci Med 2004;59: 1529–1539. World Health Organization. Community Involvement in Tuberculosis Care and Prevention—Towards Partnerships for Health. Geneva: World Health Organization, 2008. The Patients’ Charter for Tuberculosis Care. World Care Council, 2006. Gonsalves MA. Fagothey’s Right and Reason: Ethics in Theory and Practice, 9th edn. Englewood Cliffs, NJ: Prentice Hall, 1990. McCoy D, Sanders D, Baum F, et al. Pushing the international health research agenda towards equity and effectiveness. Lancet 2004;364:1630–1631. Calman KC. Equity, poverty and health for all. BMJ 1997;314:1187. Verma G, Upshur RE, Rea E, et al. Critical reflections on evidence, ethics and effectiveness in the management of tuberculosis: public health and global perspectives. BMC Med Ethics 2004;5:E2. World Health Organization and Stop TB Partnership. Advocacy, Communication and Social Mobilization to Fight TB—A 10-Year Framework for Action. Geneva: World Health Organization, 2006.
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Operational issues, compliance, and DOTS programmes Surendra K Sharma and Lakhbir S Chauhan
INTRODUCTION Effective anti-TB drugs have been available for over 50 years, but, in Europe and the United States, mortality rates began to decrease decades before the introduction of antimycobacterial drugs due to improvement in socioeconomic conditions, thereby establishing the fact that TB and poverty are closely related. Factors associated with poverty such as malnutrition, overcrowding, and sanitation increase both the risk of infection and subsequent development of clinical disease. While in the past 45 years there has been a tremendous decrease in TB cases in the developed countries, the number increased in developing countries.1 This is due to the failure to cure a high proportion of sputum smear-positive cases, population growth, human immunodeficiency virus (HIV) epidemic, lack of health services-related infrastructure especially in sub-Saharan Africa, and several other factors including poverty, migration, etc.2 Different treatment regimens and combinations have been practised over the years across the globe. Successful demonstrations from India and elsewhere in the world have shown the effectiveness of domiciliary treatment for TB.3 The regimens used have also seen significant changes over the past five decades, starting with the conventional long-term chemotherapy to the short-course regimens, and from the daily to the intermittent regimens.4 Currently the internationally recommended directly observed treatment, short-course (DOTS) strategy has been recognized as the most cost-effective approach for TB control, for reducing disease burden, and for reducing the transmission of infection. At present, about 184 countries are implementing the DOTS programme and India’s DOTS programme is now second only to China’s in size globally.1 This chapter focuses on the broad challenges in the implementation of DOTS. Some of the important operational issues towards implementation of the new STOP TB Strategy will also be highlighted. It can be stated here that there is no single solution to the operational challenges, owing to the differences based on the existing health systems and infrastructure, human and financial resources available, and the sociocultural beliefs and practices of the community/population. For the purpose of simplicity, the organization of the chapter will follow the broad components of the Stop TB Strategy.
DOTS SERVICES To deliver effective DOTS services in any region of the world, a functional public health system is essential. In countries with a
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sizeable private sector and other healthcare providers, collaboration between public and private sector, popularly known as the public– private mix (PPM), is desirable to improve reach and access to TB care for all patients. Besides the above two initiatives, working towards building community awareness and seeking its participation are important to ensure that all TB patients in the community seek early treatment and adhere to that treatment. As a result chances of being cured are improved, defaults and failures are reduced, and the emergence of drug resistance is prevented; ultimately the stigma due to the disease, as has been observed in several communities and countries, is reduced. Tuberculosis control activities are primarily a programmatic and managerial challenge, and more than a technical challenge; and the key managerial challenge is to ensure highly dedicated and motivated staff, as TB work is extensively human resource intensive. Key areas requiring human resource inputs include ensuring quality-assured laboratory services with trained laboratory technicians for diagnosis; trained medical manpower for treatment categorization; trained, accessible, acceptable, and accountable directly observed treatment (DOT) providers for treatment under direct observation; trained supervisory staff at various levels to ensure systematic monitoring and accountability; manpower for effective health management information systems; and personnel for effective drugs and logistics management for ensuring uninterrupted supply of anti-TB drugs.
FUNCTIONAL PUBLIC HEALTH SYSTEM: ENSURING LONG-TERM SUSTAINABLE POLITICAL, ADMINISTRATIVE, AND FINANCIAL COMMITMENT The International Union against Tuberculosis and Lung Diseases (IUALTD) during the 1980s provided the rational basis to promote the concept of short-course, standardized therapy under direct observation delivered through the general health services. The World Health Organization (WHO) began to promote this strategy in 1991 and, subsequent to the declaration of TB as a global emergency in 1993, the WHO developed a framework for effective TB control that clearly described the main components of the DOTS strategy.5,6 The primary component of the DOTS strategy was to ensure continued political and administrative commitment for TB control. Successful advocacy at all levels has led to recognizing TB as a major health problem, and to increased funding and availability of resources for its control.7,8 However, it must be re-emphasized
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that this arrangement in several countries is fragile and running the risk of burnout, bearing in mind that TB control is a long drawnout battle that will continue for the next two to three decades until it ceases to be a major public health problem. Although the battle has just begun, several development and funding partners and governments have already begun asking questions about how long does this support need to continue. Despite these efforts, especially in the underdeveloped and developing world where TB is a major problem compounded with the emerging threat of HIV on TB epidemiology, the public health infrastructure is weak and variable across regions. Poor infrastructure and understaffed facilities make access to TB care limited, especially for the marginalized and hard-to-reach areas. The third Stop TB Strategy component calls for strengthening health systems as a means towards achieving TB control.9 This in turn means allocation of more resources and will continue to be a major determinant in the global fight against TB. What gets supervised gets done. The priority given by political and administrative heads translates into action. Successful advocacy for prioritizing TB, which is a chronic and insidious disease with relatively low case fatality rates, is not easy, especially in settings of noticeable morbidity and mortality and socioeconomic impact from acute communicable diseases such as the HIV/ acquired immunodeficiency syndrome (AIDS) epidemic, avian influenza, dengue, and malaria make that continue to gain immediate public, media, and political attention. Ever-pressing problems of reproductive and child health in populous and resource-limited countries like India make it even more difficult to keep TB a priority agenda item amongst policy makers.
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Cough for 3 weeks or more
3 sputum smears
3 negatives
2 or 3 positives
Antibiotics course (1014 days
Cough persists Repeat 3 sputum examinations
1 positive Chest radiograph
Suggestive of TB
Sputum smear-positive TB (anti-TB treatment)
Negative for TB
Negative for TB
Non-TB
Negative
2 or 3 positives
Chest radiograph
Sputum positive TB (anti-TB treatment)
Suggestive of TB
Sputum smear-negative TB (anti-TB treatment)
Fig. 65.1 Algorithm for diagnosis of pulmonary TB case.
CASE DETECTION THROUGH QUALITYASSURED SPUTUM MICROSCOPY Despite several dramatic years of scientific and technological development, sputum microscopy for acid-fast bacilli remains the most cost-effective and primary tool for diagnosis of TB (Fig. 65.1). Its low sensitivity and limited role in smear negative and paucibacillary extrapulmonary TB are well known. Although some countries have adopted mycobacterial culture as an additional tool for diagnosis, the challenge of establishing decentralized quality-assured laboratories is difficult. The primary issues of concern for an operational laboratory network for quality-assured sputum microscopy include the following: 1. Accessible laboratory services to ensure TB suspects need not travel greater distances, and to maintain quality at the laboratory through an adequate load: it has been noted that examination of fewer than five slides per day or more than 20–25 slides can affect quality. Based on the estimated case load, the Revised National Tuberculosis Control Programme (India) (RNTCP) has established a network of one microscopy centre for every 100,000 population, which has, however, been further decentralized to one for every 50,000 in hilly, tribal, desert, and hard-to-reach areas. The operational challenge of balancing accessibility with quality is a critical event in the DOTS strategy.10 2. The establishment of sputum collection centres: the challenges in running such facilities, especially in rural/tribal and hard-to-reach areas, include method of collection and transport;11 periodicity of transport; finding personnel willing to transport sputa (stigma);
issues related to biomedical waste-handling practices; and universal precautions and effect on the sensitivity of the test results. 3. Defining whether a TB suspect is one with a cough for 2 weeks or 3 weeks: several studies have debated the utility of either method, in relation to early diagnosis and increased load on the laboratories.12 4. Two versus three sputum sample examinations: the WHO advocates examination of three sputum samples popularly noted as spot– morning–spot samples, over 2 consecutive days. The debate revolves around patient compliance and costs (direct and indirect) towards examining three samples, against losing sensitivity by doing only two samples.13 5. Establishing a quality assurance protocol in resource-poor countries: the RNTCP has provided additional contractual staff to supervise laboratory quality in the field, who in turn participate in the quality assurance protocol, which involves internal quality control, external quality assessment, and quality improvement strategies. However, training of staff, sustaining supportive supervision, and ensuring quality control over an ongoing activity without failing under routine is challenging.14 6. In countries with multiple healthcare providers, the additional challenge of initial defaulters: ‘initial defaulters’ are defined as a diagnosed sputum smear-positive patient who has been recorded in the RNTCP laboratory register with at least two positive smear results, but who has not been placed on either a DOTS treatment regimen or a non-DOTS (non-rifampicin containing) regimen, and has not been ‘referred for treatment’ at a DOTS centre outside the district. In India this averages 6–7% of the nearly 0.8 million sputum-positive cases diagnosed per year. The frequent reasons are lack of awareness about the disease and lack of
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Table 65.1 Comparison of doses and formulations for adult and paediatric patients treated under RNTCP Drugs
Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin
Adult dosage Dose (three times a week)
Number of pills a in PWB blisters
600 mg 450 mgb 1500 mg 1200 mg 0.75 gc
2 1 2 2
( ( ( (
300 mg) 450 mg) 750 mg) 600 mg)
Paediatric dosage (mg/kg)
10–15 10 30–35 30 15
Dosage in mg for weight bands in kg 6–10 kg (Box A)
11–17 kg (Box B)
18–25 kg (Box A + Box B)
26–30 kg (Box B + Box B)
1 (75 mg) 1 (75 mg) 1 (250 mg) 1 (200 mg) —
1 ( 150 mg) 1 ( 150 mg) 1 ( 500 mg) 1 ( 400 mg) —
2 (75 + 150 mg) 2 (75 + 150 mg) 2 (250 + 500 mg) 2 (200 + 400 mg) —
2 ( 2 ( 2 ( 2 ( —
150 mg) 150 mg) 500 mg) 400 mg)
PWB, patient-wise box; RNTCP, Revised National TB Control Programme of India. In category I and II blister strips. b Patients who weigh 60 kg or more receive additional rifampicin 150 mg. c Patients who are more than 50 years old receive streptomycin 500 mg. Patients who weigh less than 30 kg receive drugs as per body weight. a
availability of treatment services; loss to follow-up of collecting results of sputum examination report (done over a 2-day period); inability or slackness of the system to trace patients and initiate treatment due to wrong or incomplete addresses being recorded in the laboratory register; the patient seeking treatment from other care providers; and equally important patients residing in other TB units (administrative set-up for TB control).15,16 7. The initiation of a referral-for-treatment mechanism, wherein patients residing in other TB units/districts/states are referred back to their TB units for registration and treatment. The mechanism operates by sending out referral-for-treatment forms in multiple copies: one through the patient, one directly to the health facility, and one to the district programme manager. Despite best efforts, this mechanism has faced challenges due to poor feedback from the receiving unit, making it very difficult to estimate the actual rates.17
STANDARDIZED TREATMENT WITH SUPERVISION AND SUPPORT The WHO has categorized TB disease into three categories for treatment and the treatment regimens can be administered either daily or intermittently.18–20 There is definite evidence to prove the equal efficacy of either regimen. Some countries, including India, have adopted the intermittent regimen for operational reasons. Such policies are not uniformly accepted by the medical fraternity, and to advocate and convince all healthcare providers on the efficacy of intermittent regimens still remains an uphill task. DOT is one of the principal components of the strategy, and its provider must be accessible and acceptable to the patient and accountable to the system. To identify such providers and ensuring accountability has been a major challenge. The programmes have used a multitude of providers from the departments of health and nutrition along with those from non-governmental organizations (NGOs), as well as private practitioners and community volunteers. Community volunteers form a vital link between the patient and the system, and adequate incentives must be built in to make it attractive to providers.21–24 Based on the findings of published literature, the programmes have deliberately excluded family members from supervising DOT.25 Nearly 6% of the new patients registered annually in India are children aged 0–14 years.26 It is an accepted fact that liquid formulations for paediatric anti-TB dosages have problems related to adequate and correct dosing, bioavailability, and logistics problems.
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With the introduction of paediatric patient-wise drug boxes in India (Table 65.1), access to quality-assured drugs would be ensured and it may also improve registration of paediatric TB cases under the programme. However, one area of concern is the larger number of tablets which need to be swallowed by the older children, and issues related to DOT. With paediatric patient-wise boxes being made available, there is a need to study the barriers to providing DOT in very young children. The challenges of using fixed-dose combinations (FDCs) to simplify drug dosages, i.e. the number of pills to be consumed, have been debated.4 The major debate revolves around ease of administration of FDCs against the higher costs and bioavailability of such preparations.
EFFICACY OF TREATMENT REGIMENS IN DIFFERENT FORMS OF EXTRAPULMONARY TUBERCULOSIS The DOTS strategy has always placed due emphasis on the new smear-positive infectious cases. From an epidemiological point of view it is very pertinent. But this has led to a belief that DOTS programmes only manage smear-positive TB cases, while in fact a considerable number of smear-negative and extrapulmonary TB cases are being diagnosed and initiated on treatment. Smear-negative pulmonary TB accounts for nearly 40–45% of all pulmonary TB cases being registered, and 15–17% of all TB cases registered under the programme are extrapulmonary TB. However, it is also known that the programmes do not monitor the patterns or trends of treatment outcomes of other forms of TB. The treatment of extrapulmonary TB differs from that of pulmonary TB in several ways. This is largely because of the difficulty of diagnosis, which often leads to empirical treatment without pathological or bacteriological confirmation. Extrapulmonary TB is usually paucibacillary and any treatment regimen effective for pulmonary TB is likely to be effective in the treatment of extrapulmonary TB as well. For the purpose of treatment, extrapulmonary TB can be classified into severe (meningeal, spinal, neuro, abdominal, bilateral pleural effusion, pericardial effusion, bone, and joint TB) and non-severe (other sites such as lymph node, skin, etc.) forms of disease. The difficulty of defining a clear-cut end point for assessing the efficacy of treatment of extrapulmonary TB has led to varying durations of treatment. There have been relatively few controlled clinical trials on the efficacy of intermittent therapy in extrapulmonary TB. Principles involved in diagnosis and management have evolved mainly from experience. However, studies
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conducted on extrapulmonary TB have clearly established the efficacy of short-course chemotherapy (SCC) (6–9 months) in both children and adults, with the overall favourable response varying from 87% to 99%. Intermittent regimens have also been shown to be as effective as daily regimens.27–29 The operational challenges faced by the programmes in diagnosis and treatment of extrapulmonary TB cases include the following: 1. Diagnosis of extrapulmonary forms of TB has been a challenge, especially for bone and spinal, intestinal, and genitourinary TB due to difficulty in obtaining a pathological specimen. Diagnostic facilities for extrapulmonary TB include fine needle aspiration cytology (FNAC) or biopsy or specialized radiological investigations such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), which are available at a few selected secondary and tertiary care centres. To overcome this deficit, the programme has developed algorithms for diagnosis of the common form of TB, lymph node TB, which accounts for nearly 50% of all extrapulmonary TB cases. Tuberculosis pleural effusion cases (20–25% of all extrapulmonary TB cases) are diagnosed by simple chest radiography. 2. It needs to be emphasized that extrapulmonary TB accounts for 10–15% of all TB cases and nearly 75% of these involve the lymph nodes and the pleura. The programme has developed an algorithm for the diagnosis of lymph node TB (Fig. 65.2). 3. There is a lack of consensus on the definite end point of treatment of extrapulmonary TB (usually clinical/radiological, which is likely to take much longer than a bacteriological cure) and the duration of treatment. This is especially significant in relation to bone and spinal, meningeal, and genitourinary TB. There is a definite need to generate evidence on the efficacy of 6–9 months of DOTS treatment in these forms of extrapulmonary TB.
Lymph node enlargement of >2 cm in one or more sites, with or without periadenitis, with or without evidence of TB elsewhere; or presence of an abcess with or without discharging sinus
Prescribe a course of antibiotics for 2 weeks
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4. Another misconception of general practitioners is about the use of steroids in different forms of extrapulmonary TB. The programmatic guidelines state the importance of steroids in some severe forms of extrapulmonary TB, namely pericardial and meningeal TB, but it is the final judgement of the treating physician to decide indication, duration, and dosages.
COMPLIANCE Failure to take medications in accordance with the prescription is universal and may pose a significant challenge during treatment that must be taken into consideration when attempting to treat patients or control disease in the community.30 Several studies have shown that one out of three patients will prematurely stop taking his medication. Numerous efforts to pinpoint predictors or characteristics that could distinguish adherent from non-adherent patients have been unsuccessful.30 Intensive educational efforts and even reliance on close family members to ensure the ingestion of medication have proved futile. It is known that treatment adherence declines with the duration of treatment. ‘Directly observed’ means that every dose is administered under direct observation of health personnel or a volunteer, and convenience to the patient is essential for success (Fig. 65.3). The main advantage of DOT is that treatment is carried out entirely under programme supervision with necessary support provided to the patient by the DOT provider for completing treatment. The probability of irregularity, as may occur with self-administered regimens, is decreased. Perhaps the most immediate consequence is the high cure rates associated with assured completion of treatment. Equally important is the negligible chance of developing drug resistance as direct observation eliminates the possibility of the drug treatment being discontinued. Moreover, because there is close and continuing contact between patient and healthcare worker, adverse effects and treatment complications can be quickly identified and addressed, especially during the critical phase of the treatment. It also reduces the time between treatment interruption and retrieval of the patient by the DOT provider. Confirmed adherence to treatment further reduces the spread of infection in the community and thereby the burden of the disease and development of new cases of TB. Multiple analyses have demonstrated that the
If lymph node enlargement persists, suspect TB lymphadenitis
Pus from discharging sinus/aspirate from lymph node using FNAC Smear examination for AFB (using pus/aspirate) by ZN method, Mantoux test for children <14 years
Diagnosis confirmed if the pus /aspirate from FNAC shows: ZN stain +ve for AFB, or granulomatous changes (where facilities available)
If FNAC results are inconclusive, excision biopsy is advisable for smear and histopathological examination
Start category III treatment
Fig. 65.2 Algorithm for the diagnosis of lymph node TB. AFB, acid–fast bacilli; FNAC, fine needle aspiration cytology; ZN, Ziehl–Neelsen.
Fig. 65.3 Directly observed treatment (DOT) – one of the essential components of the DOTS.
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higher personnel and programme expenditures associated with DOT are more cost-effective, due to the savings made by averting failure and default, and thereby the number of re-treatment/ drug-resistant TB cases, as well as in the long run the number of new cases (many with primary drug resistance), due to decline in transmission, all of which arise if treatment is not directly observed.
ISSUES RELATED TO COMPLIANCE OF TREATMENT 1. Constant supervision, counselling, and motivation are essential, and some of the challenges in ensuring compliance include: a. low levels of awareness regarding the need for ensuring complete treatment; b. prolonged treatment lasting over 6–8 months; c. decline in motivation, as patients tend to improve symptomatically after 6–8 weeks of treatment in most cases; d. inconvenience in taking drugs (four to six pills for each dose); e. side effects such as nausea and vomiting, which may force a few patients to selectively avoid drugs; f. daily or thrice-weekly regular visit to the DOT centre; g. return to work inconvenient for those patients seeking DOT; and h. chronic alcoholism or other substance abuse. 2. The DOT rates across India (calculated as the number of interviewed new smear-positive patients who have received at least 21 out of 24 doses during the intensive phase under direct observation) have been found to vary between 50% and 70%, as reported and verified by the internal evaluation systems in place under the programme. Several strategies that have been adopted to decrease default include decentralized DOT, so that patients do not have to travel for more than 10–15 minutes for their DOT and no additional costs are incurred to seek treatment. Initiatives such as flexitime DOT, and workplace DOT help to improve the compliance. 3. Initial address verification to facilitate retrieval of patients who interrupt treatment, as well as counselling of the patient and Flowchart 1 Outpatients
family members at the centre and at home prior to and during treatment, is easier said than done. To find dedicated manpower for such activities is a major programmatic challenge. 4. To monitor treatment response, follow-up sputum examinations are performed at the end of the intensive phase (2 months), extended intensive phase (if found positive at 2 months), continuation phase (2 months), and end of treatment. Ensuring timely follow-up for sputum examination to monitor treatment outcomes has been one of the weak links of the programme. A majority of the patients undergo follow-up sputum examination at the end of the intensive phase. However, at the end of 2 months of the continuation phase, the health staff do not insist on sputum smear examination and the practice is variable. At the end of treatment, a sputum smear examination is performed to record outcome in the majority of the patients, but is more programme- or health staff-driven, as the patients are asymptomatic by this time and do not consider it essential. 5. With the increasing involvement of other sectors such as NGOs, private practitioners, and medical colleges, a new dimension of collaborative efforts has been added. These sectors are widely used by the community, including TB patients, for their accessibility and acceptance irrespective of the costs. To ensure standardized care across all healthcare providers, and at no cost to the patient, it is essential to seek their involvement. However, as most of these units do not have additional manpower to undertake field supervision (initial address verification/default retrieval actions), there is a need of support from such institutions. 6. Medical colleges are the pillars of standards for care and the centres where the future generations of doctors are trained. They also act as role models for practitioners outside the colleges. Patients from far and wide seek care at these facilities, through either the outpatient or inpatient department. They must be diagnosed, initiated on treatment, and subsequently at the time of discharge transferred to ensure continuation of treatment at their place of residence. Guidelines for referral and transfer mechanisms have been developed (Fig. 65.4); Flowchart 2 In-patients
Medical colleges/hospitals
Patient is from RNTCP district Treatment outcome to be sent to TU of medical college
TB suspect OPD
Register under local TU where the medical college is located
Diagnosed as TB DOTS Directory of District/State/ National (paper/electronic)
Internal referral to DOTS centre in medical college/referral register
Stay in medical college DOTS centre
Referral
Feedback
Other DOTS centre within district Register in local TU TB register
Other district within or outside state
Attending physician prescribes RNTCP regimen using prolongation pouches* Inform DOTS centre of medical college/hospital On discharge, patient transferred to the DOTS centre nearest to the residence to continue and complete treatment
*If attending physician judges that RNTCP regimen is not appropriate for the individual patient, a non-RNTCP regimen will be prescribed TU = Tuberculosis Unit RNTCP = Revised National TB Control Programme of India
Fig. 65.4 Guidelines for referral and transfer mechanisms for medical colleges under the Revised National TB Control Programme. OPD, outpatient department.
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however, the feedback mechanisms continue to be weak as feedback is received in only 40–50% of cases. In this scenario, high default rates are reported in the TB units where the medical college is situated; and possibilities of dual registration, repeat diagnosis, and initiation of treatment at the place of residence are known to occur.
SUPERVISION AND MONITORING The public health system, especially in the developing world where TB is a major health problem, does not have adequate human resource or dedicated TB staff to supervise all activities. Additional contractual staff provided under projects have been successful in addressing issues related to supervision and monitoring, but this has also raised valid questions on initiative sustainability. Provision of additional staff to support TB control activities in India and other countries has led to a belief that the programme is vertical and therefore the ownership of the general health staff, who are the primary care providers and points of contact with the patients and community, is suboptimal. A balance needs to be maintained between the roles and responsibilities of the TB staff (including programme managers and dedicated TB staff) and the administrative powers vested upon them. Tools to facilitate objective programme monitoring by health and administrative officials need to be in place. The WHO has developed a compendium of such indicators, and the same needs to be adopted in the context of national programmes.31,32 Systems for routine internal and external evaluation help to identify programmatic challenges, as well as providing credibility to the programme among different partners, funding agencies, and stakeholders. The quality of the DOTS is of paramount importance, and operational indicators for evaluating the same have been identified. Some of these include the following:
Percentage of new smear-positive cases initiated on treatment within 7 days. The point of diagnosis (laboratory) and the point of provision of DOT (DOT centre is likely to be different): in such circumstances, these patients need to be referred to their local peripheral health institution for start of treatment. The field procedures adopted for such patients from the point of diagnosis to identifying a suitable DOT provider, transporting the drug box to the DOT centre/
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provider (may be health staff/community volunteer), and starting treatment are local initiatives and different practices are followed. What is essential is that in a good functioning system at no instance should the treatment be delayed by more than 7 days. The time lag is likely to be much higher if the diagnostic services are centralized or the patient prefers to seek guidance from an institution of repute such as a medical college or TB hospital. Percentage of new smear-positive patients who receive DOT as per guidelines: ensuring patients receive at least 21 out of 24 doses during the intensive phase under direct observation is the greater challenge to healthcare providers. Information on the percentage of cured patients receiving a sputum examination within 7 days of completing treatment: such an event is important for declaring the outcome as cured/treatment complete. Since in most cases the patients are totally asymptomatic, the onus of ensuring such patients provide sputum samples falls on the healthcare provider and is delayed in few instances.
EFFECTIVE DRUG SUPPLY AND LOGISTIC MANAGEMENT One of the primary issues addressed under the DOTS is ensuring uninterrupted supply of quality-assured drugs. Systems for procuring quality-assured drugs have been put in place, thereby winning the faith of the general population for the quality of drugs and treatment. Under RNTCP, there is a system of pre-shipment batch testing, testing of samples from the national drug stores, and random testing of drugs from the field in an independent laboratory. Strict quality assurance protocols have ensured supply of qualityassured drugs during the past 7 years and led to increased confidence amongst the patients and providers in the public health delivery system and the national programme. The Indian programme has developed a unique system of patient-wise drug boxes (PWBs) containing the complete course of drugs for each patient, so that at no point must any patient’s treatment be interrupted due to non-availability of drugs. The programme has also developed and procured similar PWBs for paediatric patients based on pre-specified weight bands. PWBs have been able to improve patient care, adherence, drug supply, and drug stock management (Fig. 65.5).
Fig. 65.5 (A, B) Patient-wise boxes of anti-TB drugs for adults and children for treatment of three categories of TB.
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INVOLVEMENT OF ALL HEALTHCARE PROVIDERS Developing countries where TB is an important public health problem are confronted with the additional challenge of diverse healthcare providers. It is presumed that private providers are the first point of contact for over 70% of patients, and in India they also cater to the majority of outpatient load. A sizeable proportion of TB patients is seeking care at these centres. More important is the fact that these patients do not receive treatment under observation, and in some cases there are issues related to the use of non-standard regimens and suboptimal drug dosages and treatment monitoring.33,34 Public–private mix efforts have yielded good results. Several models have been successfully field-tested and documented, and are being replicated.35–38 Challenges to seek involvement of other healthcare providers, especially those in the private for-profit sector, NGOs, corporate sector and industries, public health facilities outside the health department, and practitioners of indigenous systems of medicine, include the following: 1. Suspicion among medical practitioners on the effectiveness of the DOTS regimens: International Standards for TB Care as advocated by the Stop TB Strategy has been an important development in this direction and tries to get the support of professional medical bodies to endorse these international guidelines. 2. Individualized tailor-made versus standardized regimen – public health versus clinical practice. 3. Proactive marketing by the pharmaceutical companies with different combinations or combi-packs: there is also increased marketing of second-line drugs, especially fluoroquinolones, for use as a first-line alternative. With the global TB control efforts lacking enough resources to counter the challenge posed by the aggressive marketing strategy of pharmaceutical companies and with the absence of legislation to regulate sales of anti-TB drugs, seeking involvement of private for-profit providers is a real challenge. 4. Lack of common platform to reach out to the various treatment providers: tuberculosis control personnel in India have sought involvement of professional bodies such as the Indian Medical Association and Indian Academy of Pediatricians to endorse national TB control guidelines and seek support of their colleagues. International support from professional bodies such as the Stop TB forum to facilitate the process is also available. 5. The development of guidelines on collaboration: the lessons learnt from collaborations with the private and NGO sectors have encouraged the RNTCP to develop national guidelines on establishing formal collaborations at the district level.39,40 Attractive schemes with financial incentives to seek continued involvement of NGOs and private practitioners do act as enablers.37
TB/HIV LINKAGES HIV has been identified as the single most important risk factor for development of TB, with its pandemic emergence having resulted in the re-emergence of TB in many parts of the developed world.41 The mode of service delivery for these dual infections has varied in countries based on the epidemiology and burden of
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the diseases, and also on the health systems. In countries where HIV has led to an emergence of TB, the HIV programme has been guiding the TB control strategy. However, in high-TB-burden countries such as India, the TB epidemiology has been primarily driven by a very large (398 million) TB-infected non-HIV pool. Hence the disease control programmes and strategies have been working more independently than as seen in Africa. Recognizing the potential threat of an HIV epidemic on TB burden, including mortality, India has developed a Joint Action Plan to combat the problem of TB/HIV coinfection. Coordination between two programmes, which have different structures and priorities, poses a major challenge in the implementation of TB/HIV collaborative activities. The service delivery points for TB control have been decentralized to the most peripheral health institution, whereas HIV counselling and testing facilities are relatively more centralized. In the programme experience it has been noted that cross-referrals between the two programmes are enhanced wherever both services are under the same roof or on the same campus. It is desirable that all people living with HIV and AIDS (PLWHAs) should have access to antiretroviral therapy (ART) and DOTS services through well-established and functioning cross-referral linkages. Specialized HIV services being centralized act as a barrier for TB patients coinfected with HIV to seek care and support, and at times force them to migrate and travel for care. Ensuring confidentiality of HIV status and anonymity surrounding PLWHA poses a further challenge of treatment with DOTS. Diagnosis and treatment of TB/HIV coinfected patients pose several challenges. Some of these include diagnosis of sputum smear-negative and extrapulmonary TB in the HIV-infected; establishing systems to improve access to both TB and HIV care in the coinfected; provision of cotrimoxazole prophylaxis; and most importantly improving compliance to treatment, and ultimately improving treatment outcome. Recent calls for routine testing of all TB suspects, especially in a low-HIV-prevalence setting, need to be researched for its potential impact on the operational feasibility, costs, additional yield of diagnosing the coinfected as compared with selective referrals, and most importantly the risk of increased social stigma that may get attached to TB patients, who are predominantly HIV negative.
CONCLUSION Over the past decade and a half, the world has seen dramatic progress in TB control efforts across the globe. India and China, the first and the second highest TB burden countries in the world, have successfully demonstrated the operational feasibility and effectiveness of the DOTS strategy. Some of the broad reasons for a successful implementation of the DOTS in India include strict appraisal criteria for the district prior to the launch of the DOTS strategy to ensure establishment of adequate diagnostic and treatment service units. Additionally, availability of the following has made a difference: 1. trained manpower at all levels; 2. drug and logistic management systems in place; 3. decentralized services delivery through the general public health system, with creation of additional subdistrict supervisory units to facilitate systematic supervision and monitoring of all TB services; 4. patient-wise drug boxes;
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Operational issues, compliance, and DOTS programmes
5. involvement of the community for provision of DOT; and 6. equally important, development of linkages with the healthcare providers outside the public health system. The programme has developed plans to address the problem of drug-resistant TB in a systematic way by first establishing a network of accredited laboratories capable of undertaking culture and drug sensitivity testing services and then linking them to specialized DOTS plus sites for enrolling multidrug-resistant-TB (MDR-TB) patients for second-line treatment. The challenge that the TB control programme faces does not stop with the implementation of DOTS and achievement of global targets of 70% case detection and 85% treatment success, but in maintaining quality DOTS and at the same time expanding to address newer challenges of TB/HIV coinfection; MDR-TB, public–private partnership, and implementing an effective advocacy, communication and social
REFERENCES 1. World Health Organization (WHO). Global Tuberculosis Control: Surveillance, planning, financing, WHO Report 2008. WHO/HTM/TB/ 2008.393. Geneva: WHO, 2008. 2. NJMS National Tuberculosis Center. Brief History of Tuberculosis, revised 23 July 1996. [online]. Accessed 19 November 2006. Available at URL: http://www. umdnj.edu/~ntbcweb/history.htm 3. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21:51–144. 4. Frieden T (ed.). Toman’s Tuberculosis Case Detection, Treatment, and Monitoring: Questions and Answers, 2nd edn (WHO/HTM/TB/2004.334). Geneva: WHO, 2004. 5. WHO. Framework for effective tuberculosis control (WHO/TB/94.179). Geneva: WHO, 1994. 6. WHO. An expanded DOTS framework for effective tuberculosis control (WHO/CDS/TB/2002.297). Geneva: WHO, 2002. 7. WHO. TB—a global emergency. WHO report on the tuberculosis epidemic 1994 (WHO/TB/94.177). Geneva: WHO, 1994. 8. WHO. 58th World Health Assembly. Resolutions and decisions: Sustainable financing for tuberculosis prevention and control (WHA58.14). Geneva: WHO, 2005. 9. WHO. The Stop TB Strategy. Building on and enhancing DOTS to meet the TB related millennium development goals (WHO/HTM/STB/2006.37). Geneva: WHO, 2006. 10. Central TB Division (CTD). Guidelines for Quality Assurance of Smear Microscopy for Diagnosing Tuberculosis. Delhi: Central TB Division, Directorate General of Health Services, Government of India, April 2005. 11. Selvakumar N, Sekar MG, Ilampuranan KJ, et al. Increased detection by restaining of acid-fast bacilli in sputum samples transported in cetylpyridinium chloride solution. Int J Tuberc Lung Dis 2005;9:195–199. 12. Santha T, Garg R, Subramani R, et al. Comparison of cough of 2 and 3 weeks to improve detection of smear-positive tuberculosis cases among out-patients in India. Int J Tuberc Lung Dis 2005;9:61–68. 13. Gopi PG, Subramani R, Selvakumar N, et al. Smear examination of two specimens for diagnosis of pulmonary tuberculosis in Tiruvallur District, south India. Int J Tuberc Lung Dis 2004;8:824–828. 14. Selvakumar N, Kumar V, Gopi PG, et al. Proficiency to read sputum AFB smears by senior tuberculosis
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mobilization (ACSM) strategy to generate awareness in the community. The Stop TB strategy and the Global Plan to control TB is an international commitment and mechanism towards realizing and achieving the TB-related Millennium Development Goals (MDG) of reversing the trend of incidence of TB, and halving the prevalence of and mortality due to TB by 2015. The need of the hour is to advocate for continued financial and technical support to make this happen.
ACKNOWLEDGEMENTS We profusely thank Dr. P. Sai Kumar, WHO RNTCP Consultant, Central TB Division, for his constant help in preparation of the draft. We also thank Ms Deepa Dhawan, Department of Medicine, AIIMS, for her help in typing the manuscript.
laboratory supervisors under training at a reference laboratory in India. Indian J Tuberc 2005;52:11–14. TB India 2006. RNTCP Status Report. Delhi: Directorate of Health and Family Welfare, Central TB Division, Goverment of India, 2006. Gopi PG, Chandrasekaran V, Subramani R, et al. Failure to initiate treatment for tuberculosis patients diagnosed in a community survey and at health facilities under a DOTS programme in a district, South India. Indian J Tuberc 2005;52:153–156. CTD. Managing the RNTCP in your area: A Training Course, Modules 1–4 & 5–9. Delhi: Central TB Division, Directorate General of Health Services, Government of India, 2005. Dickison JM, Mitichison DA. In vitro studies on the choice of drugs for intermittent chemotherapy of tuberculosis. Tubercle 1966;47:370–380. Frieden T. What is intermittent treatment and what is the scientific basis for intermittency? In: Frieden T (ed.). Toman’s Tuberculosis: Case Detection, Treatment, and Monitoring: Questions and Answers, 2nd edn (WHO/HTM/TB/2004.334). Geneva: WHO, 2004. WHO. Treatment of tuberculosis: guidelines for national programmes, 3rd edn (WHO/CDS/TB/ 2003.313). Geneva: WHO, 2003. Singh AA, Parasher D, Wares F, et al. Effectiveness of community-based Anganwadi workers in the directly observed treatment of tuberculosis patients in a rural area of Haryana. Indian J Tuberc 2005;52:15–20. Banerjee A, Sharma BV, Ray A, et al. Acceptability of traditional healers as directly observed treatment providers in tuberculosis control in a tribal area of Andhra Pradesh, India. Int J Tuberc Lung Dis 2004;8:1260–1265. Mathew A, Binks C, Kuruvilla J, et al. A comparison of two methods of undertaking directly observed therapy in a rural indian setting. Int J Tuberc Lung Dis 2005;9:69–74. Nirupa C, Sudha G, Santha T, et al. Evaluation of Directly Observed Treatment Providers in the Revised National TB Control Programme. Indian J Tuberc 2005;52:73–77. Balasubramanian VN, Oommen K, Samuel R. DOT or not? Direct observation of anti-tuberculosis treatment and patient outcomes, Kerala State, India. Int J Tuberc Lung Dis 2000;4:409–413. Central TB Division. RNTCP: TB in Children— Consensus Guidelines of Pediatricians, TB Experts and TB Control Programme Managers. Delhi: Directorate General of Health Services, Government of India, 2004. Balasubramanian R, Ramachandran R. Management of non-pulmonary forms of tuberculosis: review of TRC studies over two decades. Indian J Pediatr 2000;67:S34–40.
28. Jawahar MS, Rajaram K, Sivasubramanian S, et al. Treatment of lymph node tuberculosis—a randomized clinical trial of two 6-month regimens. Trop Med Int Health 2005;10:1090–1098. 29. Dhingra VK, Rajpal S, Aggarwal N, et al.Treatment of tuberculous pleural effusion patients and their satisfaction with DOTS—1 1/2year follow-up. Indian J Tuberc 2004;52:209–212. 30. Chandrasekaran V, Gopi PG, Subramani R, et al. Default during the intensive phase of treatment under DOTS programme. Indian J Tuberc 2005;52:197–202. 31. WHO. Compendium of Indicators for Monitoring and Evaluating National Tuberculosis Programs. Geneva: WHO, 2004. 32. Central TB Division. Strategy Document for Supervision and Monitoring of the Revised National TB Control Programme. Delhi: Directorate General of Health Services, Government of India, 2004. 33. Uplekar M, Juvekar S, Morankar S, et al. Tuberculosis patients and practitioners in private clinics in India. Int J Tuberc Lung Dis 1998;2:324–329. 34. Uplekar MW, Rangan S. Private doctors and tuberculosis control in India. Tuber Lung Dis 1993;74:332–337. 35. Murthy KJ, Frieden TR, Yazdani A, et al. Publicprivate partnership in tuberculosis control: experience in Hyderabad, India. Int J Tuberc Lung Dis 2001; 5:354–359. 36. Joseph MR, Orath SP, Eapen CK. Integrating private health care in National Tuberculosis Programme: experience from Ernakulam, Kerala. Indian J Tuberc 2001;48:17–19. 37. Lonnroth K, Uplekar M, Arora VK, et al. Publicprivate mix for DOTS implementation: what makes it work? Bull World Health Organ 2004;82:580–586. 38. Ambe G, Lonnroth K, Dholakia Y, et al. Every provider counts: effect of a comprehensive publicprivate mix approach for TB control in a large metropolitan area in India. Int J Tuberc Lung Dis 2005;9:562–568. 39. CTD. Involvement of Non-governmental Organizations in the Revised National Tuberculosis Control Programme. Delhi: Directorate General of Health Services, Government of India, 2005. 40. CTD. Involvement of Private Practitioners in the Revised National Tuberculosis Control Programme. Delhi: Directorate General of Health Services, Government of India, 2005. 41. Swaminathan S, Ramachandran R, Baskaran G, et al. Risk of development of tuberculosis in HIV-infected patients. Int J Tuberc Lung Dis 2000;4:839–844.
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Management of side effects of antituberculosis drugs Bj rn Blomberg
BACKGROUND The recommended first-line regimens for treatment of TB are highly effective, achieving cure rates in excess of 95% if taken as prescribed. Currently, TB cannot be successfully treated in less than 6 months. Compliance with such long treatment is challenging and the fragile interplay between patient and health system may easily be jeopardized by the occurrence of side effects. Fortunately, first-line antiTB drugs are generally well tolerated, and most side effects can be treated symptomatically (Box 66.1). Thus, in most cases, focus should be on maintaining uninterrupted treatment. Given the long treatment duration, even minor side effects must be taken seriously, since they increase the risk of non-adherence to treatment. Additionally, some side effects are of a serious nature and need prompt attention. Thus, it is important that health providers are familiar with the common side effects and capable of satisfactorily handling them. The World Health Organization (WHO) classifies side effects of anti-TB drugs as minor or major (Table 66.1). Patients experiencing minor side effects can usually continue the same treatment; in those with major side effects the relevant drug should be stopped and usually the patient needs hospitalization. The side effects of individual anti-TB drugs are discussed in detail in Chapter 59 and Appendix 2, and the most important side effects are summarized in Table 66.2. The main reasons for changing drugs in the chemotherapy of TB are drug resistance, interactions with other drugs and the occurrence of side effects. The impact of drug resistance on the choice of antiTB drugs is dependent on the prevalence of resistance in the area, and this is dealt with in detail in Chapters 61 and 62. This chapter will largely deal with the prevention and management of side effects of the first-line anti-TB treatment regimens. This chapter is written from a clinical viewpoint and discusses each major category of side effects in separate sections in detail, including issues regarding pathology, symptoms and signs, differential diagnosis, investigations, management, complications and prevention.
FACTORS INFLUENCING SIDE EFFECTS OF ANTITUBERCULOSIS TREATMENT HUMAN IMMUNODEFICIENCY VIRUS Human immunodeficiency virus (HIV) infection is associated with a higher frequency of side effects, particularly serious skin reactions.
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Thioacetazone, a weak anti-TB agent, was previously widely used but has now been abandoned in most areas where HIV is prevalent due to serious skin side effects, including Steven–Johnson syndrome. People with TB and HIV coinfection may also be more prone to experience hepatotoxicity because both anti-TB and antiretroviral drugs may cause hepatotoxicity. There is an increased incidence of immune reconstitution syndrome in HIV/TB coinfected patients which can be misinterpreted as a febrile reaction to drugs. Further, there are considerable interactions between antiretrovirals and rifamycins, particularly rifampicin. Cotrimoxazole prophylaxis in immunosuppressed HIV-infected patients may cause both skin and hepatic reactions.
ALCOHOL AND SUBSTANCE ABUSE Alcohol abuse occurs world-wide, albeit with cultural and religious variation. The main problem with alcoholic TB patients is ensuring treatment compliance. Patients consuming significant quantities of alcohol may be more prone to side effects, such as hepatitis. In the event of worsening liver function on anti-TB treatment, it may be challenging to diagnose whether the liver damage is due to alcohol or a result of anti-TB drug-induced hepatotoxicity. Alcoholics are frequently malnourished.
NUTRITIONAL STATUS Malnutrition and particularly vitamin deficiencies may increase the risk of side effects of anti-TB treatment. Most notably, lack of B vitamins, such as pyridoxine, increases the risk of peripheral neuropathy, and probably also other neurological side effects.
DIABETES Visual impairment, renal failure and peripheral neuropathy are common complications in patients with diabetes. Diabetic renal failure may increase the risk of renal failure as a side effect of anti-TB therapy. Peripheral neuropathy is a common side effect of both isoniazid and a number of antiretroviral drugs, most notably stavudine. Thus anti-TB treatment, particularly in combination with antiretroviral treatment, may aggravate peripheral neuropathy in diabetic patients. Ethambutol-induced optic neuritis may be more difficult to detect in a patient with diabetic retinopathy. The consequences of even modest visual reduction due to ethambutol have greater significance if vision is already impaired by diabetic complications.
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Management of side effects of antituberculosis drugs
Box 66.1 Management of side effects of antituberculosis drugs
Anti-TB treatment is generally safe and well tolerated. Trivial side effects may lead to reduced compliance with treatment. Major side effects may lead to permanent damage, hepatotoxicity, skin reactions and hearing loss. Side effects from anti-TB treatment rarely cause death. Side effects of anti-TB treatment are not more frequent when using fixed-dose combination formulations.
AGE Old age is a risk factor for hepatotoxic side effects of anti-TB treatment.4 The toxic effects of aminoglycosides on kidney function, balance and hearing are more frequent in old age. A serious concern in young children is that they may be unable to communicate with caregivers regarding sensory side effects such as reduced hearing (aminoglycosides), vision (ethambutol, isoniazid) or peripheral neuropathy (isoniazid). Similar logic applies to a certain extent in the treatment of pregnant women, since one will be unable to assess the occurrence of side effects in the fetus.
ISONIAZID ACETYLATION STATUS Isoniazid elimination is dependent on its acetylation to an inactive metabolite. The acetylation rate is genetically determined and differs among populations. Approximately half Africans and Caucasians are so-called rapid acetylators with isoniazid elimination half-lives of 0.5–1.5 hours, the remaining half being slow acetylators with elimination half-lives of 2–4 hours. Among Chinese and Japanese, 80–90% are rapid acetylators. The acetylation status has little importance for the dosage of isoniazid, and consequently standard doses are used regardless of acetylation status. However, slow acetylators have increased risk of getting certain side effects, most notably peripheral neuropathy. Thus, side effects to isoniazid
may be somewhat more frequent in people of European or African descent than in people originating from the Western Pacific region.
ANAPHYLAXIS AND ALLERGY BACKGROUND AND EPIDEMIOLOGY In principle, any drug can cause anaphylaxis, a dreaded and very serious allergic reaction. Fortunately, anaphylaxis is very rare, and it is not more frequent with anti-TB drugs than with other drugs. Because of its acute presentation and potential serious consequences, it is imperative that health workers are familiar with anaphylaxis and prepared to manage patients with this rare side effect. Anaphylaxis occurs as a consequence of an allergic response that leads to the release of immunological and other mediators. These mediators produce peripheral vasodilatation and leakage of plasma, which may lead to hypotension and circulatory collapse and oedema and obstruction in the bronchial tree and larynx.
DIFFERENTIAL DIAGNOSIS In typical cases, the diagnosis will be evident. Differential diagnoses will be other forms of shock caused by infection, bleeding or cardiac arrest, as well as poisonings. In the early stages, anaphylaxis may be mistaken for vasovagal reaction to, for instance, injection of a drug.
MANAGEMENT The management of a patient with anaphylaxis may include basic life support maintaining free airways, breathing and circulation, and monitoring of the patient. Adrenaline (epinephrine) (1 mg/mL) should be given by deep intramuscular injection as soon as possible in a dose of 0.01 mg/kg (children) to a maximum of 0.3–0.5 mg (adults). Adrenaline can be repeated after 20 minutes, if necessary. Additionally, corticosteroids and antihistamines should be given. All anti-TB drugs should be stopped immediately. It is imperative
Table 66.1 Symptom-based approach to managing minor and major side effects of antituberculosis drugs Side effect Minor side effects Minor gastrointestinal upset, anorexia, nausea, abdominal pain Joint pains Burning sensation in the feet Orange/red urine Major side effects Itching, skin rash Deafness (no earwax on otoscopy) Dizziness, vertigo, nystagmus Jaundice (other causes excluded), hepatitis Confusion Visual impairment (other causes excluded) Shock, purpura, acute renal failure
a
Drug(s) probably responsible
Management
Pyrazinamide, rifampicin
Continue anti-TB drugs, check doses Give drugs with small meal or just before going to bed
Pyrazinamide Isoniazid Rifampicin
Aspirin, NSAIDs Pyridoxine 100 mg daily Harmless. Reassurance. Inform patient at start of treatment
Thioacetazone (streptomycin, isoniazid, rifampicin, pyrazinamide) Streptomycin Streptomycin Isoniazid, pyrazinamide, rifampicin Most anti-TB drugs
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Stop responsible drugs Stop anti-TB drugs (see text below for details) Stop streptomycin and give ethambutol instead. Stop streptomycin, use ethambutol. Stop anti-TB drugs (see text below for details)
Ethambutol
Stop anti-TB drugs. Suspect acute liver failure if jaundice is present. Urgent liver function test and prothrombin time Stop ethambutol
Rifampicin
Stop rifampicin
NSAIDs, non-steroidal anti-inflammatory drugs. a Modified from WHO.1
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Table 66.2 Side effects of antituberculosis drugs Drugs
Side effects Common (> 1%)
Uncommon (0.1–1%)
Rare (< 0.1%)
Isoniazid
None (mild elevation of liver enzymes)
Hepatitis (common with age > 50 years), cutaneous hypersensitivity reactions including erythema multiforme, peripheral neuropathy
Rifampicin
None (mild elevation of liver enzymes)
Hepatitis, flushing, itching with or without rash, gastrointestinal upsets, ‘flu-like syndrome’, headache
Pyrazinamide
Anorexia
Ethambutol
None
Hepatitis, nausea with or without vomiting, urticaria, arthralgia Optic neuritis, arthralgia
Streptomycin
None
Vertigo, ataxia, deafness, tinnitus, cutaneous hypersensitivity
Other aminoglycosides Thiacetazone
None
Paraaminosalicylic acid Ethionamide, prothionamide
Gastrointestinal upsets
Cutaneous hypersensitivity, vertigo, deafness Hepatitis, erythema multiforme, exfoliative dermatitis, haemolytic anaemia Cutaneous hypersensitivity, hepatitis, hypokalaemia
Vertigo; convulsions; optic neuritis and atrophy; psychiatric disturbance; haemolytic anaemia; aplastic anaemia; dermal reactions including pellagra, purpura and lupoid syndrome; gynaecomastia, hyperglycaemia, arthralgia Dyspnoea, hypotension with or without shock, Addisonian crisis, haemolytic anaemia, acute renal failure, thrombocytopenia with or without purpura, transient leucopenia or eosinophilia, menstrual disturbances, muscular weakness, pseudomembranous colitis Sideroblastic anaemia, photosensitization, gout, dysuria, aggravation of peptic ulcer Hepatitis, cutaneous hypersensitivity including pruritus and urticaria, photosensitive lichenoid eruptions, paraesthesia in extremities, interstitial nephritis Renal damage, aplastic anaemia, agranulocytosis, peripheral neuropathy, optic neuritis with scotoma, severe bleeding due to antagonism of factor V, neuromuscular blockade in patients receiving muscle relaxants and in those with myasthenia gravis Renal damage, hypoglycaemia, hypokalaemia Agranulocytosis
Gastrointestinal upsets, salivation, metallic taste
Cutaneous hypersensitivity, hepatitis
Capreomycin, viomycin
Eosinophilia, pain and induration at injection site
Clofazimine
Ofloxacin
Discoloration of skin and body fluids, nausea, vomiting, abdominal pain, diarrhoea Convulsions, drowsiness, sleep disturbance, headache, tremor, vertigo, confusion, irritability, aggression, personality changes, psychosis, sometimes suicidal tendency None
Loss of hearing, vertigo, tinnitus, electrolyte disturbances including hypokalaemia, leucopenia or leucocytosis Dryness of skin, ichthyosis, photosensitivity Cutaneous hypersensitivity, hepatitis, hepatitis, megaloblastic anaemia
Linezolid
Headache, diarrhoea
Cycloserine
Gastrointestinal upsets, cutaneous hypersensitivity, vertigo, conjunctivitis
Modified from Grange and Zumla.2,3
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Gastrointestinal upsets, headache, dizziness, insomnia, cutaneous hypersensitivity reactions
Myelosuppression, thrombocytopenia, anaemia, leukopenia, rash
Acute renal failure, haemolytic anaemia, thrombocytopenia, hypothyroidism Alopecia, convulsions, deafness, diplopia, gynaecomastia, hypotension, impotence, psychiatric disturbance, menstrual irregularity, hypoglycaemia, peripheral neuropathy Renal impairment, hepatitis, thrombocytopenia
Intestinal obstruction Congestive heart failure
Restlessness; convulsions; psychiatric disturbances including psychotic reactions and hallucinations; oedema of face, tongue and epiglottis; disturbance of taste and smell; anaphylactoid reactions Peripheral neuropathy, optic neuropathy, lactic acidosis
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Management of side effects of antituberculosis drugs
to identify the offending drug; if identified, the patient should never receive it again. When the patient has been stabilized, the anti-TB drugs can be reinstated with a system of drug challenging. If a likely offending drug has been identified, no attempt should be made at challenging with that drug. Typically, the challenge may start with a tenth of the original dose of the drug, doubling this dose daily for 2 days, and then start full dose again on the fourth day.
PREVENTION It is difficult to foresee such rare events as anaphylaxis. However, risks can be minimized by documenting allergic reactions in patient records and taking a detailed patient history with regards to previous allergic reactions. Apart from this, one should aim at preventing complications of anaphylaxis (death or serious sequela) by ensuring health workers are trained to tackle anaphylaxis.
DERMATOLOGICAL SIDE EFFECTS BACKGROUND AND EPIDEMIOLOGY Cutaneous reactions are among the most common side effects of anti-TB drugs, and range from mild itching, through rashes to life-threatening toxic epidermal necrolysis. Among the primary anti-TB drugs, all can give skin reactions, although ethambutol is less likely than the others.5 Thioacetazone is far more likely than other anti-TB agents to cause a skin reaction, and particularly in HIV-infected people.6 This drug has been removed from first-line regimens from most countries, particularly those with a high HIV burden. Rash has been reported in 3.6% of patients treated with pyrazinamide, and 0.3% and 0.1% of those treated with rifampicin and ethambutol, respectively.7 Yee and colleagues8 found serious skin reactions with an incidence per month of treatment of 0.6% for pyrazinamide, 0.3% for rifampicin and 0.15% for isoniazid. Toxic epidermal necrolysis is thought to be an immunological cytotoxic reaction against keratocytes, and tumour-necrosis factor-alpha (TNF-a) has been implicated in the genesis. Stevens– Johnson syndrome is considered by some to be a more serious variant of toxic epidermal necrolysis.
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other insect infestations or bites, atopic dermatitis, allergic or irritant contact dermatitis and psoriasis. The differential diagnosis for toxic epidermal necrolysis includes skin reactions caused by other drugs, staphylococcal scalded skin syndrome and impetigo.
MANAGEMENT The management of skin side effects of anti-TB drugs is dependent on whether the patient receives thioacetazone as part of the regimen. The development of any skin reaction, even itching without an evident rash, should lead to stopping thioacetazone. A patient who has reacted to thioacetazone should never receive this drug again; thioacetazone can be replaced with ethambutol. In patients on anti-TB treatment not including thioacetazone, it is less urgent to alter the anti-TB regimen. With mild itching, but no visible rash or only a very mild rash, treatment may be continued. Any other plausible cause of the itch, such as scabies, should be identified and treated. If no such cause is evident, anti-TB treatment can be continued and symptoms relieved by antihistamines, reassurance and advice on avoiding dry skin. If a more marked rash accompanies the itch, it is advisable to stop all anti-TB drugs. In the presence of severe rashes suspect of toxic epidermal necrolysis or Stevens–Johnson-like reactions that include the mucosa or are accompanied by hypotension, all anti-TB drugs and other drugs must be stopped immediately. Prompt withdrawal of drugs has been shown to reduce mortality. If at all possible based on the clinical situation, delay drug challenging until the patient is stabilized.
Toxic epidermal necrolysis is often preceded by several days of nonspecific prodromal symptoms, including malaise, loss of appetite, nausea, vomiting, sometimes diarrhoea, as well as fever, rashes, muscle and joint aches, cough, rhinitis and conjunctival affection. The skin lesions start with a painful erythematous, macular rash, spreading outwards from the head and thorax to the whole body. Thereafter follows an acute phase with fever, sloughing of the epidermis and development of sores in mucous membranes. The epidermis falls off in sheets, and pressure on skin easily makes the epidermis separate from the underlying dermis. Sores with haemorrhagic crusts develop on the lips. The diagnosis can be verified by a skin biopsy.
Drug challenging after skin reaction Once the rash has healed, anti-TB drugs can be reintroduced, a process labelled drug challenging. However, thioacetazone never should be given again to the patient. It is unfortunately not possible to know which anti-TB drugs have caused the reaction. There are two ways to minimize the hazards of a serious allergic reaction. First, the drugs should be reintroduced in a sequence starting with the drug least likely to cause skin reactions. Second, drugs should be introduced at a small dose in anticipation that a small dose will cause less severe adverse effects than a larger dose. Among the first-line drugs, it is common to start with isoniazid, which is least likely to cause the reaction.5 Isoniazid can be given in a dose of 50 mg, gradually increasing to normal dose within 3 days,3 although some authorities suggest starting with 150 mg.5 If isoniazid is successfully introduced and tolerated, the procedure is repeated for each drug, continuing with rifampicin with a starting dose of up to 75 mg daily (Table 66.3). If itching, fever or rash occurs soon after drug ingestion, this may indicate hypersensitivity. A reaction after introducing a particular drug is then held as evidence that this is the drug which caused the reaction, and that particular drug should be omitted. Once a particular drug is identified as the cause of the skin reaction, this drug should never be given to the patient again, and the patient should be so informed. The schedule in Table 66.3, challenging with increasing doses of the drugs, is often successful, allowing all drugs to be reintroduced. When drug(s) must be omitted, it is important to ensure that the patient receives an adequate regimen for an appropriate length of time, especially if the reaction is caused by rifampicin or isoniazid.
DIFFERENTIAL DIAGNOSIS
PREVENTION
There are a number of differential diagnoses for itching skin with and without rash. Common conditions to consider include scabies,
Thioacetazone should not be given to persons with HIV coinfection. In areas with high prevalence of HIV thioacetazone is better
SYMPTOMS AND SIGNS
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Table 66.3 Sequence of reintroduction of antituberculosis drugs after skin reaction Drug
Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin
Sequence of introduction
Likelihood of drug causing the reaction
Importance of drug in regimen
1 2 3 4 5
þ þþ þþþ þ þþ
þþþþ þþþþ þþþ þ þþ
Challenge dose Day 1
Day 2
Day 3
50 mg 75 mg 250 mg 100 mg 125 mg
300 mg 300 mg 1000 mg 500 mg 500 mg
300 mg Full dose Full dose Full dose Full dose
Modified from Grange and Zumla.3
Joint pains are frequent in patients on anti-TB treatment, and most likely caused by pyrazinamide.
and vomiting are common in the beginning of anti-TB therapy, but tend to resolve with time. Haematemesis, melena or haematochezia is rare. While mild gastrointestinal symptoms usually are relatively innocent, it is important to remember that they can be prodromal symptoms of hepatitis; therefore, clinical monitoring is necessary. More commonly, gastrointestinal symptoms may be caused by dehydration and accompanying electrolyte disturbances that may be revealed by blood tests. Liver enzymes should be measured if hepatotoxicity is considered.
DIFFERENTIAL DIAGNOSIS
MANAGEMENT
Pyrazinamide-induced arthralgias should be distinguished from other causes of arthralgia such as septic arthritis, osteomyelitis and TB osteomyelitis. Clinical assessment for other causes should be undertaken. Blood tests may show increased uric acid levels and the mechanism behind pyrazinamide-associated arthralgia is thought to be accumulation of uric acid because it inhibits the excretion of uric acid. Among the second-line anti-TB drugs, fluoroquinolones may cause arthralgia.
Gastrointestinal upset usually does not warrant stopping anti-TB drugs. An exception is the reserve drug clofazimine, which may cause such severe abdominal pain that it should be discontinued. However, it is important to minimize the patients’ distress, because ignoring the symptoms may lead patients to fail to comply with treatment. Gastrointestinal upset may be an early warning of hepatotoxicity; thus clinical follow-up is important. Mild to moderate gastrointestinal upset may be prevented or reduced by interventions such as taking medications with food or before going to bed. With signs of dehydration, oral or intravenous rehydration should be given. Anti-emetics may reduce nausea and vomiting. If symptoms of gastritis predominate, proton-pump inhibitors or other antacids such as histamine2 blockers and calcium carbonate may be helpful. However, antacids can affect the absorption of anti-TB drugs; rifampicin absorption may be reduced by 20–40% by magnesium- or aluminium-containing antacids. Thus, antacids should not be taken simultaneously with anti-TB drugs, but preferably at least 2 hours before or after. If symptoms are more severe, particularly in the case of gastritis, it may be possible to identify the offending drug by withholding suspect drugs one at a time for a short time, i.e. up to 1 week. In such cases, one may try lowering the dose or stopping the offending drug as long as an effective alternative is available.
avoided altogether. Death and serious complications from skin side effects are prevented by early and prompt response to any side effects, the most important being stopping the offending drugs.
BONE AND JOINT PAINS
MANAGEMENT Joint pains do not warrant stopping the anti-TB drugs, and symptoms may resolve with time. Encourage some physical exercise as it helps to reduce the pain. Treatment with aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) usually eases the joint pains. See that the patient is receiving the correct dosage of pyrazinamide. Although uric acid levels are often increased in these patients, allopurinol does not reduce uric acid levels nor alleviate the symptoms.
PREVENTION Ensuring that pyrazinamide is prescribed and taken in the correct dose may prevent some cases of arthralgia.
GASTROINTESTINAL UPSET Mild to moderate gastrointestional upset is a frequent side effect of anti-TB drugs, which may disturb the normal balance of commensal gut microbes. Dehydration and electrolyte disturbances may cause such symptoms. Electrolyte disturbances, such as hypokalaemia and hypomagnesaemia, can be caused by the aminoglycosides, but are more frequent following capreomycin. Symptoms such as nausea
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COMPLICATIONS There are two main pitfalls with regards to the side effect of gastrointestinal upset. Firstly, it is important not to overlook a case of serious liver toxicity. Prodromal symptoms may precede serious hepatotoxicity by only a few days, making it very important to monitor these patients. Secondly, ignoring patients’ symptoms, although perceived as minor, may lead to poor compliance with treatment and consequently poor outcome.
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Management of side effects of antituberculosis drugs
PREVENTION Taking the drugs with food and/or before bedtime will often be enough to prevent the symptoms.
HEPATOTOXICITY BACKGROUND AND EPIDEMIOLOGY Antituberculosis drugs are among the most common causes of drug-induced liver injury. The reported incidence of hepatotoxicity due to anti-TB drugs varies from 2.5% to 34.9%. However, this often includes mild elevation of transaminases, whereas serious liver injury occurs in less than 5% of cases, and a definite change in anti-TB drugs is necessary in only 1–2%.9,10 The incidence of hepatitis increases with age, from less than 1% in patients under 20 years of age to approximately 5% in patients older than 60 years.4,7,11–14 Other risk factors for hepatotoxicity include a history of alcohol abuse or alcoholic liver disease, viral liver disease including hepatitis B and C, exposure to other substances that induce cytochrome P450 enzymes, elevated transaminases or bilirubin at baseline and possibly HIV coinfection.4,9,10,14–20 Fatal outcome due to anti-TB drug hepatotoxicity is reported mostly in patients older than 50 years of age with additional risk factors.4,9,13,18,21 Of the first-line drugs, isoniazid, rifampicin and pyrazinamide are potentially hepatotoxic drugs. Because they are used in combination, it may be difficult to pinpoint which drug is responsible for the reaction. Frequently, re-challenging a patient with the same drugs after an episode of hepatotoxicity will not lead to recurrence of the symptoms. Consequently, estimates of the relative importance of individual drugs as a cause of hepatotoxicity may not be very accurate. Pyrazinamide is associated with the highest incidence of hepatitis of approximately 0.5% per month of treatment.8 When given alone as prophylaxis for 1 year, isoniazid causes elevation of liver enzymes in approximately 10% and clinical hepatitis in 1%,22,23 although these incidences increase with old age. In the treatment of active TB, there is evidence that isoniazid may be more commonly associated with hepatitis than rifampicin.8,24 Rifampicin can also cause hepatitis, although more frequently it can cause isolated hyperbilirubinaemia, possibly due to inhibition of bilirubin excretion.24 Ethambutol and streptomycin rarely cause liver damage. The hepatotoxicity of isoniazid is considered an idiosyncratic reaction. Metabolism of isoniazid results in reactive metabolites that bind to and damage hepatic cellular macromolecules. The mild asymptomatic elevation of transaminases seen in many patients is thought to be the result of the direct toxicity of the hydrazine metabolites. However, in some patients, there is more serious liver damage, which is thought to be due to a diversion of the metabolism to a different pathway through the cytochrome P450 system. Indirect evidence of this is that slow acetylators seem to be more prone to serious isoniazid hepatotoxicity.
SYMPTOMS AND SIGNS There is great variation in manifestations of drug-induced hepatotoxicity, from asymptomatic elevation of transaminases to fulminant hepatic failure. Symptoms may occur only a few days before serious liver damage and liver failure. Constitutional symptoms include fatigue, loss of appetite, malaise, nausea, vomiting, fever,
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myalgia and arthralgia. Hepatic inflammation may manifest as abdominal pain or discomfort and tenderness in the right upper quadrant, sometimes hepatomegaly, but rarely ascites. Symptoms of liver failure include jaundice, dark urine, pale stools, propensity to bleeding, pruritus, and confusion progressing to coma.25 Jaundice may be a late finding and is usually not detectable clinically until serum bilirubin levels are at least 51 mmol/L (3.0 mg/dL), more than twice the upper normal limit.26 Yellow discoloration of the eyes is more sensitive than skin coloration, particularly in dark-skinned patients.
DIFFERENTIAL DIAGNOSIS It is important to decide whether the anti-TB drugs are the cause of the liver damage or whether there are other explanations such as viral hepatitis. Differential diagnoses for anti-TB drug-induced liver damage include infectious causes such as viral hepatitis A, B and C, yellow fever virus, Epstein–Barr virus and cytomegalovirus. Jaundice can also be caused by bacterial infections, including pneumococci and leptospira, and parasite infection such as malaria, schistosomiasis and a number of other flukes, as well as Ascaris lumbricoides, which can obstruct the bile ducts.27 Even TB itself can affect the liver. Non-infectious causes to consider are alcohol abuse and other hepatotoxic substances such as mushrooms and chlorinated hydrocarbons.
INVESTIGATIONS Investigations should be directed towards determining the cause and the extent of the damage. The investigations performed will depend on the available resources. In many settings of high TB prevalence, these patients are managed based on clinical assessment without reliance on blood tests or other investigations. In a more resource-affluent setting, one would perform a number of blood tests and imaging studies. Serum transaminases (AST, ALT) are important for determining the seriousness of the liver damage. Generally, a less than threefold elevation of transaminases suggests that anti-TB drugs may be continued, while a more than threefold elevation should lead to discontinuation of potentially hepatotoxic drugs. Serological testing for viral hepatitis may be performed. A significantly increased prothrombin time, measured by the international normalized ratio (INR), may indicate severe liver damage, especially if not responding to vitamin K, and should lead to consultation with a hepatologist with regards to evaluation for liver transplantation, if available. The differential diagnosis of haemochromatosis is suggested by concomitant elevation of ferritin and iron saturation. Serum ceruloplasmin can be tested to exclude hereditary hepatolenticular degeneration, Wilson’s disease, which most often manifests in young adults aged from late teens to early twenties. Ultrasonographic investigation of the liver is not mandatory unless biliary obstruction is suspected, for instance if there is a relatively higher increase in alkaline phosphatase than in transaminases. Liver biopsy is usually not indicated.
MANAGEMENT In a patient on anti-TB drugs who develops signs of liver damage, one should always suspect anti-TB drugs to be responsible, unless convincing evidence of another explanation is found, and the offending drugs must be stopped. In practice, the important drugs
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to stop are pyrazinamide, isoniazid and rifampicin. Ethambutol may rarely cause hepatitis, but streptomycin is unlikely to do so. Thus, it is considered safe to let the patient continue on streptomycin and ethambutol. Among second-line drugs, ethionamide, paraaminosalicylic acid (PAS) and, less often, fluoroquinolones may cause hepatitis. As symptoms may precede serious liver damage by only a few days, it is important that severe hepatotoxicity be recognized as soon as possible; delay in stopping anti-TB drugs increases the risk of fatal outcome.9,10 There are various strategies for restarting treatment, both with regards to timing and drug selection. Once anti-TB drugs have been stopped, efforts should be made to rule out other causes of hepatitis including alcohol and viral hepatitis.
Timing of reintroduction of antituberculosis drugs If blood tests for assessing the liver function are available, reintroduction of anti-TB drugs can be started as soon as the liver tests have been normalized. However, in many high-burden settings, laboratory testing facilities are scarce and liver function testing may not be possible. In these situations, treatment will be guided by the symptoms. Usually, jaundice and other symptoms will subside in 1–2 weeks. The WHO recommends that the regular antiTB drugs be reintroduced 2 weeks after jaundice has disappeared.1 Temporary regimen before reintroduction of original antituberculosis drugs If the patient is severely ill, the patient may die if left without treatment until the hepatitis resolves. In such patients, treatment should be given with two or three of the least hepatotoxic drugs, which are streptomycin, ethambutol and ofloxacin.5 This regimen would be sufficient to control the infection temporarily, while at the same time having a reasonably low risk of selecting for resistant strains of TB bacilli. If the patient does not have jaundice, but only malaise and nausea, rifampicin may be continued. Choice of antituberculosis drugs after jaundice/ hepatitis The general principle is, once the drug-induced hepatitis has resolved, to introduce the same anti-TB drugs one at a time. Frequently it is possible to introduce all suspected offending drugs without recurrence of hepatitis. While rifampicin probably is the least likely cause of hepatitis, it is commonplace to start isoniazid first. One reason for this is that rifampicin frequently causes asymptomatic jaundice, which, if it were to occur, might be interpreted as recurrence of hepatitis and thus would further delay the introduction of effective chemotherapy with isoniazid. When re-starting isoniazid, it first should be given at a reduced dose at 50 mg daily. Provided there is no recurrence of symptoms or signs of deterioration, the dose can be doubled to 100 mg daily on the fourth day, then doubled again to 200 mg on the seventh, and then the full dose is given from the 14th day.5,25 The patient should then be monitored for 1 week, and, if the drug is well tolerated, one may then proceed to reintroduce rifampicin. If isoniazid and rifampicin are well tolerated for another week, one may consider reintroducing pyrazinamide. However, if there has been hepatitis with frank jaundice, the WHO advises avoiding pyrazinamide reintroduction. If pyrazinamide has already been given for 2 months prior to stopping the regimen, i.e. up to the completion of the intensive phase, there is no need to reinstate this drug anyway, as it is not used for continuation phase treatment. Asymptomatic jaundice without evidence of hepatitis is most
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often due to rifampicin. If both pyrazinamide and rifampicin need to be avoided, one may use a prolonged regimen with 2SHE/10HE.
COMPLICATIONS Among patients who experience elevated transaminases, approximately one-tenth may proceed to severe hepatotoxicity and liver failure if the offending drug is not stopped. Furthermore, onetenth of patients with liver failure may die if liver transplantation is not available.
PREVENTION Clinical monitoring with at least monthly questioning on hepatotoxicity-related symptoms is advised. If available, it is recommended to perform blood tests for transaminases at baseline for patients with certain risk factors for hepatotoxicity including known pre-existing liver disorder, a history of viral hepatitis or HIV infection; for pregnant or postpartum (first 3 months) women; and for people who consume alcohol regularly. Age (> 35years) is no longer considered an indication for baseline transaminase testing.28 It is recommended that patients who develop hepatotoxicity be followed up with blood tests until transaminases are normalized. Again, in many settings these blood tests are not available and patients are managed based on symptoms and clinical findings. If a patient has had hepatitis and an offending drug has been identified, this should be documented in the patient record and the patient should be properly informed about this, preferably in writing, and should not be given this drug again.
ACUTE RENAL FAILURE BACKGROUND AND EPIDEMIOLOGY Renal failure is not a frequent side effect of anti-TB treatment, but a serious one if it occurs. Symptoms include reduced urine production, oedema, hypertension, itching and constitutional symptoms such as fatigue.
DIFFERENTIAL DIAGNOSIS Among anti-TB drugs, rifampicin is the most likely cause of renal failure. If the patient is dehydrated or very sick, pre-renal causes (i.e. low perfusion) of kidney failure must be ruled out. Haemolytic anaemia, glomerulonephritis and interstitial nephritis may cause renal failure, most often related to rifampicin. Streptomycin is less nephrotoxic than other aminoglycosides, but may still cause renal failure. Among the second-line drugs, kanamycin, amikacin and capreomycin are likely culprits.
MANAGEMENT In a very sick or dehydrated person, pre-renal kidney failure may ensue, and appropriate rehydration is mandatory for such patients. Among the TB drugs, rifampicin is the most likely drug causing renal failure, and should be discontinued and not given again to that patient. Other drugs which may cause renal failure are streptomycin and, among second-line drugs, kanamycin, amikacin and capreomycin. Ethambutol and streptomycin are excreted almost
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Management of side effects of antituberculosis drugs
exclusively through the kidneys. Thus, if renal failure ensues, doses of these drugs must be reduced accordingly. In the settings where facilities are not available to measure kidney function by laboratory tests, it is recommended that the dose of streptomycin be halved if urinary output is reduced. If offending drugs are not stopped reasonably quickly, chronic renal failure may result.
PREVENTION Diabetes or pre-existing renal disease may increase the risk of nephrotoxicity. Potentially nephrotoxic drugs may still be used, but patients must be monitored more closely. In a high-income country regular blood tests for renal function will be performed, for instance with monthly intervals. In most TB-endemic countries this is not possible and, instead, patients should be followed clinically, and asked to ensure sufficient fluid intake and to report if urinary output decreases significantly.
HAEMATOLOGICAL SIDE EFFECTS BACKGROUND AND EPIDEMIOLOGY Haematological side effects account for only approximately 10% of side effects of anti-TB treatment. However, once they occur, they are relatively severe and blood dyscrasias may be responsible for as many as 40% of side effect-related fatalities on TB treatment.5,29 Such blood dyscrasias may be caused by any one of the primary anti-TB drugs and present with leucopenia, thrombocytopenia or anaemia. In clinical practice, it may be very difficult to find out which drug causes the problem. All first-line anti-TB agents may be responsible. In patients receiving thioacetazone-containing regimens, this drug may be the most likely to cause blood dyscrasias. Isolated thrombocytopenia is usually caused by rifampicin. In other cases, isoniazid may be considered as a potential cause. Haemolytic anaemia and leucopenia may be due to isoniazid, and should be managed by discontinuing isoniazid. Steroids may help reverse haemolysis. Sideroblastic anaemia due to isoniazid toxicity can be reversed by treatment with pyridoxine. Less frequently, red cell aplasia or neutropenia, eosinophilia and thrombocytopenia may respond to discontinuation of isoniazid. Among the second-line drugs, linezolid is known to frequently cause myelosuppression. Other causes of anaemia, such as malaria, bleeding, iron deficiency and malnutrition, should be considered. Similarly, other causes of thrombocytopenia and leucopenia should be excluded, although this may be practically difficult.
MANAGEMENT In principle, the drug responsible for the haematological side effect should be discontinued, and never given again. However, in practice, it may be very difficult to find out which drug is actually responsible.
PREVENTION There are few primary prophylactic measures to take against haematological side effects of anti-TB drugs, although avoiding thioacetazone may reduce the risk. Instead, emphasis should be on preventing complications of these side effects. Foremost, proper clinical monitoring is useful in that it will allow early discontinuation of the offending drug. Furthermore, fatalities may be prevented by appropriate care for
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patients, including aggressive treatment with appropriate antimicrobials for neutropenic patients with sepsis and availability of safe blood transfusions for severely anaemic patients.
VISUAL IMPAIRMENT BACKGROUND AND EPIDEMIOLOGY Shortly after the discovery of ethambutol in 1961,30 it was observed that almost half of patients receiving this drug in the proposed dose of 60–100 mg/kg bodyweight developed blindness termed ‘toxic amblyopia’.31 Optic neuritis was found to be dose related and reversible if ethambutol was discontinued in time. There has been justified caution regarding the use of ethambutol in young children since ocular side effects may go undetected in children who may not be able to communicate this problem. However, a recent review of the literature found ethambutol to be relatively safe in children at the usually recommended doses.32
PATHOGENESIS Ethambutol causes an optic neuritis, and it has been hypothesized that the chelating properties of ethambutol are important in the pathogenesis. The risk of optic neuritis increases with high dose and long duration of treatment. Most cases of ethambutol-induced optic neuritis occur when the dose has exceeded 25 mg/kg bodyweight daily, and it has been shown that this side effect is infrequent if one does not exceed the WHO-recommended doses. There are reports, however, of such side effects in people who have received lower doses as well.
DIFFERENTIAL DIAGNOSIS Visual impairment may have a number of common causes, which need to be excluded. However, if visual impairment occurs on anti-TB treatment, ethambutol should always be considered as the most likely cause. There are rare reports of optic neuritis attributed to streptomycin and isoniazid, but, for practical purposes, ethambutol is responsible in most cases. Among second-line anti-TB drugs, linezolid has been reported to cause optic neuropathy. If the patient has HIV infection, cytomegalovirus retinitis should also be considered, and it is advisable to examine the patient with ophthalmoscopy. Other toxic substances may also produce visual impairment, particularly methanol poisoning.
INVESTIGATIONS Unfortunately, ophthalmoscopic examination does not help in detecting optic toxicity in the early stage. In the beginning, the fundi will appear normal, and only at a later stage are there signs of atrophy. Thus, the diagnosis must be based on clinical suspicion and testing of visual acuity if a patient experiences visual impairment on anti-TB treatment. In the rarer case of isoniazid toxicity to the optic nerve one may detect swelling of the optic nerve on fundoscopy.
MANAGEMENT Whenever a patient on an anti-TB treatment regimen containing ethambutol reports visual impairment, ethambutol should be suspected and stopped immediately. If another certain cause of visual impairment is demonstrated, one may consider continuing ethambutol, but the author’s opinion is that it would be safer to stop
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ethambutol since one cannot reliably rule out its implication in visual impairment. If the patient is in the intensive phase, on a regimen with isoniazid, rifampicin, pyrazinamide and ethambutol, ethambutol should be stopped; it is not strictly mandatory to replace ethambutol with another drug, since ethambutol is considered a companion drug safeguarding against resistance development, and a three-drug regimen with isoniazid, rifampicin and pyrazinamide generally would be sufficient to cure the patient provided drug resistance levels are low. If streptomycin is available under the programme conditions and can be given by safe injections, it may be added to the regimen, particularly if there is the possibility of resistance emerging. If visual impairment occurs in the continuation phase on an ethambutol regimen, it is mandatory to replace ethambutol with another drug, since it is grave malpractice to give monotherapy with a single drug to any TB patient. In most cases, it would be convenient to replace ethambutol with rifampicin although in some settings thioacetazone with isoniazid may be an alternative in areas with low prevalence of HIV infection or if the patient is known to be non-HIV-infected. Permanent blindness or visual impairment may result if ethambutol is not stopped in patients who experience optic toxicity. This scenario is particularly challenging to discover in time in children who may be unable to communicate visual impairment to their caregivers. Using fixed-dose combination tablets may reduce the risk of incorrect dosing.
PERIPHERAL NEUROPATHY BACKGROUND AND EPIDEMIOLOGY Along with hepatotoxicity, peripheral neuropathy is the other major side effect of isoniazid treatment. A high dose of isoniazid, as in intermittent regimens, increases the risk of peripheral neuropathy. Peripheral neuropathy is more common during pregnancy, malnutrition, alcohol abuse, diabetes or liver disease. Peripheral neuropathy is a particularly complicated problem in patients with HIV/TB coinfection; it can be caused by anti-TB drugs, foremost isoniazid, by antiretroviral drugs, particularly stavudine, but also by other nucleoside reverse transcriptase inhibitors (NRTIs), by HIV infection itself or by a number of accompanying conditions such as malnutrition and alcohol abuse. In many circumstances the neuropathy can be attributed to a mixture of these factors. Although less frequently than isoniazid, ethambutol and streptomycin may also cause peripheral neuropathy, as may the second-line drugs, particularly linezolid, but also cycloserine, fluoroquinolones, kanamycin, amikacin, capreomycin and ethionamide.
PATHOGENESIS Isoniazid causes increased excretion of pyridoxine (vitamin B6) and the ensuing pyridoxine deficiency in turn results in a neuropathy, which can be combined sensorimotor. Deficiencies in other B vitamins such as thiamine (vitamin B1) and niacin (vitamin B3) can also result in neuropathy but are not linked to isoniazid therapy. Alcohol abuse is associated with peripheral neuropathy. While alcohol probably has a direct toxic effect on peripheral nerves, alcohol is frequently associated with malnourishment and may thus precipitate neuropathy caused by pyridoxine deficiency.
DIFFERENTIAL DIAGNOSIS Loss of cutaneous sensitivity may be caused by anti-TB drugs and antiretroviral drugs, particularly stavudine and other NRTIs, but
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may also be caused by nutritional deficiencies or diabetic neuropathy. Nerve entrapment syndromes as occurring in hypothyroidism, another side effect of anti-TB drugs, can be mistaken for isoniazidinduced neuropathy.
MANAGEMENT Pyridoxine should be given at a dose of 100 mg daily, i.e. 10 times the prophylactic dose, or even up to 200 mg daily. Paracetamol and NSAIDs may reduce the symptoms. If pain is persistent and intractable an antidepressant may be added. In most cases, it should not be necessary to stop anti-TB drugs. However, if not compromising the anti-TB treatment, one may consider lowering the doses of the suspected offending drug, or stopping it altogether. Attention should be paid to nutritional issues, as malnutrition is particularly common in both TB and HIV patients. Sometimes, the poverty of the patient limits the opportunities to intervene on the dietary issues, since foods which contain pyridoxine include more expensive ones such as meat from chicken, cows, fish and other animals, as well as liver. However, some inexpensive foodstuffs such as lentils and brown beans also contain pyridoxine. Alcohol consumption should be discouraged, at least until the end of treatment. Permanent peripheral nerve damage may occur although some patients’ symptoms improve when they stop treatment.
PREVENTION Giving 10 mg of pyridoxine daily can prevent peripheral neuropathy. Pyridoxine is inexpensive and has virtually no side effects. If malnutrition is common in the area, this increases the importance of pyridoxine supplementation. Special attention must be given to this issue in HIV coinfected patients, as they are particularly prone to this side effect.
SEIZURES BACKGROUND AND EPIDEMIOLOGY Among the first-line drugs, isoniazid is the likely cause of seizures. Among the second-line drugs, cycloserine is a more likely culprit, but fluoroquinolones may also be responsible.
SYMPTOMS AND SIGNS Seizures caused by isoniazid are frequently of generalized grand mal type and may result in status epilepticus.33 In the case of acute toxicity or isoniazid overdose, the seizure may be preceded by nausea, vomiting, rash, fever, ataxia, slurring of speech, peripheral neuritis, dizziness and stupor. On clinical examination, there may be additional signs of pyridoxine deficiency such as peripheral sensory loss or even paresis.
DIFFERENTIAL DIAGNOSIS The most important differential diagnoses for seizures may be preexisting convulsive disorder or a direct effect of a tuberculoma. In patients with HIV coinfections, the possibility of cerebral toxoplasmosis, cryptococcal meningitis and intracerebral lymphoma must be considered.
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Management of side effects of antituberculosis drugs
INVESTIGATIONS Clinical assessment including neurological testing may give hints as to other causes of seizures or accompanying features of pyridoxine deficiency such as peripheral neuropathy. Electroencephalogram (EEG) can help evaluate the patient for epilepsy. If available, imaging techniques such as computed tomography or magnetic resonance imaging can be used to rule out intracranial causes of the seizure, such as tuberculoma or toxoplasmosis.
MANAGEMENT In the case of overdose with isoniazid, the seizure may be refractory to standard anticonvulsant therapy, and intravenous pyridoxine may be the only effective treatment.34 The agent suspect of causing the seizures should be stopped immediately, i.e. isoniazid in a patient on first-line treatment, and cycloserine or fluoroquinolones in the case of second-line treatment. The anticonvulsant therapy should be continued until the end of anti-TB treatment with the offending drug. However, supplement with pyridoxine may be even more important, and preferably at a higher dose (200 mg once daily). If essential to the regimen used, and if no other appropriate alternatives are available, the offending drug may be reinstated. However, it may be wise to give a lower dose. Pyridoxine may prevent both seizures and peripheral neuropathy. This vitamin is cheap and without significant side effects. Thus, it may be wise to give pyridoxine routinely to all patients on anti-TB treatment. Pre-existing convulsive disorder may increase the risk of seizures when a patient is put on anti-TB treatment. However, as long as the seizures are well controlled, this is no obstacle to commence treatment.
VESTIBULO-COCHLEAR TOXICITY
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aminoglycosides appear to take a long time to be cleared from the inner ear.36 Aminoglycoside-induced hearing loss is more or less irreversible, although some partial recovery of hearing may occur, particularly in the early phase of high-frequency hearing loss.37 There is evidence that mammalian vestibular hair cells can regenerate, although this seems not to be the case for hair cells in the cochlear system.38,39 In contrast to nephrotoxicity, aminoglycoside ototoxicity appears more related to total dose.40 A recent prospective study found no difference in vestibular and cochlear toxicity with once daily or thrice-weekly dosing of streptomycin and other aminoglycosides.41 Cochlear damage was associated with older age and increasing cumulative dose given.
SYMPTOMS AND SIGNS Many people will not notice or be bothered by a hearing loss involving the higher frequencies. However, when it involves significant reduction in hearing in the speech frequencies, most will feel their hearing is compromised. Hearing loss due to aminoglycoside toxicity is sensory type, and usually the highest frequencies are the first affected. Those are also the frequencies least likely to be noticed by the patient. Often there is associated tinnitus. Most cases have bilateral, symmetrical hearing loss, but it can be asymmetrical or unilateral. Typically the patient will experience the loudness recruitment phenomenon; it becomes increasingly difficult to hear low sounds, while loud sounds may appear even louder than normal as the dynamic range of the ear is compressed. The timing of the hearing loss is variable, with some experiencing hearing loss after a single dose, and others weeks or months after completed treatment. Vestibular toxicity may cause imbalance, which usually is worse in darkness, ataxia and visual disturbance. Oscillopsia, i.e. inability of the eyes to maintain an image of a steady horizon, may occur when the head is moving. Positional nystagmus may be present early before other symptoms become significant.
BACKGROUND AND EPIDEMIOLOGY
DIFFERENTIAL DIAGNOSIS
The aminoglycosides are known for relatively frequent adverse effects on the cochlear and vestibular apparatus.35 Streptomycin has been abandoned from the first-line regimens in many countries due to this consideration, emerging resistance and risk of transmitting other infections by unsafe injections. Among the commonly used anti-TB drugs, streptomycin is the first agent to be suspected of causing hearing or balance problems. Other aminoglycosides (amikacin, kanamycin) or the polypeptide capreomycin may cause vestibulo-cochlear loss in the same way as streptomycin. The cochlear nerve is affected by aminoglycosides in the same way as the auditory nerve. If a patient develops dizziness, vertigo, nystagmus or ataxia, side effects of streptomycin, or any other aminoglycoside drug, must be suspected. While streptomycin and capreomycin tend to cause vestibular damage, the second-line anti-TB aminoglycosides amikacin and kanamycin tend to cause cochlear damage.
After excluding innocent and common conditions such as obliterating earwax or infection in the middle ear or external ear, drug toxicity should be suspected; streptomycin is the most likely cause of hearing loss among the anti-TB drugs. Dizziness or vertigo can also have a number of different causes, including dehydration, anaemia, various neurological conditions and cardiac and cerebrovascular disease. If no other obvious cause can be found for vertigo in a patient taking a streptomycin-based regimen, this drug must be stopped immediately.
PATHOGENESIS Streptomycin and other aminoglycosides exert their toxicity on the hair cells in the cochlea, causing sensorineural hearing loss, and
INVESTIGATIONS Hearing loss should be documented and compared with baseline hearing by audiometry. Investigations with audiometric equipment will first reveal reduced hearing in the high frequencies, i.e. higher than 4000 Hz. Sometimes, a rule of thumb is used, delineating that, if a patient can hear normal conversation with each ear separately at a distance of 6 m (20 ft), hearing can be assumed to be normal. If the hearing distance for normal conversation is less than that, one should be alert to the possibility of hearing loss, and if it is less than 3.5 m (12 ft), there is definitely some degree of hearing loss.42
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While this measure for hearing loss can be useful for a rough estimate, it is quite crude, and we discourage over-reliance on it. Particularly, it will fail to identify those with early highfrequency hearing loss, since speech occurs at lower frequencies. Thus, if the patient insists that his hearing has deteriorated, it is wise to assume that he is correct, and, if available, there should be a low threshold to refer the patient to audiometric testing. A patient with imbalance or ataxia can be clinically examined for evidence of vestibular dysfunction by anamnestic hints of oscillopsia observation for nystagmus, Romberg’s test and other vestibular tests, including provocation of vestibular symptoms by positional changes.
MANAGEMENT If a patient on a streptomycin-containing anti-TB regimen experiences hearing loss, tinnitus, vertigo, imbalance or ataxia, streptomycin, or any other aminoglycoside, should be stopped immediately and assessed for vestibulo-cochlear toxicity. Streptomycin should be replaced with ethambutol during the intensive phase of first-line treatment.
PREVENTION The aminoglycoside vestibulo-cochlear toxicity is usually dosedependent, and increased age increases the risk of this side effect. Giving the correct dose is one step of prevention. The risk of vestibulo-cochlear toxicity increases with concomitant treatment with other potential ototoxic agents, with renal insufficiency, with known pre-existing hearing loss and with a family history of such a side effect. It may be better to opt for an alternative to streptomycin in these cases, or to be highly alert with regards to ensuing vestibulo-cochlear toxicity.
Careful history-taking from the patient and relatives, if possible, as well as observation of the patient, may be enough to establish the nature of the depressive condition.
MANAGEMENT In the case of reactive depression, a supportive attitude from health workers is important. Considering the great number of people dying from TB and HIV/TB coinfection it is not surprising that many people think of TB as incurable. Thus, health workers must make efforts to ensure that the patients understand that they can be cured from TB despite underlying HIV. Counselling may be done individually or in groups; the latter may have the advantage of patients supporting each other and feeling less isolated. Even when depression is a side effect of the anti-TB drugs general and social support for the patient is important. If not compromising the regimen, one may consider lowering the dose of the suspected offending drugs (i.e. isoniazid, or among second-line drugs cycloserine, fluoroquinolones or ethionamide). It may be necessary to discontinue the offending drug completely, but careful attention is needed to ensure that the alternative regimen is appropriate. Antidepressant medication may be necessary. If the patient is suspected to be suicidal or homicidal, admission to hospital may be necessary for compulsory treatment. If a patient on anti-TB treatment presents with symptoms of psychosis, the suspected offending drug should be stopped. Antipsychotic medication, such as haloperidol, should be started. If psychotic symptoms resolve upon withdrawal of the suspected offending drug, this is an indication that the symptoms are a side effect. An attempt should be made to provide an appropriate alternative anti-TB regimen. If not possible and the given dose of the drug was on the higher side, one may attempt to lower the dose and reinstate the same drug.
PREVENTION
DEPRESSION AND PSYCHOSIS BACKGROUND AND EPIDEMIOLOGY Tuberculosis disproportionally affects poor people, from both a global and individual perspective. Additionally, many TB patients may recently have been diagnosed with HIV infection. Thus, reactive depression to chronic illness and poverty is probably a frequent cause of depression in TB patients. However, a number of anti-TB drugs may cause depression and sometimes psychosis. Patients with serious psychiatric disease are among the most difficult patients to treat successfully for chronic infections, be it TB or HIV. Cycloserine is the most likely drug to cause depression or psychosis. However, isoniazid, ethionamide and amoxicillin-calvulanate are also capable of causing depression or psychosis, and psychosis may also be precipitated by fluoroquinolones.
A supportive attitude and good counselling of the patient with regard to the treatment and the fact that the disease is curable may help prevent reactive depression. Attention to correct dosing of medicines may prevent side effects. Pre-existing history of psychiatric disease may increase the likelihood of psychiatric symptoms ensuing while on anti-TB treatment, but even patients with active psychiatric manifestations must be treated for TB. Unless no alternatives exist, one should probably avoid cycloserine, and possibly fluoroquinolones and ethionamide in patients with pre-existing psychotic symptoms. Isoniazid is such an important drug in the treatment of drug-susceptible TB that it is advised to attempt treatment that includes this drug in patients with preexisting psychiatric disease and to continue the drug unless psychotic symptoms worsen.
OTHER SIDE EFFECTS
DIFFERENTIAL DIAGNOSIS
ORANGE OR RED DISCOLORATION OF BODY FLUIDS
The main differential diagnoses to drug-induced depression are pre-existing depressive conditions such as bipolar affective disorder and reactive depression due to poverty, chronic disease and social problems.
It is common for various body fluids to acquire an orange or reddish colour during rifampicin treatment. The red coloration of the urine is not dangerous and anti-TB treatment should not be stopped. Patients should be informed about this effect of rifampicin
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before commencing treatment. Patients who are wearing contact lenses should be warned that red coloration of the tear fluid may discolour lenses. It may be preferable to wear glasses instead of lenses during rifampicin therapy.
66
INFLUENZA-LIKE SYNDROME Rifampicin may cause an influenza-like syndrome with shivering, malaise, headache and bone pains. This is more common with intermittent treatment. Symptomatic treatment may include paracetamol or NSAIDs.
INJECTION-RELATED SIDE EFFECTS The most serious side effect of injections of streptomycin or other drugs is iatrogenic spread of infectious diseases such as HIV in cases where needles are reused and not properly sterilized. The WHO estimates that 2.5% of new HIV infections are caused by unsafe injections. Streptomycin injections are among the commonest injections given in low-income countries and TB patients have a high rate of HIV coinfection; therefore it is possible that streptomycin is implicated in the iatrogenic transfer of HIV. Injections may lead to local skin or soft-tissue infection, such as cellulitis or abscess formation. Local irritation and pain at the injection site is a frequent complaint from patients treated with streptomycin or other injectable drugs.
HYPOTHYROIDISM The second-line drugs PAS and ethionamide can both cause hypothyroidism, and particularly if given in combination. A high degree of suspicion is necessary to diagnose hypothyroidism in TB patients, since many symptoms of hypothyroidism are common symptoms of TB, such as fatigue and loss of appetite, or side effects of TB drugs, such as muscle and joint pain, paraesthesia, peripheral nerve dysfunction, impaired hearing and blurred vision. The mental symptoms of hypothyroidism, such as lethargy, sleepiness, depression, emotional lability and forgetfulness, may also easily be attributed to TB or drug side effects. The typical weight gain of hypothyroidism may not be evident in a TB patient since successful treatment often causes weight gain. Cold intolerance may be interpreted as fever. Menstrual disturbance is regularly seen in severe chronic infection. Dry skin and hair changes may be attributed to malnutrition, and constipation may be considered a side effect of rifampicin. If resources are available one may consider screening patients on PAS or ethionamide with blood tests for thyroid function. If hypothyroidism is diagnosed, one should give substitution therapy with thyroxin tablets, and treatment should be guided by periodical measurement of thyroid-stimulating hormone. The hypothyroidism caused by PAS/ethionamide is reversible upon discontinuation of treatment, and it is not generally necessary to stop the offending anti-TB agents unless other equally effective anti-TB drugs are readily available.
CONFUSION Confusion may be a manifestation of a number of different conditions. However, when a patient on anti-TB treatment presents with confusion, one must suspect acute liver failure (see above). The presence of jaundice on clinical examination supports this diagnosis. In patients with underlying HIV infection, other central nervous manifestations, particularly cryptococcal meningitis, cerebral toxoplasmosis and HIV encephalopathy, should be considered. In a patient who develops confusion on anti-TB treatment, the anti-TB drugs should be stopped until the reason for the confusion is established.
RESPIRATORY AND SHOCK SYNDROME On rare occasions, rifampicin may cause shortness of breath, wheezing, hypotension and collapse. This is more common with intermittent treatment. Antituberculosis drugs must be stopped immediately. Corticosteroids may be used. Rifampicin should never be given to the patient again.
ACUTE HAEMOLYTIC ANAEMIA AND RENAL FAILURE This is more common with rifampicin intermittent treatment. Antituberculosis drugs should be stopped immediately, and rifampicin should never be used again.
INTERACTIONS BETWEEN RIFAMPICIN AND OTHER DRUGS Rifampicin has a number of clinically important interactions with other drugs. Antacids containing aluminium, calcium and magnesium reduce the uptake of rifampicin by approximately one-third. Patients should be informed about this, since antacids are commonly used and readily available without prescriptions. Rifampicin stimulates increased production of liver enzymes, which in turn leads to increased inactivation of other drugs. Most importantly, rifampicin leads to a lowering of the serum levels of a number of antiretroviral drugs used for the treatment of HIV. Furthermore, rifampicin lowers the serum levels of oestrogen used in contraceptive pills. Thus, it is mandatory to inform women of childbearing age about this. Depot injection contraceptives can be used but should be given at shorter intervals, i.e. 10 weeks instead of 12 weeks. The anticoagulant warfarin is also affected by rifampicin, and doses must usually be increased under guidance of blood testing for prothrombin time/INR. Other drugs which develop reduced serum concentrations as a result of this mechanism include oral diabetic drugs, digoxin, dapsone, opiates and phenobarbitone.
MANAGEMENT OF SIDE EFFECTS USING FIXED-DOSE COMBINATION ANTITUBERCULOSIS DRUGS While the majority of TB patients may receive treatment in the form of single-drug formulations,43 the WHO recommends the use of quality fixed-dose combination tablets (FDCs) of anti-TB drugs with the rationale that they simplify procurement, prescription and ingestion of TB drugs, and are thought to increase compliance with treatment.44 The underlying important notion is that, by facilitating compliance with treatment and making monotherapy virtually impossible, FDCs may contribute to reducing the emergence of drug-resistant strains of TB bacilli.45 Circumstantial evidence from countries using FDCs at programme level indicates that long-term use of quality FDCs is associated with low levels of anti-TB drug resistance. However, one particular concern regarding the use of FDCs is related to how to manage treatment in the event of side effects of treatment.
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There has been speculation as to whether giving anti-TB treatment as FDCs would have an impact on the occurrence of side effects. Available evidence indicates that using FDCs does not result in more side effects than single-drug formulations.46,47 A report from Indonesia comparing the use of a four-drug FDCbased regimen with a single-drug regimen containing the same drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) showed that, while treatment results were excellent in both groups, the group on a single-drug regimen had more side effects, particularly gastrointestinal upset and arthralgia. This difference may be explained by a higher dose of pyrazinamide in the single-drugbased regimen (1500 versus 1200 mg daily).48
REFERENCES 1. Blanc L, Chaulet P, Espinal M, et al. Treatment of Tuberculosis: Guidelines for National Programmes (Chapter 4 revised 2004). WHO/CDS/TB/2003.313. Geneva: World Health Organization; 2003. 2. Grange JM, Zumla A. Antituberculosis agents. In: Armstrong D, Cohen J (eds). Infectious Diseases, vol. 2. London: Richard Furn, 1999: 7.13.14–16. 3. Grange JM, Zumla A. Tuberculosis. In: Cook GC, Zumla A (eds). Manson’s Tropical Diseases, vol. 1, 21st edn. London: WB Saunders, 2003: 1036–1045. 4. Teleman MD, Chee CB, Earnest A, et al. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore. Int J Tuberc Lung Dis 2002;6(8):699–705. 5. Rieder HL. Interventions for Tuberculosis Control and Elimination. Paris: International Union Against Tuberculosis and Lung Disease (IUATLD), 2002. 6. Nunn P, Kibuga D, Gathua S, et al. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991;337(8742):627–630. 7. Ormerod LP, Horsfield N. Frequency and type of reactions to antituberculosis drugs: observations in routine treatment. Tuber Lung Dis 1996;77(1):37–42. 8. Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167(11):1472–1477. 9. Thompson NP, Caplin ME, Hamilton MI, et al. Anti-tuberculosis medication and the liver: dangers and recommendations in management. Eur Respir J 1995;8(8):1384–1388. 10. Vidal Pla R, de Gracia X, Gallego B, et al. [The hepatotoxicity of tuberculosis treatment]. Med Clin (Barc) 1991;97(13):481–485. [In Spanish] 11. Sharma SK, Balamurugan A, Saha PK, et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002;166(7):916–919. 12. Pande JN, Singh SP, Khilnani GC, et al. Risk factors for hepatotoxicity from antituberculosis drugs: a casecontrol study. Thorax 1996;51(2):132–136. 13. Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002;35(4):883–889. 14. Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazidrelated hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis 1978;117(6):991–1001. 15. Fernandez-Villar A, Sopena B, Vazquez R, et al. Isoniazid hepatotoxicity among drug users: the role of hepatitis C. Clin Infect Dis 2003;36(3):293–298. 16. Devoto FM, Gonzalez C, Iannantuono R, et al. Risk factors for hepatotoxicity induced by antituberculosis drugs. Acta Physiol Pharmacol Ther Latinoam 1997; 47(4):197–202. 17. Gilroy SA, Rogers MA, Blair DC. Treatment of latent tuberculosis infection in patients aged > or ¼35 years. Clin Infect Dis 2000;31(3):826–829.
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While using FDC anti-TB drugs is not associated with increased risk of side effects, side effects may still occur, and, in those few cases, management gets more complicated. If the side effect in a patient on FDCs is serious enough to warrant the discontinuation of one or more drugs, it is recommended that patients be referred to a TB care institution where stock of single-drug formulations should be kept.49,50 For national TB programmes, the authors recommend that, until more experience is gained, approximately 5% of TB drugs should be ordered as single-drug formulations, in order to allow for proper treatment of patients with side effects.49
18. Wong WM, Wu PC, Yuen MF, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000; 31(1):201–206. 19. Ungo JR, Jones D, Ashkin D, et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998;157(6 Pt 1):1871–1876. 20. Gordin FM, Cohn DL, Matts JP, et al. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons? Clin Infect Dis 2004;39(4):561–565. 21. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998;53(7):536–548. 22. Scharer L, Smith JP. Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 1969;71(6):1113–1120. 23. Garibaldi RA, Drusin RE, Ferebee SH, et al. Isoniazid-associated hepatitis. Report of an outbreak. Am Rev Respir Dis 1972;106(3):357–365. 24. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99(2):465–471. 25. Singh J, Garg PK, Tandon RK. Hepatotoxicity due to antituberculosis therapy. Clinical profile and reintroduction of therapy. J Clin Gastroenterol 1996; 22(3):211–214. 26. Spratt D, Kaplan MM. Jaundice. In: Kasper DL, Braunwald E, Fauci A, et al., (eds). Harrison’s Internal Medicine, vol. 1, 16th edn. New York: McGraw-Hill, 2005: 238–243. 27. Cook GC. Tropical gastroenterological problems. In: Cook GC, Zumla A (eds). Manson’s Tropical Diseases, vol. 1, 21st edn. London: Saunders, 2003: 111–147. 28. Wallace RJ Jr, Griffith DE. Antimycobacterial agents. In: Kasper DL, Braunwald E, Fauci A, et al., (eds). Harrison’s Internal Medicine, vol. 1, 16th edn. New York: McGraw-Hill, 2005: 946–953. 29. Holdiness MR. A review of blood dyscrasias induced by the antituberculosis drugs. Tubercle 1987;68(4): 301–309. 30. Thomas JP, Baughn CO, Wilkinson RG, et al. A new synthetic compound with antituberculous activity in mice: ethambutol (dextro-2,20 (ethylenediimino)-di-l-butanol). Am Rev Respir Dis 1961;83:891–893. 31. Carr RE, Henkind P. Ocular manifestations of ethambutol, Toxic amblyopia after administration of an experimental antituberculous drug. Arch Ophthalmol 1962;67:566–571. 32. Donald P, Maher D, Maritz S, et al. Ethambutol Efficacy and Toxicity: Literature Review and Recommendations for Daily and Intermittent Dosage in Children. WHO/HTM/TB/2006.365. Geneva: World Health Organization, 2006. 33. Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and review of the literature. Intensive Care Med 1995;21(8):641–644. 34. Morrow LE, Wear RE, Schuller D, et al. Acute isoniazid toxicity and the need for adequate pyridoxine supplies. Pharmacotherapy 2006;26(10): 1529–1532.
35. Kahlmeter G, Dahlager JI. Aminoglycoside toxicity a review of clinical studies published between 1975 and 1982. J Antimicrob Chemother 1984;13(Suppl A): 9–22. 36. Israel KS, Welles JS, Black HR. Aspects of the pharmacology and toxicology of tobramycin in animals and humans. J Infect Dis 1976;134(Suppl): S97–103. 37. Symonds JM. Aminoglycoside ototoxicity. J Antimicrob Chemother 1978;4(3):199–201. 38. Forge A, Li L, Corwin JT, et al. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear. Science 1993;259(5101):1616–1619. 39. Warchol ME, Lambert PR, Goldstein BJ, et al. Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans. Science 1993;259(5101):1619–1622. 40. Freeman CD, Nicolau DP, Belliveau PP, et al. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 1997;39(6):677–686. 41. Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis 2004;38(11):1538–1544. 42. Hutchison R. Hutchison’s Clinical Methods, 19th edn. London: Bailliere-Tindale, 1989. 43. Norval PY, Blomberg B, Kitler ME, et al. Estimate of the global market for rifampicin-containing fixed-dose combination tablets. Int J Tuberc Lung Dis 1999;3(11 Suppl 3):S292–300; discussion S317–221. 44. Blomberg B, Spinaci S, Fourie B, et al. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 2001;79(1):61–68. 45. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998;2(1):10–15. 46. Chaulet P, Boulahbal F. [Clinical trial of a combination of three drugs in fixed proportions in the treatment of tuberculosis. Groupe de Travail sur la Chimiotherapie de la Tuberculose]. Tuber Lung Dis 1995;76(5):407–412. [In French] 47. Hong Kong Chest Service/British Medical Research Council. Acceptability, compliance, and adverse reactions when isoniazid, rifampin, and pyrazinamide are given as a combined formulation or separately during three-times-weekly antituberculosis chemotherapy. Am Rev Respir Dis 1989;140(6): 1618–1622. 48. Gravendeel JM, Asapa AS, Becx-Bleumink M, et al. Preliminary results of an operational field study to compare side-effects, complaints and treatment results of a single-drug short-course regimen with a fourdrug fixed-dose combination (4FDC) regimen in South Sulawesi, Republic of Indonesia. Tuberculosis (Edinb) 2003;83(1–3):183–186. 49. Blomberg B, Fourie B. Fixed-dose combination drugs for tuberculosis: application in standardised treatment regimens. Drugs 2003;63(6):535–553. 50. Laing RO, McGoldrick KM. Tuberculosis drug issues: prices, fixed-dose combination products and second-line drugs. Int J Tuberc Lung Dis 2000; 4(12 Suppl 2):S194–207.
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67
Immune reconstitution inflammatory syndrome Guillaume Breton
INTRODUCTION, BACKGROUND IMMUNE RECONSTITUTION IN HIV INFECTION AFTER ANTIRETROVIRAL THERAPY The introduction of antiretroviral therapy (ART) produces a rapid suppression of human immunodeficiency virus (HIV) replication (about 90% in 1 or 2 weeks), which is associated with an at least partial reconstitution of the immune system.1,2 The typical recovery of CD4 cells following ART is biphasic. The initial rise is rapid and mainly due to the redistribution of memory CD4 cells from lymphoid tissue. Thereafter, a slow increase in CD4 cells, mainly due to naı¨ve CD4 cell regeneration, is observed.1–3Moreover, ART also produces a rapid decrease in immune hyperactivation due to viral suppression, as well as an increase in the diversity of the T-cell repertoire and an ability to produce the T-helper (Th)-1 cytokines.4 The functional immune reconstitution is documented in vitro by the reconstitution of immune responses against environmental or infectious antigens.5,6 The best demonstration of this is the major decline in the incidence of opportunistic infections and in acquired immunodeficiency syndrome (AIDS)-related mortality observed since 1996 when combination ART was introduced.7
FROM PARADOXICAL REACTION TO IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) The occurrence of clinical manifestations attributed to immune reconstitution during TB has been observed since 1955 with the introduction of anti-TB drugs.8 Clinicians have described a variety of inflammatory syndromes after an initial improvement as ‘paradoxical reaction’ or ‘paradoxical worsening’. The most frequent cases were represented by meningitis, intracranial tuberculoma, pulmonary infiltrate, pleural effusion, and lymphadenopathy.9 The paradoxical reaction has been attributed to a reversal of the immunosuppression induced by TB itself and has been associated with the conversion of the tuberculin skin test, suggestive of the recovery of delayed-type hypersensitivity (DTH).10 Although the introduction of ART in HIV-infected patients has led to a major decrease in AIDS-related mortality, this immune reconstitution can sometimes be harmful and may cause inflammatory manifestations similar to paradoxical reactions.11 The high frequency of these manifestations has led to a rediscovery of this entity. Many terms have been used, such as ‘immune recovery diseases’ or ‘immune reconstitution diseases’; however, the term ‘immune reconstitution inflammatory syndrome’ is now widely used.12–17
IRIS DEFINITION IRIS is a collection of all manifestations attributed to an exaggerated immune response to various infectious or non-infectious antigens after ART initiation. Many agents are associated with IRIS (Table 67.1). Mycobacterium tuberculosis, Mycobacterium avium, Cryptococcus neoformans, and cytomegalovirus are the most frequently involved infectious agents (Table 67.1). Briefly, three different presentations of IRIS can be identified. 1. exacerbation of a previously treated infection, the most frequent cause being TB; 2. latent infection unmasked by ART in a previously asymptomatic patient, observed frequently with M. avium and rarely with TB; and 3. autoimmune and inflammatory disease, e.g. sarcoidosis. Incidence of IRIS varies from 3% to 45% in retrospective studies.12,13,15–17 The diagnosis of IRIS is difficult. IRIS may be suspected when unexpected inflammatory symptoms occur in a patient responding to ART. ART response is usually defined by a decrease in HIV viral load of more than 1 log10 copies/mL. The recovery of CD4 cell count is frequently associated but sometimes lacking and is not required for the diagnosis of IRIS. Thereafter IRIS is an exclusion diagnosis and all differential diagnoses, such as relapse or resistance of TB, adverse effect of drugs, or a new opportunistic infection, must be excluded (Box 67.1).13,15,17,18
EPIDEMIOLOGY Tuberculosis is the most frequent infectious disease associated with IRIS, representing one-third of IRIS cases and probably more in countries with a high prevalence of TB.19 Before HIV infection, paradoxical reactions had been observed among 2–23% of the patients treated with anti-TB drugs.20,21 The incidence of IRIS has increased in HIV-coinfected patients since the introduction of ART. In one study IRIS incidence was 36% in 33 HIV/TB-coinfected patients treated with ART, whereas in a historical control group of 28 HIV/ TB-coinfected, untreated patients it was only 7% (p = 0.013). Breen et al.22 found that IRIS incidence was 28% among 50 HIV/TBcoinfected patients treated with ART versus 10% among 50 HIVuninfected TB patients not treated with ART. In a third study IRIS incidence was 35% among 17 HIV/TB patients treated with ART and 0% among 19 HIV/TB untreated patients (p < 0.001).23
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Table 67.1 Main aetiologies of IRIS in HIV-infected patients Agent
Main clinical manifestations
Mycobacteria, bacteria Mycobacterium tuberculosis Mycobacterium avium complex Mycobacterium leprae Bartonella henselae
Fever, lymphadenitis Fever, lymphadenitis Reversion reaction Granulomatous splenitis
Mycoses Cryptococcus neoformans Histoplasma capsulatum Pneumocystis jiroveci Aspergillus fumigatus
Aseptic meningitis, fever, lymphadenitis Fever, lymphadenitis Pulmonary worsening Necrosing pneumopathy
Virus Varicella zoster virus Herpes simplex virus Cytomegalovirus Epstein–Barr virus Hepatitis C virus, hepatitis B virus Human herpesvirus 8 John Cunningham virus Parvovirus B19 Human papillomavirus Human immunodeficiency virus BK virus Parasites Leishmania
Recurrence, extensive lesions Recurrence, extensive lesions Uveitis, vitritis, pneumonitis Lymphoma ALT elevation Extensive Kaposi’s sarcoma PML exacerbation Encephalitis Condyloma Encephalitis, vasculitis Cystitis Uveitis, extensive cutaneous lesion
Autoimmune, inflammatory diseases Sarcoidosis, Graves’ disease, Guillain–Barre´ syndrome, systemic lupus
SYMPTOMS AND SIGNS CLINICAL CHARACTERISTICS
Appearance or exacerbation
Box 67.1 Proposed criteria for the diagnosis of immune reconstitution inflammatory syndrome associated with tuberculosis The diagnosis of IRIS requires the three following criteria: 1. Atypical or inflammatory clinical manifestations after ART initiation. 2. Active antiretroviral therapy: HIV viral load decrease > 1 log10 copies/mL increase in CD4 cell count (frequently observed but not required). 3. Clinical manifestations not explained by: TB relapse or resistance non-adherence to treatment drug side effect new infection or other diagnosis.
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In the great majority of cases, IRIS occurs in patients coinfected with TB and HIV, naı¨ve of ART, when both therapies are initiated simultaneously or within 2 months. As of November 2006, more than 180 cases had been reported in single-case reports, case series, and retrospective case–control studies (Table 67.2).20–51 Among 648 HIVinfected patients treated for both TB and HIV from 11 retrospective case–control studies and one prospective study, the overall incidence of IRIS was 20% and varied from 8% to 45%.21–31,52 There are few data from low-income countries where TB and HIV are highly endemic. Among the three published studies from these setting the IRIS frequency is lower, range 8–12.6%, than the frequency of IRIS in similar studies in Europe or USA, which varies from 30% to 45%.21–31,52 However, IRIS may explain a portion of the higher mortality rate observed in the first months after ART initiation in cohort studies of patients from low-income countries with an adjusted hazard ratio of 4.3 (95% confidence interval (CI) 1.6– 11.8) in comparison with cohort studies from high-income countries.53 We thus can hypothesize that IRIS is underdiagnosed due to the limited medical resource in low-income countries. The incidence of IRIS unmasking TB in previously asymptomatic patients is much lower. Few cases have been reported (Table 67.3). However, the frequency of IRIS unmasking TB is probably underestimated. Bonnet and colleagues54 observed a high frequency of TB (6.6%) in the first months after ART initiation in 3,151 patients from countries with a high TB burden. Even if this remains controversial, other authors having found a decrease in TB incidence after ART initiation, the possibility of IRIS unmasking subacute or latent TB should be further investigated.55 At the present time, because of the limited availability of diagnostic tools in these settings, it is difficult to distinguish between subacute TB undiagnosed at the time of ART initiation, recently acquired TB, and IRIS-unmasked TB. A retrospective study in London with patients mostly originating from sub-Saharan Africa has, however, given similar results. Among 267 HIV-infected asymptomatic patients, 3% developed TB in the first 3 months of ART. Furthermore a very high percentage (62%) of these patients developed IRIS.56
Among the IRIS cases published, clinical features were available for 171 patients (Table 67.2).21–51 At time of TB diagnosis the median CD4 cell count was 68/mm3 (range 2–435/mm3) and the median HIV viral load was 5.5 log10 copies/mL (range 3.0–6.9 log10 copies/mL). After an initial improvement of TB symptoms with antiTB drugs, the initiation of ART induced IRIS after a median time of 4 weeks (2 days to 1.5 year). At the time of IRIS diagnosis, the median CD4 cell count was 196/mm3 (range 5–533/mm3) and median HIV viral load was 2.7 log10 copies/mL (range < 1.7–4.5 log10 copies/mL) and frequently below the detection level. The most commonly reported manifestations of IRIS were the appearance or the exacerbations of lymphadenopathy. Peripheral, mainly cervical, and mediastinal or intra-abdominal lymphadenopathy were observed in 66% of the patients. Peripheral lymphadenopathies may become fluctuant and painful with sometimes draining sinus. Fever was observed in 42% of the patients but this is probably underestimated because it was not recorded in some series. The appearance or the exacerbation of pulmonary infiltrate or miliary or pleural effusion was described in 23% of the patients. Many
Table 67.2 Case reports, case series, and case–control studies of IRIS associated with tuberculosis in HIV-infected patients Author, reference
No.
Localization of TB
Clinical manifestation of IRIS
Duration of ART before IRIS (weeks)
CD4 cell count 3 (/mm )
HIV viral load (log10 copies/mL)
Treatment of IRIS
Before ART initiation
IRIS
Before ART initiation
IRIS
4.1 6.5 6.0 5.8 6.1 5.9 4.5 6.6 Ns 5.4 4.8 6.3 5.5 (5.2– 5.9) 6.1 (6–6.3)
3.8 2.8 3.0 3.6 3.7 3.8 < 2.6 3.4 3.9 3.3 3.6 3.8 nd
ART stop None None None None None None None None None None None Steroid (8)
–2.4 (2.1–4.2)
ART stop (4), steroid (2)
Patients who initiated ART after TB therapy Case–control studies 12 Narita et al.21
nd
Breen et al.22
14
Disseminated (9)
Navas et al.23
6
nd
Wendel et al.24 Ollala et al.25
3
Extrapulmonary (3)
6
nd
Shelburne et al.26 Breton et al.27
26
nd
16
Disseminated Disseminated Disseminated Lung, mediastinal LN Lung, cutaneous
Fever, mediastinal LN, lung Fever, mediastinal LN, cervical LN Fever Fever Mediastinal LN, cervical LN Fever, ascites, lung, pleural Cutaneous, pleural Fever, mediastinal LN, cervical LN Fever, mediastinal LN Fever, mediastinal LN, cervical LN, lung Cervical LN Lung, mediastinal LN Fever (4), LN (7), central nervous system (2), lung (2), pleural effusion (1), ascites (1) Fever (6), LN (4), lung (2)
2 0.3 1.5 0.5 2.5 0.7 0.7 2.7 2.3 1.7 6 4.5 1.5 (1–3)
12 80 27 91 2 35 75 133 87 20 73 17 58 (30–143)
5 67 33 16 32 169 30 110 194 65 283 62 nd
nd
46.5 (30– 112)
LN (3), tracheal compression by LN, psoas abscess (2) Lung, fever Cervical LN Cervical LN Axillary LN, fever Meningitis, ascites, fever Cervical LN, fever LN (19), lung (5), pleural effusion (4), meningitis (1) Fever, cervical LN Fever, parotitis abscess, spondylodiscitis
Range 4–10
Mean 69
+71 (12– 220) nd
nd
nd
Surgery
3 30 0.5 4 1 2 ad
ad
ad
ad
ad
nd
ad
ad
ad
ad
nd
1 0.5
151 76
340 172
6.9 5.8
3.7 < 2.7
4
109
92
5.5
< 2.7
NSAID ART stop, steroid None
4 2
133 199
198 497
5.2 5.1
2.6 < 2.3
Steroid None
Fever, mediastinal LN with bronchial compression, lung Fever, cervical LN Fever, cutaneous
(Continued)
691
692 Table 67.2 Author, reference
Case reports, case series, and case–control studies of IRIS associated with tuberculosis in HIV-infected patients—(cont’d) No.
Localization of TB
Disseminated Disseminated Lung, mediastinal LN Lung, mediastinal LN, abdominal LN Disseminated Disseminated Lung, mediastinal LN Disseminated Disseminated Disseminated Disseminated Kumarasamy et al.28
11
nd
Michailidis et al.29
14
Disseminated (8)
Bourgarit et al.30
7
Pleural effusion Liver, LN Lung Lung, bone marrow, LN, liver Lung, LN
Clinical manifestation of IRIS
Duration of ART before IRIS (weeks)
CD4 cell count 3 (/mm )
HIV viral load (log10 copies/mL)
Before ART initiation
IRIS
Before ART initiation
IRIS
Treatment of IRIS
Spleen abscess Fever, abdominal LN Psoas abscess, ureteric compression Fever, abdominal LN
6 2 16 1
245 41 435 59
237 137 533 93
5.3 4.9 4.8 5.4
3.6 2.7 3.4 2.4
None None None Steroid
Fever, axillary LN, pulmonary embolism
1
4
103
5.3
2.6
Fever, arthritis, mediastinal LN with bronchial compression, spleen rupture Fever, abdominal LN, spleen abscess, splenic vein thrombosis Fever, abdominal LN, ascites
0.5
33
446
5.5
2.2
9
13
232
6.6
2.4
ART stop, steroid ART stop, surgery None
1
33
135
5.4
< 2.3
Fever, miliary Fever Fever, cervical LN, abdominal LN, vein thrombosis Fever, mediastinal LN, cervical LN Fever, mediastinal LN, cervical LN Fever, cervical LN
2 1.5 1
74 35 136
268 97 460
5.4 6.2 6.9
< 2.3 nd 3.7
1.5 11 7.5
194 168 48
nd 224 315
nd nd nd
nd nd nd
Fever, cervical LN Cervical LN Fever, cervical LN, axillary LN Cervical LN Inguinal LN Cervical LN, axillary LN Fever, cervical LN Cervical LN LN (12), fever (8), cutaneous (2), spleen abscess (1), gluteal abscess (1)
34.5 75 6 9 5 8 1.5 5 2.4 (n = 9)
56 100 123 187 172 90 71 181 80 (33–117)
238 244 290 238 499 200 439 339 nd
nd nd nd nd nd nd nd nd 5.0 (3.5– 5.4)
nd nd nd nd nd nd nd nd nd
Peritonitis, tubal granuloma Fever, hepatitis Pericarditis Fever, abdominal LN
ad
26 9 16 15
112 131 31 122
4.7 5.7 5.0 6.5
ad ad ad ad
115
209
5.8
ad
Fever, peritonitis, abdominal LN
NSAID, steroid None ART stop ART stop, steroid NSAID Steroid Aspiration, NSAID NSAID Steroid Steroid NSAID NSAID Steroid Steroid Steroid Steroid (11) IL-2+GMCSF (1) nd
Manosuthi et al.31
21
Lung Miliary, abdominal LN Lung (2), extrapulmonary (19), disseminated (9), cervical LN (5), abdominal LN (4), central nervous system (1)
Fever, lung, LN Fever, abdominal LN Fever (14), LN (12), abdominal pain (4), headache (3)
8.7 (5.3–11.9)
24 6 44 (18–84)
391 20 +72 (47– 150)
5.7 5.6 5.8 (5.5– 5.9)
ad ad –3.9 (3.5– 4.2)
Case reports and series John & French32 Chien & Johnson33 Kunimoto et al.34 Furrer & Malinvemi35
1
Lung, mediastinal LN
Lung (alveolitis), mediastinal LN
12
55
320
6.0
< 2.7
Oxpentifylline
1
Lung
Mediastinal LN, cervical LN
6
220
530
> 5.9
4.5
Steroid
1
Lung
Lung (alveolitis)
1
9
50
5.3
< 2.7
Steroid
3
French et al.12 Fishman et al.36 Orlovic & Smego37 Shelburne & Hamill14
1 7
Liver, intestine Lung, peritoneal Lung Lung, mediastinal LN ad
<2 <2 <2 10 1.7 (range 0.3–4.5)
25 37 26 55 47 33
nd nd nd 320 ad
5.9 4.9 5.5 nd nd
nd nd nd nd nd
Steroid Steroid Steroid nd nd
1
Miliary
Liver, abdominal LN Liver, spleen, ascites, pleural effusion Epididymo-orchitis Mediastinal LN, lung (alveolitis) Lung (5), pleural effusion (3), mediastinal LN (5), cervical LN (2), ascites (1), cutaneous (1), fever (5) Cervical LN
5
103
178
3.0
nd
None
2
Lung
Abdominal LN
1
30
90
5.7
< 2.3
Steroid
Wanchu et al.38 Guex et al.39 Fernandes et al.40
1
nd Mediastinal
Lung Cervical LN, abdominal LN
4.5 2
63 26
267 nd
5.4 4.7
< 2.6 nd
nd None
1 2
Ileocaecal Cervical LN Lung
Ileocaecal perforation Cervical LN Mediastinal, cervical, inguinal LN
44 8 2
29 177 187
167 328 264
6.0 5.4 5.0
< 2.3 4.6 < 2.3
Ramos et al.41 Vidal et al.42 de Lange43 Buckingham et al.44 Lawn & Macallan45 Jehle et al.46
1 1 1 2 1
Disseminated Brain abscess Mediastinal LN Lung, LN Lung, LN Lung
Cervical LN, lung (miliary) Brain abscess Axillary, lung, abdominal abscess LN (tracheal compression) Lung (alveolitis), pleural effusion Lung (alveolitis), hypercalcaemia
2 4 2.5 8 1.5 4
68 55 10 ad ad 8
nd 110 200 ad ad 110
5.9 5.2 6.0 ad ad 5.7
ns < 2.3 3.0 ad ad 2.7
Surgery Steroid Thalidomide, steroid Steroid Steroid None ns ns Steroid
1
Miliary
Acute renal failure
6
68
82
6.1
2.0
Steroid (Continued)
693
694 Table 67.2
Case reports, case series, and case–control studies of IRIS associated with tuberculosis in HIV-infected patients—(cont’d)
Author, reference
No.
Localization of TB
Clinical manifestation of IRIS
Duration of ART before IRIS (weeks)
CD4 cell count 3 (/mm )
HIV viral load (log10 copies/mL)
Before ART initiation
IRIS
Before ART initiation
IRIS
Treatment of IRIS
Ferrand et al.47 Me´an et al.48
1
Disseminated
Hypercalcemia
2.5
2
Ratman et al.49
4
Miliary LN CNS, lung Lung Lung Lung, LN
Mediastinal LN, psoas abscess Abdominal LN Intracranial tuberculoma Lung Lung Cervical, axillary, abdominal LN
8 4 4 3 8 12
103 110 155 104 208 217
200 240 138 137 300 239
5.8 > 5.9 nd 5.4 2.9 3.5
2.8 2.5 < 1.7 nd < 1.7 3.3
Steroid None nd Steroid nd nd
TB 1 1
None None
Cervical LN, miliary, intracranial tuberculoma Caecal TB
24 24
210 177
nd 234
5.5 4.2
< 2.6 < 2.6
Steroid Surgery
1
None
Respiratory failure
2
121
298
5.6
4.4
Ventilation
1
None
Liver, CNS, lung
2
40
50
> 5.9
3.2
nd
IRIS unmasking Crump et al.50 Shelburne & Hamill14 Goldsack et al.51 Me´an et al.48
No, number of patients; nd, not determined; ag, aggregated data; LN, lymphadenopathy; ART stop, interruption of ART; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL, interleukin; NSAID: non-steroidal anti-inflammatory drugs; CNS, central nervous system. Results of case–control studies are given in median and interquartile range.
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Immune reconstitution inflammatory syndrome
Table 67.3 Clinical features of 171 patients with IRIS-associated tuberculosis Symptoms
No. of patients (%)
Lymphadenopathy Fever Lung (alveolitis, miliary), pleural effusion Abdominal (abdominal pain, ascites, hepatomegaly, splenic abscess, ileocaecal involvement) Central nervous system (tuberculoma, meningitis, headache) Muscle abscess, spondylodiscitis, osteomyelitis, arthritis Cutaneous lesion Other (renal, hypercalacaemia, parotitis, pericarditis, gluteal abscess, epididymo-orchitis, tubal abscess)
114 (67) 72 (42) 40 (23) 19 (11) 9 (5) 6 (3.5) 5 (3) 7 (4)
other manifestations have been described; they were mainly due to granulomatous lesions (Table 67.3). The clinical features of the uncommon cases of IRIS-unmasked TB were similar (Table 67.2). Only few data from IRIS in children have been reported. Puthanakit and colleagues57 reported three cases of IRIS revealing latent TB and Narendran and colleagues58 reported one case of IRIS in a 12-year-old child treated for TB 3 days after ART initiation with fever and enlarged mediastinal lymph nodes.
DETERMINANT OF IRIS Ten retrospective case–control studies and one prospective study with a small number of patients have been published and have
67
given some information about the factors associated with IRIS occurrence.21–31 Because of the retrospective design and limited number of patients in most of these studies, the following identified factors remain controversial and their accuracy needs to be confirmed in further studies.
Time of ART initiation (Table 67.4) A short time interval between anti-TB therapy initiation and ART initiation is considered a key factor of IRIS risk as, for example, in the case of patients with cryptococcal infection-related IRIS: 83% of patients with IRIS cases initiated ART within 2 months of initiating antifungal therapy, whereas it was the case in only 37% of patients without IRIS (p = 0.004).59 Three retrospective studies have found a significant association between IRIS occurrence and time of ART initiation; however, one of these studies analysed patients with IRIS related to TB, M. avium, and cryptococcal infection, which could represent a bias.22,26 This factor was not found in other studies, reflecting probably the limit of retrospective studies. In cases of IRIS associated with other pathogens, 83% of the patients with cryptococcal infection-related IRIS initiated ART within 2 months of initiating antifungal therapy, whereas it was the case in only 37% of patients without IRIS (p = 0.004).59 Tuberculosis dissemination (Table 67.4) The localization of TB with extrapulmonary or disseminated lesions was significantly associated with IRIS occurrence in three out of four studies which evaluated this parameter.22,27,30,32 Disseminated infection has also been shown to be a significant factor for IRIS related to C. neoformans or cytomegalovirus infections.59,60 Similarly extrapulmonary TB was also the major risk factor associated with paradoxical reaction in non-HIV-infected
Table 67.4 IRIS risk factors in HIV/tuberculosis-coinfected patients initiating ART after antituberculosis therapy No. of patients, reference
Parameter studied
Patients with IRIS
Patients without IRIS
p
n = 30, Narita et al.21 n = 17, Navas et al.23
Median CD4 (/mm3) Median time to ART (days) CD4 < 100/mm3 Time to ART <6 weeks Disseminated TB CD4 < 50/mm3 Median time to ART (days) Median CD4 (/mm3) Median time to ART (days) Disseminated TB Median CD4 (/mm3) Median time to ART (days) Median CD4 (/mm3) Median time to ART (days) Disseminated TB Median CD4 (/mm3)
54 (range 2–133) 22.5 (range 0–60) 83% 88% 75% 24% 27 30 33 (range 0–80) 100% 75 (range 4–435) 22 123 24 (IQR 9–54) 57% 80 (IQR 33–117) CD4 < 100/mm3: 79% 40 31 27 32 61 (IQR 37–83) 91% 44 (IQR 18–84)
83 (range 5–820) 110 (range 0–375) 82% 46% 46% nd 50 33 30 (range 0–105) 62% 128 (range 9–488) 25 Nd 18 (IQR 3–66) 17% 139 (IQR 77–284) CD4 < 100/mm3: 39% 117 74 45 60 68 (IQR 43–122) 49% 34 (IQR 13–67)
0.15 0.01 ns 0.03 0.09 0.7 < 0.001 0.529 0.62 0.01 0.43 0.8 < 0.001 0.730 0.006 0.05 0.011 < 0.001 0.003 ns 0.052 0.266 < 0.001 0.482
n = 36, Breen et al.22 n = 180, Shelburne et al.26a n = 37, Breton et al.27 n = 144, Kumarasamy et al.28 n = 55, Michailidis et al.29
n = 160, Lawn et al.72 n = 19, Bourgarit et al.30 n = 167, Manoshuti et al.31
ART timing (days) Median CD4 (/mm3) ART timing (days) Median CD4 (/mm3) Median time to ART (days) Disseminated TB Median CD4 (/mm3)
Parameter range or interquartile range (IQR) is given if available. Time to ART, time between anti-TB therapy initiation and ART initiation; nd, no data; ns, not significant. a Study including 86 patients with TB and 94 patients with Mycobacterium avium or cryptococcal infections.
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patients: Cheng and colleagues61 observed that non-HIV-infected patients with paradoxical reaction were more likely to have extrapulmonary TB (62.5 versus 17%; p < 0.05) in a retrospective study of 104 TB patients with 16 (15.4%) cases of paradoxical reaction. Despite TB dissemination being correlated with low CD4 cell count, it remains to been seen whether the two represent independent factors of IRIS.
CD4 cell count before ART initiation (Table 67.4) The predictive value of CD4 cell count for the occurrence of IRIS remains controversial. Even if a low CD4 cell count (below 100 or 50/mm3) is usually considered predictive of IRIS associated with various pathogens, the data concerning TB are less evident.12,62 In a recent prospective study in South Africa, patients with IRIS associated with tuberculosis or others pathogens had significantly lower CD4 cell count before ART initiation (79 vs 142/mm3; p ¼ 0.02).73 In the case of tuberculosis, most studies showed a trend to a lower CD4 cell count in IRIS cases and three showed a statistically significant results.28,29,72 The gathering of all available individual data (n ¼ 71 patients, Table 67.2) showed that 63% of IRIS cases were observed in patients with < 100 cells/mm3, 29% in patients with CD4 between 100 and 200 cells/mm3 and only 7% in patients with > 200 cells/mm3 (Fig. 67.1). This probably reflects the severe immunosuppression in patients coinfected with TB and HIV. Despite TB dissemination being correlated with low CD4 cell count, it remains to been seen whether the two represent independent factors of IRIS. Type of ART and immunovirological change at time of IRIS (Table 67.5) Most cases of TB-associated IRIS were observed after combination ART associating two nucleoside reverse transcriptase inhibitors (NRTIs) with one protease inhibitor or one non-NRTI, or three NRTIs; few cases were reported with two NRTIs. No association was found between the type of antiretroviral drugs and the
50/mm3
100 mm
3
CD4 <50/mm3
7% 38%
30% 25%
CD4 >200 mm3
Fig. 67.1 CD4 cell counts before ART initiation in 71 patients with TB-associated IRIS.
occurrence of IRIS.17 IRIS occurrence is commonly associated with immunovirological change, suggestive of immune reconstitution, drop in HIV viral load, and increase in CD4 cell count. Most of the retrospective case–control studies showed a trend to a higher increase in CD4 cell count and a more pronounced HIV viral load decrease in patients with IRIS, but these parameters were rarely statistically significant.21–31 CD4 percentage and CD4/CD8 ratio changes from baseline have been associated with IRIS.27 These parameters have only been studied once and further studies are needed.
Tuberculin skin test Tuberculin skin test (TST) is an easy way to explore the immune response against mycobacterial antigens. Narita and colleagues21 have shown that IRIS was more frequent before ART initiation in HIV/ TB-coinfected patients with negative TST (70% in 11 patients) than in those with positive TST (11% in 16 patients). Moreover, a TST conversion was observed in seven out of eight patients with IRIS. The value of repeating TST to diagnose IRIS needs further investigations.
3 Table 67.5 Median CD4 cell count (/mm ) and median HIV viral load (log10 copies/mL) change after ART initiation in patients with or without IRIS
No. of patients, reference
Time of measurement
Patients with IRIS
Patients without IRIS
p
n = 30, Narita et al.21
IRIS
n = 17, Navas et al.23
nd
n = 180, Shelburne et al.26a
IRIS
n = 37, Breton et al.27
IRIS
CD4 +27.5 VL –2.2 (range –1.2 to –3.2) CD4 +71 (IQR +12 to +220) VL –2.4 (IQR –2.1 to –4.2) CD4 +43 VL –2.11 CD4 +99 (range –17 to 413) CD4% +11 (range +1 to +42) CD4/8 +0.19 (range –0.01 to 1.06) VL –2.97 (range –1.36 to –5.09) CD4 +83
CD4 +32.5 VL –1.34 (range +0.38 to –3.26) CD4 +51 (IQR –113 to +89) VL +0.4 (IQR +0.2 to –2.8) CD4 +14 VL –1.37 CD4 +35 (range –96 to +331) CD4% +2 (range –2 to +12) CD4/8 +0.02 (range –0.1 to +0.33) VL –2.63 (range –0.52 to –3.37) CD4+ 88
0.763 0.084 0.25 0.02 0.102 < 0.001 0.07 < 0.001 < 0.001 0.07 0.97
CD4 +124 CD4 x1.5 CD4 +107 VL –5.7 CD4 +72 (IQR +47 to +150) VL –3.9 (IQR –3.5 to –4.2)
nd CD4 x0.7 CD4 +51 VL –5.2 CD4+ 83 (IQR +43 to +129) VL –3.8 (IQR –3.4 to –4.1)
ns 0.046 0.02 ns 0.979 0.449
n = 160, Lawn et al.72 n = 144, Kumarasamy et al.28 n = 55, Michalidis et al.29 n = 19, Bourgarit et al.30 n = 167, Manosuthi et al.31
6 months 3 months 3 months 1 month 3 months
VL, HIV viral load log10 copies/mL; nd: not determined; ns: not significant. a Study including 86 patients with TB and 94 patients with Mycobacterium avium or cryptococcal infection; range or interquartile range (IQR) is mentioned if available.
696
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Immune reconstitution inflammatory syndrome
DIFFERENTIAL DIAGNOSIS AND INVESTIGATION The diagnosis of IRIS is one of exclusion. The differential diagnosis varies according to the symptoms and to the immunosuppression level. The heterogeneity of IRIS cases makes investigation strategies uncertain. The most important aspect of patient care is the ability of the clinician to avoid two deleterious strategies. Firstly, it may be harmful to exclude all potential differential diagnoses with invasive procedures. Secondly, it is clearly harmful to consider that all symptoms occurring after ART initiation are IRIS without further investigation. Immune reconstitution is a long-term process and opportunistic infections can occur in the first months of ART due to a delayed immune reconstitution. Then positive argument for IRIS should be investigated. The temporal association between ART initiation and the occurrence of clinical features of illness is essential. It is a favourable point to avoid initiating anti-TB drugs and ART at the same time; the initial improvement after anti-TB drugs initiation followed by clinical deterioration after ART initiation gives a strong argument for the diagnosis of IRIS. The presence of clinical manifestations consistent with an inflammatory condition is also required. It is not a problem in cases of high fever or of peripheral enlarged lymph nodes; however, clinical examination is usually insufficient and radiological examination (radiograph, computed tomography (CT) scan, echography) is frequently required. A diagnostic fluid tap should be performed in cases of pleural effusion or ascites, and in case of peripheral lymph node enlargement a fine needle aspirate, to look for granulomatous reaction and for acid-fast bacilli in smear examination and in culture. Acid-fast bacilli are sometimes observed in lymph node histology but culture remains negative. Even if it has been evaluated in only one study, a TST should be performed in order to document a reconstitution of DTH. Thereafter differential diagnoses should be ruled out. Firstly, a relapse of TB should be investigated by sputum smear and culture. Non-adherence to anti-TB drugs, resistance of M. tuberculosis, drug interaction, and drug malabsorption in patients with chronic diarrhoea or wasting syndrome should be investigated. Intravenous anti-TB therapy should be used if necessary. Secondly, in case of fever, a drug hypersensitivity should be ruled out: cotrimoxazole is the most frequent drug associated with hypersensitivity in HIV-infected patients; however, rifampicin, abacavir, or nevirapine, for example, could be involved. An attentive clinical examination to look for skin rash and a biological test for eosinophil count, transaminase, and renal function are useful. The transient interruption of a drug potentially involved should be discussed. The search for a bacterial infection, such as pneumococcal pneumonitis or Salmonella septicaemia, should be realized by a clinical examination and, in absence of any symptoms, at least by blood culture, urinary culture, and chest radiograph. Malaria should be systematically investigated in endemic countries. Then, and according to the nadir of CD4 cell count and to the primary prophylaxis of opportunistic infections used, the most frequent opportunistic infections should be ruled out by clinical examination and adapted investigation: cerebrospinal fluid punction for cryptococcosis, bronchoalveolar lavage for pulmonary pneumocystosis, cerebral CT scan for toxoplasmosis, polymerase chain reaction for cytomegalovirus, and ophthalmic examination for retinitis. In case of adenopathy, a punction should be performed with cytological and bacteriological examination. A surgical biopsy is not indicated, considering the risk of adherence due to inflammatory processes. Main differential diagnoses are represented by
67
bacterial lymphadenitis (streptococci and staphylococci), M. avium and other mycobacteria, lymphoma, Kaposi’s sarcoma, cryptococcosis, histoplasmosis, and, more rarely syphilis, inoculation diseases (e.g. cat scratch disease), lymphogranuloma venereum, Yersinia pestis, actinomycosis, sarcoidosis, and cancer.
FUTURE STRATEGIES REMAINING TO BE INVESTIGATED The documentation of an immune-specific response against TB represents a strong argument for the diagnosis. A preliminary study has demonstrated an association between IRIS and a proliferative response against purified protein derivative.30 This response was not observed with mycobacterial protein ESAT-6, which suggests that tests using that protein are probably not adequate to detect a response during IRIS. Work is ongoing to identify a more specific antigenic target of IRIS in order to elaborate a diagnostic test. In the meantime, it is also possible to elaborate guidelines to improve the diagnosis. A diagnostic score of IRIS using the number of previous opportunistic infections, the CD8 cell count, and the haemoglobin level has been elaborated and needs to be evaluated in prospective studies.63 The diagnosis of IRIS is difficult in low-income countries due to limited medical resources. Some researchers have proposed adapted clinical criteria (Box 67.2).19
MANAGEMENT (BOX 67.3) The heterogeneity of IRIS presentation and the lack of clinical trials for the management of IRIS make treatment recommendations uncertain. Although a randomized, placebo-controlled trial of prednisolone in IRIS treatment is currently under way in South Africa, the following recommendations are based on retrospective studies, clinician experience, and expert opinion.17,19,64 The most important aspect of patient care is the ability of the clinician to recognize this entity and to avoid unnecessarily invasive procedures. Given that immune reconstitution is the goal of ART, it must be continued in order to decrease the risk of occurrence of another opportunistic infection. Moreover, in our personal experience ART interruption has not proven its efficacy. ART interruption in nine patients with IRIS was not sufficient to control the symptoms in four and ART re-initiation led unsurprisingly to IRIS recurrence in six out of nine patients (personal unpublished data). Anti-TB therapy itself is also associated with the occurrence of paradoxical reaction in non-HIVinfected patients. Considering that the presence of the M. tuberculosis antigen is the target of the excessive immune response, anti-TB therapy must be continued in order to decrease the antigen load. Then, and according to the severity of symptoms, the therapeutic choice is a wait-and-see attitude without any treatment modification, the use of antipyretic or of non-steroidal anti-inflammatory drugs (NSAIDs), the use of steroids, or, in the most severe life-threatening cases, the interruption of ART. The choice of NSAIDs is not well established, and pharmacological interaction with a ritonavir-containing ART regimen should be taken into account. The drug of choice is steroids. The dose and the duration are not stated and should be judged clinically for each patient. The potential deleterious effect on longterm immune reconstitution of steroids should also be borne in mind while waiting the results of prospective studies. The suggestion is to use a relatively high dose (prednisone 0.5–2 mg/kg/day) for a short period of time (2 weeks) that is then tapered progressively while monitoring for the recurrence of clinical symptoms and for inflammatory parameters. Before initiating steroid treatment it is important
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Box 67.2 Suggested definition of tuberculosis-associated IRIS for use in countries with limited resources TB-treated patient at the start of ART: 1. A suspected IRIS case can be defined as a patient who meets the following three criteria: a. An initial clinical response to TB treatment, based on a combination of some of the following factors: cessation of fever, relief of pulmonary symptoms, decrease in lymph node size, termination of meningeal signs (depending on presenting symptoms). b. New persistent fevers without an identifiable source or reason (e.g. an allergic reaction, malaria) and/or worsening or emergence of dyspnoea, stridor, increase in lymph node size, development of abscesses, and/or development of abdominal pain with ultrasound evidence of abdominal adenopathies and/or unexplained CNS symptoms. c. Adequate adherence to ART and TB treatment. 2. A confirmed IRIS case can be defined as a patient who meets the following three criteria: a. Radiological examinations showing worsening or emergence of intrathoracic lymphadenopathy, pulmonary infiltrates, pleural effusions, abdominal lymph nodes, and hepatosplenomegaly. b. A good virological response,a an increased CD4 cell count,a conversion of TST from negative to positive, and/or adequate adherence to ART and TB treatment. c. A clear exclusion of other conditions that could explain the clinical manifestations of the patient, such as TB treatment failure or other concomitant infections, tumours, or allergic reactions. Unapparent TB at the start of ART ‘unmasking’ a type of IRIS. Before the start of ART there were insufficient clinical symptoms/signs to justify the start of TB treatment: chest radiograph (CXR) was normal and in patients presenting with cough at least three sputum smears were negative for acid-fast bacilli. Patients should have the following characteristics: 1. Good virological response,a an increased CD4 cell count,a conversion of TST from negative to positive, and/or adequate adherence to ART. 2. TB appeared within the first 6 months of starting ART. 3. Formation of abscesses, symptomatic enlarged mediastinal and/or abdominal lymph nodes, and/or pulmonary infiltrates develop within < 2 weeks. a
The degree of virological or immunological response or adherence needed will have to be established in prospective studies. Scientific Foundations of Urology Vol 1, Chapter 30 (eds. D. Innes Williams and G.D. Chisholm), pp 211–217. London, Heinemann. Figure 15.
Box 67.3 Proposals for IRIS prevention 1. Initiate ART early before severe immunosuppression and tuberculosis. 2. Search systematically for TB in endemic countries and treat subacute TB before ART initiation. 3. Delay or defer ART according to CD4 cell counta a. 0 < CD4 < 100/mm3: start ART rapidly, wait 2–4 weeks until a clinical improvement of TB symptoms after anti-TB therapy b. 100/mm3 < CD4 < 200/mm3: delay ART until the completion of the initial phase of TB therapy (2 months) c. CD4 > 200/mm3: defer ART until the end of TB therapy and monitor CD4. 4. If patients at high risk of IRIS could be identified, ART initiation in association with steroids could represent an option. a
Remains to be evaluated.
698
to ensure that an appropriate anti-TB drug regimen is in place, taking into account the possibility of multidrug resistance, to look for cytomegalovirus infection in patients with a CD4 cell count < 100/mm3, and to eradicate Strongyloides asymptomatic infection in patients originating or living in intertropical areas. Surgery could be recommended for large abscesses. Among the 97 reported cases of IRIS with available management data, a spontaneous favourable outcome without treatment modification was observed in 23% of the patients. In most cases the symptoms disappeared spontaneously, while investigations to exclude a differential diagnosis were still ongoing. Steroids were the most frequently used treatment in 48% of the patients with a mean posology of 0.5 mg/kg/day. ART and sometimes anti-TB therapy were temporally interrupted in 13% of them. NSAIDs and thalidomide were less commonly used (7%) and surgery was rarely required (3%) (Table 67.2). For cases of IRIS unmasking TB, anti-TB drugs are recommended; of course, depending of the severity of symptoms the same recommendation could be applicable.
COMPLICATIONS Severe manifestations occurred in less than 10% of the patients. The most frequent complications were related to compressive lymph nodes responsible for airways or ureteric obstruction, or deep vein compression leading to thromboembolic events. Other complications such as expansive intracranial tuberculoma, meningitis with intracranial hypertension, bowel perforation, respiratory failure, splenic rupture, and acute renal failure have been reported (Table 67.2). A lethal outcome is rarely observed and seems to be mainly the consequence of expansive brain tuberculoma. It is possible that such lesions are underdiagnosed in low-income countries owing to the limited medical resources and we can hypothesize that IRIS is one cause of the high mortality incidence observed in these areas in the first months following ART initiation.53
PATHOLOGY The development of IRIS appears to be mediated by an increased capacity of the immune system to respond to mycobacterial antigens brought about by ART and by the treatment of TB itself. This hypothesis has been suggested by the TST conversion observed during IRIS and also during paradoxical reaction in non-HIV-infected patients.10,21 The functionality of the immune response is documented by the well-formed granulomas with giant cells and sometimes with caseation during IRIS. This finding is unusual in deeply immunocompromised patients. The ability to form granulomas reflects the functionality of the macrophage response related to the CD4 Th-1 activation.65 Reports of IRIS cases with hypercalcaemia are also indirect evidence of the functionality of these granulomas.45,47 The hypothesis of a recovery of cellular immune responses was recently documented in vitro. IRIS had been associated with an explosive proliferative CD4 Th-1 response against purified derivative protein (tuberculin) which involved about one-third of the total CD4 cells.30 An acute burst of non-specific Th-1 and proinflammatory cytokines and chemokines has also been observed during IRIS and is probably responsible for the systemic inflammatory manifestations.30,66 Whether IRIS is only the result of an excessive immune response or is also related to a high antigen burden or to a lack of immune regulation remains to be elucidated.
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Immune reconstitution inflammatory syndrome
The occurrence of IRIS after few days of ART, even before any detectable increase in circulating CD4 cells, suggests that the functional improvement of immune response consequential to the suppression of HIV replication could play an independent role in IRIS pathogenesis. Moreover, the reconstitution of DTH has been related to the decrease in HIV viral load and not to CD4 cell count improvement.67 Even if the mechanisms which can explain why some patients experience IRIS remain to be determined, the crucial role of genetic polymorphism is highly suspected and a preliminary study suggests the role of Th-1–Th-2 balance and of the tumour necrosis factor-a gene in mycobacterial infection-associated IRIS.68
PREVENTION Even if low CD4 cell count remains controversial as an IRIS risk factor, the majority of IRIS cases develop in patients with < 100 cells/mm3. The initiation of ART early in the course of HIV infection before severe immunosuppression decreases the risk of disseminated TB and also the risk of latent infection and should thus decrease the risk of IRIS occurrence. Latent and subacute TB are frequently found in deeply immunocompromised patients in high-endemic countries; positive sputum smear and culture for M. tuberculosis have been observed in 4% of asymptomatic patients with CD4 > 200/mm3 screened before a TB vaccine trial in Tanzania.69 The high incidence of IRIS observed in patients with subacute TB could be reduced by a careful screening and treatment for TB.56 The hypothesis that the temporal association of immune reconstitution due to ART and to anti-TB treatment leads to a major risk of IRIS occurrence is suggested by the observation that the majority of IRIS cases are observed when ART is initiated within the first 2 months of anti-TB treatment. The fact of delaying ART initiation could thus be associated with a lower risk of IRIS occurrence. Two ongoing trials in Cambodia and in South Africa begun in 2006 comparing immediate and early (2 weeks) ART initiation versus late (8 weeks) should provide some answers. However, is it really a good option? The question about the safety
REFERENCES 7. 1. Autran B, Carcelain G, Li TS, et al. Positive effect of combinated antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997;277:112–116. 2. Pakker NG, Roos MT, van Leeuwen R, et al. Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16:318–326. 3. Li TS, Tubiana R, Katlama C, et al. Long-lasting recovery in CD4 T cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998;351:1682–1686. 4. Imami N, Antonopoulos C, Hardy GA, et al. Assessment of type 1 and type 2 cytokines in HIV type 1-infected individuals: impact of highly active antiretroviral therapy. AIDS Res Hum Retroviruses 1999;15:1499–1508. 5. Pontesilli O, Kerkhof-Garde S, Notermans DW, et al. Functional T cell reconstitution and human immunodeficiency virus-1-specific cell-mediated immunity during highly active antiretroviral therapy. J Infect Dis 1999;180:76–86. 6. Valdez H, Smith KY, Landay A, et al. Response to immunization with recall and neoantigens after prolonged administration of an HIV-1
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of ART deferment in HIV/TB-coinfected patients with low CD4 cell count has been addressed by two retrospective studies of 188 and 96 patients in London. The risk of AIDS events and death in patients not treated by ART was 25% versus 3.5% (p < 0.001) in patients receiving ART.70 Moreover a extremely high rate (249/100 person-years) of death and AIDS events was observed early within the first 2 months after anti-TB treatment initiation in patients with > 100 cells/mm3 not treated with ART.71 The conclusion of these two studies is an advocate against the deferment of ART in the more immunocompromised patients even if ART and TB therapy in association produce a high incidence of adverse effects, drug interactions, and treatment interruptions. Thus, we can propose the following options which, of course, remain to be evaluated. For patients with < 100 cells/ mm3, ART should be initiated as soon as possible. It is probably reasonable to wait 2–4 weeks for a clinical improvement after TB therapy initiation. For the patient with > 200 cells/mm3, it seems reasonable to wait until the end of TB therapy or longer according to CD4 cell counts evolution. For patients with CD4 cell counts between 100 and 200/mm3, waiting 2 months could be a good option. At last, several predictive factors of IRIS have been identified. Because of the retrospective design and the limited number of patients, all these predictive factors remain controversial and need to be confirmed. The identification of predictive factors of IRIS in prospective studies could make it possible to select high-risk patients and to evaluate preventive strategies, for example, the association of ART with a short course of steroids. The majority of people living with HIV/AIDS are in countries where TB is highly endemic and ART is rarely available. A better knowledge of IRIS prevention is needed in order to face a potential IRIS epidemic, which could occur when ART is used on a large scale. However, the high frequency and the difficult management of IRIS should not make one forget the frequently favourable outcome, spontaneously or following steroid treatment. The risk due to hazardous preventive strategies should not exceed the risk of complication due to IRIS.
protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group. AIDS 2000;14:11–21. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853–860. Chloremis CB, Padiatellis C, Zoumboulakis D, et al. Transitory exacerbation of fever and roetgenographic findings during treatment of tuberculosis in children. Am Rev Tuberc 1955;72:527–536. Cheng VC, Ho PL, Lee RA, et al. Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 2002;21: 803–809. Rooney JJ, Crocco JA, Kramer S, et al. Further observations on tuberculin reactions in active tuberculosis. Am J Med 1976;60:517–522. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1 infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 2000;133:447–454. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIVinfected patients with highly active antiretroviral therapy. HIV Med 2000;1:107–115. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly
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active antiretroviral therapy. Medicine 2002;81: 213–227. Shelburne SA, Hamill RJ. The immune reconstitution inflammatory syndrome. AIDS Rev 2003;5:67–79. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18:1615–1627. Hirsch HH, Kaufmann G, Sendi P, et al. Immune reconstitution in HIV-infected patients. Clin Infect Dis 2005;38:1159–1166. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–373. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006; 57:167–170. Colebunders R, John L, Huyst V, et al. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc lung Dis 2006;10:946–953. Hawkey CR, Yap T, Pereira J, et al. Characterization and management of paradoxical upgrading reactions in HIV-uninfected patients with lymph node tuberculosis. Clin Infect Dis 2005;40:1368–1371. Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157–161.
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22. Breen RA, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59:704–707. 23. Navas E, Martin-Davila P, Moreno L, et al. Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 2002;162:97–99. 24. Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIVinfected persons. Chest 2001;120:193–197. 25. Olalla J, Pulido F, Rubio R, et al. Paradoxical responses in a cohort of HIV-1-infected patients with mycobacterial disease. Int J Tuberc Lung Dis 2002;6:71–75. 26. Shelburne SA, Visnegarwala F, Darcourt, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005;19:399–406. 27. Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39:1709–1712. 28. Kumarasamy N, Chaguturu S, Mayer KH, et al. Incidence of immune reconstitution syndrome in HIV-tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr 2004;37:1574–1576. 29. Michailidis C, Pozniak AL, Mandalia S, et al. Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis. Antivir Ther 2005;10:417–422. 30. Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1 responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1–F7. 31. Manosuthi W, Kiertiburanakul S, Phoorisri T, et al. Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculous and antiretroviral therapy. J Infect 2006;53:357–363. 32. John M, French MA. Exacerbation of the inflammatory response to Mycobacterium tuberculosis after antiretroviral therapy. Med J Aust 1998;169:473–474. 33. Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933–936. 34. Kunimoto DY, Chui L, Nobert E, et al. Immune mediated ‘HAART’ attack during treatment for tuberculosis. Highly active antiretroviral therapy. Int J Tuberc Lung Dis 1999;3:941–947. 35. Furrer H, Malinvemi R. Systemic inflammatory reaction after starting highly active antiretroviral therapy in AIDS patients treated for extrapulmonary tuberculosis. Am J Med 1999;106:371–372. 36. Fishman JE, Saraf-Lavi E, Narita M, et al. Pulmonary tuberculosis in AIDS patients: transient chest radiographic worsening after initiation of antiretroviral therapy. AJR Am J Roentgenol 2000;174:43–49. 37. Orlovic D, Smego RA Jr. Paradoxical tuberculous reactions in HIV infected patients. Int J Tuberc Lung Dis 2001;5:370–375. 38. Wanchu A, Sud A, Bambery P, et al. Paradoxical reaction in HIV and tuberculosis coinfection. J Assoc Physicians India 2002;50:588–589. 39. Guex AC, Bucher HC, Demartines N, et al. Inflammatory bowel perforation during immune restoration after one year of antiretroviral and antituberculous therapy in an HIV-1-infected patient: report of a case. Dis Colon Rectum 2002;45:977–978. 40. Fernandes GC, Vieira MA, Lourenco MC, et al. Inflammatory paradoxical reaction occurring in
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tuberculosis patients treated with HAART and rifampicin. Rev Inst Med Trop Sao Paulo 2002;44: 113–114. Ramos A, Asensio A, Perales I, et al. Prolonged paradoxical reaction of tuberculosis in an HIVinfected patient after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 2003;22:374–376. Vidal JE, Cimerman S, Schiavon NR, et al. Paradoxical reaction during treatment of tuberculous brain abscess in a patient with AIDS. Rev Inst Med Trop Sao Paulo 2003;45:177–178. de Lange WC. Immune reactivation and paradoxical worsening in an HIV-infected tuberculosis patient. Adv Exp Med Biol 2003;531:261–266. Buckingham SL, Haddow LJ, Shaw PJ, et al. Immune reconstitution inflammatory syndrome in HIVinfected patients with mycobacterial infections starting highly active anti-retroviral therapy. Clin Radiol 2004;59:505–513. Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis 2004;38:154–155. Jehle AW, Khanna N, Sigle JP, et al. Acute renal failure on immune reconstitution in an HIV-positive patient with miliary tuberculosis. Clin Infect Dis 2004;38:e32–e35. Ferrand RA, Elgalib A, Newsholme W, et al. Hypercalcemia complicating immune reconstitution in an HIV-infected patient with disseminated tuberculosis. Int J STD AIDS 2006;17:349–350. Me´an P, Pavese P, Blanc M, et al. Immune reconstitution syndrome and mycobacterial diseases during HAART. Presse Med 2005;34:1511–1514. Ratnam I, Chiu C, Kandala NB, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin Infect Dis 2006;42:418–427. Crump JA, Tyrer MJ, Lloyd-Owen SJ, et al. Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis 1998; 26:1008–1009. Goldsack NR, Allen S, Lipman MC. Adult respiratory distress syndrome as a severe immune reconstitution disease following the commencement of highly active antiretroviral therapy. Sex Transm Infect 2003;79:337–338. Patel A, Patel K, Patel J, et al. Safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with tuberculosis and HIV 1. J Acquir Immune Defic Syndr 2004;37:1166–1169. Braitstein P, Brinkhof MW, Dabis F, et al. ARTLINC Collaboration; ART-CC groups. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between lowincome and high-income countries. Lancet 2006; 367:817–823. Bonnet M, Pinoges L, Varaine F, et al. Tuberculosis after HAART initiation in HIV-positive patients from five countries with high tuberculosis burden. AIDS 2006;20:1275–1279. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002;359: 2059–2064. Breen RAM, Smith CJ, Cropley I, et al. Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy. AIDS 2005;19:1201–1206.
57. Puthanakit T, Oberdorfer P, Akarathum N, et al. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis J 2006;25:53–58. 58. Narendran G, Swaminathan S, Sathish S, et al. Immune reconstitution syndrome in a child with Tb and HIV. Indian J Pediatr 2006;73:627–629. 59. Lortholary O, Fontanet A, Ne´main N, et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005;19:1043–1049. 60. Karavellas MP, Azen SP, MacDonaled JC, et al. Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcome. Retina 2001;21:1–9. 61. Cheng VC, Yam WC, Woo PC, et al. Risk factors for development of paradoxical response during antituberculosis therapy in HIV negative patients. Eur J Clin Microbial Infect Dis 2003;22:597–602. 62. Jevtovic DJ, Salemovic D, Ranin J, et al. The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy. HIV Med 2005;6:140–143. 63. Robertson J, Meier M, Wall J, et al. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006;42:1639–1646. 64. MMWR Morb Mortal Wkly Rep 2004;53:RR-15. 65. Lucas SB. Histopathology in Clinical Tuberculosis. London: Chapman and Hall, 1998: 3–127. 66. Morlese JF, Orkin CM, Abbas R, et al. Plasma IL-6 as marker of mycobacterial immune restoration disease in HIV- infection. AIDS 2003;17:1411–1413. 67. Wendland T, Furrer H, Vemazza PL, et al. HAART in HIV-infected patients: restoration of antigenspecific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia. AIDS 1999; 13:1857–1862. 68. Price P, Morahan G, Huang D, et al. Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS 2002;16:2043–2047. 69. Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania. Clin Infect Dis 2005;40:1500–1507. 70. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16:75–83. 71. Dheda K, Lampe FC, Johnson MA, et al. Outcome of HIV-associated tuberculosis in the era of highly active antirehoviral therapy. J Infect Dis 2004;190:1670–1676. 72. Lawn SD, Myer L, Bekker LG, Wood R. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21:335–341. 73. Murdoch DM, Venter WDF, Feldman C, Van Rie A. Incidence and risk factors for immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008;22:601–610.
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Strategic risk management for preventing the transmission of Mycobacterium tuberculosis in healthcare settings Robert J Pratt
INTRODUCTION Exposure to patients with infectious TB in healthcare settings is a well-recognized hazard and, although the risks associated with this peril cannot be completely eliminated, they can be controlled and minimized. Hospitals and other healthcare facilities do this by developing and implementing a comprehensive and dynamic TB infection prevention and control plan that is responsive to identified risks and provides detailed evidence-based guidelines for preventing the transmission of Mycobacterium tuberculosis in healthcare settings. This chapter will describe the elements of a risk assessment strategy that will assist different healthcare facilities to identify the level of risk in their own institution and then outline appropriate risk management responses which can be incorporated in local infection prevention and control plans.
RISK MANAGEMENT STRATEGY Risk management effectiveness is essential to the provision of a safe environment for nursing care, medical treatment, and recovery from illness or trauma. Local infection prevention and control policies need to be based on comprehensive and ongoing assessments of the risks to patients, hospital staff, and visitors of exposure to a range of pathogenic microorganisms, including M. tuberculosis. This assessment (and periodic reassessment), conducted in each ward, department, clinic, and healthcare facility, is essential for developing a proper risk management strategy.
RISK ASSESSMENT The concept of risk management has always been a key feature of proactive infection prevention and control strategies, as a failure to control such risks can have disastrous consequences for healthcare organizations, practitioners, and patients. The ongoing cycle of risk management (Fig. 68.1) involves a continual evaluation in order to identify potential risks and assess the methods in place to control them. In addition, effective reporting of adverse events, errors, and ‘near misses’ is essential to the continuing identification of risk and the development of effective risk management responses. Hospitals and other healthcare facilities in most industrially developed countries are legally required to conduct a formal assessment of the risk of being exposed to ‘substances hazardous to health’, including the risk of exposure to pathogenic microorganisms, such
as M. tuberculosis. Information from the assessment will be used to guide management decisions and policy development focused on efforts to improve patient safety and minimize risk.
RISK ASSESSMENT EXERCISE: TUBERCULOSIS When conducting a risk assessment exercise for TB, a variety of data are collected that will enable the precise local nature of the risk from TB in a given healthcare facility to be assessed. In addition, specific elements of risk, such as environmental, administrative, and clinical practice safety deficits, need to be identified. A periodic reassessment should be built into the risk management cycle. The frequency of repeat assessments will be determined by the results of the most recent assessment. The Centers for Disease Control and Prevention (CDC) in the USA has published detailed guidance for conducting a TB risk assessment in a healthcare facility and determining the level of risk in a particular institution.1 This guidance, and a Tuberculosis Risk Assessment Worksheet, is available online (Appendix B at http://www.cdc.gov/ mmwr/preview/mmwrhtml/rr5417a1.htm) and can be modified and adapted to local circumstances. Acquiring a comprehensive understanding of the potential risks for the transmission of TB currently existing in the different areas of practice in our hospitals and healthcare facilities is a necessary prelude to developing an effective and relevant TB infection prevention plan. The majority of risks identified in local assessment exercises will be familiar and will have been previously addressed by others and are available as evidence-based guidelines for preventing healthcare-associated TB.1–3 These guidelines recommend infection control measures used to develop risk management responses to the assessment findings and to formulate a locally relevant evidence-based TB infection control plan.
TUBERCULOSIS INFECTION CONTROL PLAN: RISK MANAGEMENT Healthcare practitioners carrying out clinical procedures should whenever possible follow the infection prevention and control guidelines and operational policies issued by their employing authorities. Local infection prevention and control guidelines should incorporate advice and recommendations contained in current evidence-based guidelines developed by government health departments and a range of other relevant national organizations and professional bodies, e.g. CDC and the National
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efficacy currently available. They are not detailed procedural protocols but are designed for incorporation into local practice guidelines.
Control assessment
Identification and evaluation of risk
Ongoing cycle of risk management
Mechanism for reporting a risk
Development of risk management process
Fig. 68.1 Risk management process. Best practice for risk management, defined as the identification, evaluation, and control of potential adverse outcomes that threaten the delivery of safe and appropriate care to patients.
Institute for Health and Clinical Excellence (NICE) in England and Wales.1–3 All healthcare organizations must have in place a current TB infection control plan responsive to the level of risk identified in the baseline risk assessment. This plan must be integrated into the local TB policy and the hospital’s general policies and procedures for preventing healthcare-associated infections (HAI).
GENERAL INFECTION PREVENTION AND CONTROL MEASURES Healthcare strategies designed to protect patients and their carers from becoming infected during periods of hospitalization and community and home care have evolved over many decades. Current approaches for preventing HAI consist of a single set of standard infection prevention and control principles and three sets of precautions based on routes of transmission. These transmissionbased infection precautions were designed to reduce the risk of airborne, droplet, and contact transmission and are intended for use when clinically indicated, in addition to standard principles (precautions).
TRANSMISSION-BASED INFECTION PRECAUTIONS In addition to the standard principles, transmission-based infection precautions are used for those patients infectious – known or suspected – with highly transmissible or epidemiologically important pathogenic microorganisms. Three types of transmission-based infection precautions are used: contact, droplet, and airborne.6 These precautions can be combined for diseases that have multiple routes of transmission or for patients suffering from multiple infections. Contact infection precautions are used to prevent transmission of infectious microorganisms by direct or indirect contact. Direct contact refers to skin-to-skin transmission and indirect contact involves contact with a contaminated intermediate object, such as medical or surgical instruments, dressings, or a contaminated environment. Droplet infection precautions apply to patients known to have or suspected of having invasive disease, such as pneumonia, meningitis, or sepsis caused by Haemophilus influenzae type b, Neisseria meningitides disease, and pneumonia, and other diseases caused by a variety of bacteria and viruses. The microorganisms are transmitted by large respiratory droplets measuring more than 5 mm in size and expelled during coughing, sneezing, or talking, or during certain investigations and treatment, such as suctioning and bronchoscopy. The large droplets do not remain suspended in air and can only travel short distances, rarely more than a metre (3 ft.). Consequently, droplet transmission requires close contact between the source and recipient, particularly of the large respiratory droplets with the conjunctivae or the mucous membranes of the nose or mouth of a susceptible person. Airborne infection precautions are used for patients known to be or suspected of being infected with microorganisms transmitted by minute airborne droplet nuclei, such as those causing measles, varicella, and TB. Droplet nuclei are small particle residues (5 mm or smaller) of evaporated respiratory droplets containing microorganisms suspended in the air and scattered widely by normal air currents within a room or corridor or over long distances. More detailed information on standard principles for preventing HAI and transmission-based infection precautions can be found in the epic guidelines from the Department of Health and NICE in England and Wales,4,5 and in the isolation guidelines from CDC,6 all of which can be accessed online and are free to download (see references for website address).
STANDARD PRINCIPLES FOR PREVENTING HEALTHCARE-ASSOCIATED INFECTIONS
TUBERCULOSIS INFECTION PREVENTION AND CONTROL PLAN
Standard infection prevention and control principles are the first tier of isolation precautions designed to reduce the risk of transmission of infectious microorganisms from both recognized and unrecognized sources in healthcare settings. Evidence-based standard principles in England, known as epic guidelines, provide guidance for healthcare practitioners in the care of all patients regardless of their diagnosis or presumed infection status.4,5 These guidelines include recommendations for hospital hygiene, hand hygiene, the use of personal protective equipment, and the use and disposal of needles and other sharp instruments, and are broad general statements of good practice based on the best evidence of
In addition to the general infection prevention and control measures described earlier, specific guidelines for preventing healthcareassociated TB have been developed by many different agencies in different countries. As a framework for describing essential TBspecific prevention and control recommendations in the following sections, evidence-based guidelines from either the CDC or NICE have been chosen.1–3 Although these guidelines were developed for healthcare facilities in developed countries, many of the principles are also applicable to developing countries and can be adapted in a resource-limited setting. CDC and NICE guidelines are available online (see references for website addresses).
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Strategic risk management for preventing the transmission of Mycobacterium tuberculosis in healthcare settings
PREVENTING HEALTHCARE-ASSOCIATED TUBERCULOSIS A TB infection control plan (programme) incorporates a variety of precautionary measures adapted in each healthcare facility depending on the level of risk identified during a TB risk assessment.
CLASSIFYING RISK A hospital or health clinic in a community in which there are no TB patients and no TB patients had been admitted for in-patient care during the previous year would be assessed as having a minimal risk for healthcare-associated TB. Many, especially smaller hospitals and clinics that occasionally identify TB patients at triage or diagnostic evaluation but then refer those patients requiring in-patient care to a collaborating facility with expertise and appropriate resources would be assessed as having a very low risk.7 In developed countries such as the UK and the USA, most nurses work in hospitals or other healthcare facilities that have been assessed as having a minimal or very low risk for healthcare-associated transmission. Other hospitals and healthcare facilities, however, especially those in large urban areas of any country, particularly developing countries with a high TB prevalence, are assessed as having a greater risk. Three risk classifications are used by the CDC for healthcare settings that serve communities with a high TB incidence: low risk,
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medium risk, and evidence of ongoing transmission of M. tuberculosis (Table 68.1).1
TUBERCULOSIS INFECTION CONTROL PLAN The components of a TB infection control plan are somewhat different for a healthcare setting in which patients with suspected or confirmed TB are expected to be encountered from those healthcare settings in which these patients are not expected to be encountered (Table 68.2).
PRIORITIZING CONTROL MEASURES The infectiousness of patients with TB is directly related to the number of tubercle bacilli that they expel into the atmosphere. Consequently, a TB infection control plan should achieve the following goals: early identification of patients with active TB; prompt respiratory isolation; early diagnostic evaluation; and early effective anti-TB treatment. These goals are achieved by a variety of evidence-based infection prevention and control measures that need to be prioritized on the basis of the assessed risk of transmission and their relative effectiveness in reducing that risk. This ranking is referred to as the hierarchy of controls and separates these measures into administrative controls, environmental (engineering) controls, and respiratory protection.1–3,8,9
Table 68.1 CDC risk classifications for healthcare settings that serve communities with high incidence of tuberculosis a
Setting
Risk classification Low risk
Medium risk
In-patient < 200 beds
< 3 TB patients/year
3 TB patients/year
In-patient 200 beds Outpatient; and nontraditional facilitybased TB treatment facilities
< 6 TB patients/year < 3 TB patients/year
6 TB patients/year 3 TB patients/year
Settings in which: Persons who will be treated have been demonstrated to have LTBI and not TB disease A system is in place to promptly detect and triage persons who have signs or symptoms of TB disease to a setting in which persons with TB disease are treated No cough-inducing or aerosol-generating procedures are performed Laboratories in which clinical specimens that might contain M. tuberculosis are not manipulated
Settings in which Persons with TB disease are encountered Criteria for low risk are not otherwise met
Laboratories
Potential for ongoing transmissionb Evidence of ongoing M. tuberculosis transmission, regardless of setting
Laboratories in which clinical specimens that might contain M. tuberculosis are manipulated
LTBI, latent TB infection. Courtesy of the Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005. MMWR 2005; 54(RR-17): 1–142. Available online at: http://www.cdc.gov/mmwr/. a Settings that serve communities with a high TB incidence, treat populations at high risk (e.g. those with HIV infection or other immunocompromising conditions), or treat patients with drug-resistant TB disease might need to be classified as medium risk, even if they meet the low-risk criteria. b ‘Potential ongoing transmission’ is applied to a specific group of healthcare workers or to a specific area of the healthcare setting in which evidence of ongoing transmission is apparent. Otherwise, it is applied to the entire setting. The classification is temporary and warrants immediate investigation and corrective steps after it has been determined that ongoing transmission has ceased. The setting is reclassified as medium risk, the recommended time frame for which is at least 1 year.
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Table 68.2 Steps to be taken to establish a tuberculosis infection control programme Settings in which patients with suspected or confirmed TB disease a are expected to be encountered
Settings in which patients with suspected or confirmed TB disease b are not expected to be encountered
1. Assign supervisory responsibility for the TB infection control programme to a person or group with expertise in LTBI and TB disease, infection control, occupational health, environmental controls, and respiratory protection. Give the supervisor or supervisory body the support and authority to conduct a TB risk assessment, implement and enforce TB infection control policies, and ensure recommended training and education of HCWs. Train the persons responsible for implementing and enforcing the TB infection control programme. If supervisory responsibility is assigned to a committee, designate one person as the TB resource person to whom questions and problems should be addressed. 2. Write up a TB infection control plan that outlines the protocol for the prompt recognition and initiation of airborne precautions of persons with suspected or confirmed TB disease, and update it annually. Conduct a problem evaluation if a case of suspected or confirmed TB disease is not promptly recognized and appropriate airborne precautions are not initiated, or if administrative, environmental, or respiratory-protection controls fail. 3. Perform a contact investigation in collaboration with the local or regional health department if healthcare-associated transmission of M. tuberculosis is suspected. Implement and monitor corrective action. 4. Collaborate with the local, state, or regional health department to develop administrative controls consisting of the risk assessment, TB infection control plan, management of patients with suspected or confirmed TB, training and education of HCWs, screening and evaluation of HCWs, problem evaluation, and coordination. 5. Implement and maintain environmental controls, including airborne infection isolation (AII) room(s). 6. Implement a respiratory-protection programme. 7. Perform ongoing training and education of HCWs. 8. Create a plan for accepting patients who have suspected or confirmed TB disease when they are transferred from another setting.
1. Assign responsibility for the TB infection control programme to appropriate personnel. 2. Write up a TB infection-control plan that outlines the protocol for the prompt recognition and transfer to another healthcare setting of persons who are suspected of having or confirmed to have TB. The plan should include procedures for separating persons with suspected or confirmed infectious TB from others in the setting until time of transfer. Evaluate the plan annually, if possible, to ensure that the setting remains one in which persons who have suspected or confirmed TB are not encountered but are promptly transferred. 3. Conduct a problem evaluation if a case of suspected or confirmed TB disease is not promptly recognized, separated from others, and transferred. 4. Collaborate with the local or state health department in investigation whenever healthcare-associated transmission of M. tuberculosis is suspected. 5. Collaborate with the local or state health department to develop administrative controls consisting of the risk assessment and TB infection control plan.
LTBI, latent TB infection; HCWs, healthcare workers. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005. MMWR 2005; 54(RR-17): 1–142. Available online at: http://www.cdc.gov/mmwr/. a Settings in which services are provided to persons who have suspected or confirmed infectious TB, including laboratories and non-traditional facilitybased settings, should have a TB infection control plan consisting of administrative, environmental, and respiratory-protection controls. b Settings in which TB patients might stay before transfer should still have a TB infection control programme consisting of administrative, environmental, and respiratory-protection controls.
ADMINISTRATIVE CONTROLS Administrative controls are the systems that should be in place to identify, investigate, and promptly and effectively treat patients in hospital (or other healthcare facilities) who may have TB. These measures are intended primarily to reduce the risk of exposing uninfected persons to those who have infectious TB. They are the most effective for reducing the risk of healthcare-associated TB and should be implemented first by all healthcare facilities that admit patients with active TB. Administrative controls include the following:1–3,9
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development and implementation of effective evidence-based TB control policies and procedures based on local risk assessments; in-service education and training; and screening and counselling of employees.
Developing and implementing tuberculosis infection control policies and procedures Local policies can provide guidance on how to promptly identify, isolate, diagnostically evaluate, and treat persons likely to have infectious TB. These policies can also detail supervisory responsibility for TB and outline a series of effective work practices that minimize the risk to healthcare workers (HCWs), patients, and visitors of exposure to M. tuberculosis. Identification of potentially infectious patients Those healthcare personnel with supervisory responsibility for TB in outpatient (ambulatory-care) and in-patient settings need to develop, implement, and audit protocols for promptly identifying potentially infectious TB patients. During audit, key performance standards, for example, time from presentation to isolation, to specimen
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collection, to sputum microscopy result, to initiation of anti-TB therapy, should be elicited. The criteria used in these protocols will be based on the prevalence and characteristics of TB in the population served as identified in the risk assessment. Any patient with signs and symptoms of TB (see Chapters 16 and 17) and who is sputum smearpositive for acid-fast bacilli (AFB) should be isolated until a diagnosis of active TB has been excluded.9 The implementation of these protocols needs to be periodically evaluated and revised appropriately as warranted by new risk assessment and audit data.
Isolation of infectious cases Patients with suspected infectious TB need to be placed in an area away from other patients and certainly away from immunocompromised patients. Tuberculosis patients may be isolated in either negative pressure respiratory isolation rooms (discussed later) or a single room (with the door closed) and preferably a room where the air is vented to the outside. Any patient in whom multidrugresistant (MDR)-TB or extensively drug-resistant (XDR)-TB is suspected (see Chapters 53 and 54) should only be cared for in a negative pressure respiratory isolation room, if available.1–3 All patients with suspected (or proven) active pulmonary or laryngeal TB being cared for in a ward or unit where immunocompromised patients are placed, for example a care area for patients with human immunodeficiency virus (HIV) disease, must be placed in a fully monitored negative pressure respiratory isolation room (airborne infection isolation room, AII room).1–3,9 The algorithm developed by NICE (Fig. 68.2) illustrates appropriate patient placement as
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determined by risk assessment.3 The local TB infection control policy will outline arrangements for transferring patients with suspected MDR/XDR-TB or HIV-related TB to another facility when negative pressure respiratory isolation rooms are not available. Additional isolation practices are often used in order to offer added safety and patient benefits when patients need to leave their respiratory isolation room for treatment or diagnostic procedures in other areas of the hospital.8–10 These include the following:
Masking patients: patients with suspected or known infectious TB should wear a surgical mask when they are not in a respiratory isolation room or another area where there is appropriate and effective exhaust ventilation. The purpose of the mask is to block aerosols produced by the patient when coughing, breathing, or talking. A particulate filter respirator (PFR) is not required for this purpose and should not be used. A surgical mask on a cooperative patient provides short-term protection. The mask is changed when damp. Isolating and segregating suspected infectious TB patients: in order to further minimize the risk of transmission, and to avoid embarrassment and concern to both the patient and others in the department, masked patients should ideally be escorted to a private waiting area or examination room. Fast tracking: arrangements need to be made in advance for consultations or investigations in other departments so that masked patients can be ‘fast tracked’ through the procedure. This means that they are expected when they arrive and are
Known or suspected MDR-TB. based on risk assessment?
Yes
No
Admit to negative pressure room
Admit to single room
Sputum smear positive (1 or more from 3 samples)? Yes
No
Risk for MDR-TB?
Risk for MDR-TB? No
Yes
Fig. 68.2 Isolation decisions for patients with suspected respiratory TB. Courtesy of the National Collaborating Centre for Chronic Conditions. Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London. Royal College of Physicians. March 2006.
Negative pressure room (irrespective of HIV status). Molecular probe for rifampicin resistance
Yes
No
Does ward have immunocompromised patients? No Single room on ward
Does ward have immunocompromised patients? Yes
Yes
No
Negative pressure room
Standard ward
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quickly seen and processed and returned to respiratory isolation. Patients need to be accompanied by a HCW to ensure that they do not remove the mask or get lost. Delay of high-risk procedures: aerosol-generating and coughinducing procedures not immediately required for diagnosis or treatment should be delayed if at all possible until a suspected or proven infectious TB patient is no longer infectious. Cough hygiene: unmasked patients should be instructed to cover their mouth and nose with tissues when they cough. Tissue dispensers should be placed within easy reach of all patients throughout the hospital. Aerosol-generating procedures: for all patients in HIV wards, units, and clinics, aerosol-generating procedures, such as bronchoscopy, sputum induction, or nebulizer treatment, must be carried out in an appropriately engineered and ventilated area. These procedures must never be done on an open ward or bay as they have been responsible for outbreaks of healthcare-associated TB.11–13
Patients remain in isolation until they are deemed non-infectious by the medical and nursing team caring for them. Patients with sputum smear-positive TB not known or suspected to have MDR-TB usually become non-infectious after 2 weeks of effective anti-TB treatment and remain so if regular adequate treatment is continued, even though tubercle bacilli might still be occasionally seen in sputum smears. In hospitals and other institutional healthcare facilities, segregation for reasons of infectiousness is generally required for only 2 weeks following the commencement of effective anti-TB therapy.1,3 This assumes that the patient has had a minimum of 2 weeks of anti-TB treatment, and that his (or her) signs and symptoms are regressing, that his general condition is improving, that he is coughing less, and usually that he has had three negative sputum smears on 3 consecutive days. However, criteria for discontinuing respiratory isolation must be judged individually. Care must be taken in discontinuing respiratory isolation in a patient on an HIV ward (Table 68.3),14 as the consequences of a patient with infectious TB on an open ward with many other HIVinfected immunocompromised patients may be life-threatening.11–13 Clearly patients with MDR-TB and, more rarely, those with XDRTB are infectious for a longer period of time and, consequently, need to remain in respiratory isolation for a longer period.
Diagnostic evaluation for active tuberculosis All patients with a provisional diagnosis of active TB need to be examined by a physician as soon as possible and appropriate diagnostic measures conducted. Prompt laboratory results are essential to initiating anti-TB therapy. Healthcare facilities which do not have their own TB experienced laboratory need to have arrangements in place for referral to a reference laboratory which uses the most rapid methods for the culture and identification of mycobacteria, and for drug-susceptibility testing. Results of sputum microscopy for the detection of AFB should be available within 24 hours (or within 1 working day) of specimen collection. Serology for HIV infection should be offered and encouraged for patients with suspected (or proven) TB. Diagnostic investigations are fully described in Section 4 of this book. Early antituberculosis treatment Patients who have confirmed active TB or who are considered highly likely to have active TB should promptly commence appropriate anti-TB therapy. Most patients with drug-susceptible TB are quickly rendered non-infectious within just a few weeks of treatment.
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Table 68.3 Cessation of respiratory isolation in an HIV setting A patient with active TB on an HIV ward can be considered non-infectious if the following criteria are met: Sputum smear-positive cases a. The patient has had a minimum of 2 weeks of appropriate multidrug therapy; and b. If potentially being moved to accommodation (in-patient or home) with HIV-infected or immunocompromised persons, the patient has had a minimum of three negative sputum microscopic smears on separate occasions over at least a 14-day period; and c. The patient has shown tolerance to the prescribed treatment, and an ability and agreement to adhere to treatment; and either d. There has been a complete resolution of cough in the patient; or e. The patient shows definite clinical improvement to treatment, for example, remaining afebrile for 1 week. Sputum smear-negative cases The patient has had a minimum of three negative sputum microscopic smears on separate occasions over at least a 14-day period; or If no sputum, and bacteriology is only from bronchoscopy and lavage, (a), (c), (d), and (e) above apply. Note: The bacteriological response to anti-TB chemotherapy is equally good in HIV-and non-HIV-infected individuals. Courtesy of the Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Thorax 2000;55:887–901. Available online at: http://thorax.bmjjournals.com/content/vol55/issue11/index.shtml#BTS% 20GUIDELINES.
In-service education All HCWs, including physicians, should receive training and education regarding TB relevant to their particular occupational group. Ideally, training should be given as part of their orientation/induction programme and repeated on an annual basis. The level and detail of the training given will vary according to the HCWs’ clinical responsibility and level of risk in the hospital or healthcare facility. Multimodal educational methods, such as faceto-face, trainer-led, and self e-learning, provide opportunities for HCWs to update their knowledge and skills without necessarily leaving their ward or department. Employee screening, counselling and prevention programme Occupational health departments need to have effective services in place to screen HCWs for TB. Those who have a positive tuberculin skin test result, a tuberculin skin test conversion, or symptoms suggestive of TB should be identified and evaluated in order to rule out a diagnosis of active TB, or commenced on anti-TB therapy or preventative therapy if indicated. For example, recommendations for screening healthcare staff in the UK include the following measures. Pre- and on-employment measures Pre- and on-employment measures described by NICE are outlined in Fig. 68.3.3 A pre-employment personal health questionnaire and on-employment health check should elicit any previous history of TB or symptoms suggestive of TB, information of previous Bacillus Calmette–Gue´rin (BCG) vaccination and the presence or absence of a BCG scar, and, if indicated, tuberculin skin testing and a chest
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Pre-employment questionnaire
No
Yes
New entrant?
Chest radiograph
Suspicious symptoms?
Yes Medical assessment, chest radiograph
Normal?
No
Normal?
No TB clinic
Yes Working with patients or clinical materials?
Yes Yes No
Prior BCG (scar or documented)?
Mantoux,interferon-gamma test, unless performed in past 5 years No
No
Yes Medical assessment
Mantoux or interferon-gamma test positive?
Yes
No Suspicious symptoms or circumstances? No Yes
Fig. 68.3 Screening newly appointed healthcare workers. Courtesy of the National Collaborating Centre for Chronic Conditions. Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. London. Royal College of Physicians. March 2006.
TB clinic
No action
radiograph. A tuberculin skin test is only necessary in those new employees who either do not have a BCG scar (as recorded by an experienced person) or reliable documentary evidence of previous BCG vaccination. New healthcare employees from a country where the annual TB incidence is greater than 40/100,000 of the population and who have not been screened for TB on entry into the UK or by a previous employer in Britain should routinely have both a chest radiograph and a tuberculin skin test. Tuberculin skin test-negative employees from countries with a high HIV prevalence should have HIV serological testing prior to BCG vaccination. HIV-infected persons may have a suppressed reaction to tuberculin skin testing and test negative regardless of infection with M. tuberculosis, a condition known as anergy.
Inform and advise, consider treatment for latent TB infection
Yes
Risk assessment
Chest radiograph normal? No TB clinic
Record refusals, Notify occupational health
Offer BCG
HCWs in employment Although it is uncommon for HCWs to acquire TB from patients in the UK, it is always a potential risk. In some other countries, the risk to HCWs of occupationally acquired TB may be increased due to the greater prevalence of TB and lack of adequate resources to effectively diagnose and isolate infectious patients. The in-service education programme described earlier will increase staff awareness and encourage them to promptly seek medical advice should they experience any signs or symptoms suggestive of active TB. The risk to patients and other HCWs from a member of staff with undiagnosed infectious TB is severe, especially in those units caring for immunocompromised patients. Routine periodic chest radiography for HCWs is not effective in detecting TB.
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HIV-infected HCWs HIV-infected HCWs have an increased susceptibility to develop active TB following previous infection and/or reinfection. Any protection conferred by previous BCG vaccination will be reduced naturally over time and, more importantly, as a result of a progressive decline in cell-mediated immunity caused by ongoing HIV replication. Consequently, previous BCG vaccination will not protect them from new infection. Additionally, in some countries, a higher than expected incidence of drug and multidrug resistance has been encountered in localized epidemics of HIV-related TB. Many HIV-infected HCWs choose to care for HIV-infected patients. As TB is the most common opportunistic infection associated with HIV disease, immunocompromised HCWs who work in HIV wards, units, and clinics are more frequently exposed to infectious TB, and are probably more frequently exposed to MDR-TB. There is a substantial risk to immunocompromised HCWs from HIV-infected patients who have undiagnosed or confirmed active TB. There is also a serious risk to HIV-infected patients from immunocompromised HCWs who develop active TB and continue to work before their condition is identified and they are isolated and treated. Consequently, all HCWs who believe they may have been exposed to HIV infection in whatever circumstances have an ethical responsibility to seek expert medical advice and serological testing if indicated. If HIV infection is confirmed, they need to inform occupational health services, who can advise whether an alternative clinical assignment is necessary to avoid possible exposure to TB (or any highly infectious disease, such as chickenpox or measles). In no circumstances should immunocompromised HCWs care for patients with active TB. As stated previously, HIV-infected HCWs should not receive BCG vaccination as this is a live vaccine which can cause severe local lesions or even disseminated BCG infection (BCG-osis), as discussed in Chapter 74. All immunocompromised HCWs need to remain under the care of specialist medical services and the occupational health service. ENVIRONMENTAL (ENGINEERING) CONTROLS Engineering controls, the second level of the TB control hierarchy, are based primarily on the use of adequate ventilation systems, sometimes supplemented with high-efficiency particulate air (HEPA) filtration and ultraviolet germicidal irradiation (UVGI).1–3,9 These controls are used to further minimize the risk of healthcare-associated TB by decreasing the concentration of infectious droplet nuclei in the air, preventing the dissemination of droplet nuclei throughout the hospital or healthcare facility, and rendering droplet nuclei non-infectious by killing the tubercle bacilli they contain.
Ventilation Ventilation systems for healthcare facilities should meet the needs of the institution’s risk assessment and be designed and modified when necessary by ventilation engineers in collaboration with infection control and occupational health staff. Hospital ventilation systems are described in detail in CDC guidelines,1,2 and their diversity and complexity preclude giving specific advice here, except for brief comments on general ventilation and local exhaust
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ventilation (LEV), and descriptions of ventilation features of negative pressure respiratory isolation rooms.
General ventilation General ventilation systems in healthcare facilities are designed to dilute and remove contaminated air, control airflow patterns within rooms, and control the direction of airflow throughout a hospital or healthcare facility. They are fully described in CDC guidelines.1,2 Local exhaust ventilation (LEV) LEV is designed to capture airborne contaminates at or near their source and remove them before they disperse without exposing persons in the area to infectious microorganisms. LEV is the preferred source control technique for enclosing devices used for aerosol-generating procedures, such as laboratory hoods, booths for sputum induction or the administration of aerosolized medications, and hoods and tents made of vinyl or other materials to enclose and isolate a patient. Booths, tents, and hoods should have sufficient airflow to remove at least 99% of airborne particles during the interval between the departure of one patient and the arrival of the next. Exterior devices are generally a hood very near but not enclosing the infectious patient. Further information on their specification and use is available online from the CDC.1,2 Negative pressure respiratory isolation rooms Ventilation for respiratory isolation rooms is designed to achieve a negative pressure in respect to adjacent areas, preventing contaminated air from escaping the room to other areas in the hospital or healthcare facility. Negative pressure rooms are used for respiratory isolation, which is known in the USA as airborne infection isolation (AII); i.e. the isolation of patients infected with microorganisms that spread via airborne droplet nuclei < 5 mm in diameter, such as M. tuberculosis. Salient features recommended by CDC for AII rooms are described in Table 68.41,2 Isolation rooms need to be monitored on a daily basis when in use to ensure that the negative pressure is maintained. Isolation room exit doors need to be kept closed (preferably having self-closing devices), except when patients or HCWs must enter or exit, in order to maintain negative pressure. There should be a pressure gauge on the outside of the door that continuously indicates whether the room is under negative pressure. High-efficiency particulate air filtration HEPA filters may be used in ventilation systems to remove droplet nuclei from the air, or installed in ventilation ducts to filter air for recirculation into the same room or recirculation to other areas of a healthcare facility (although air exhausted directly outside is preferable). Portable HEPA filtration units are sometimes used for supplemental air cleaning and some incorporate an ultraviolet germicidal irradiation feature. HEPA filters must be carefully installed and maintained. Ultraviolet germicidal irradiation UVGI can kill tubercle bacilli contained within droplet nuclei. Because exposure to ultraviolet light can be harmful to the skin and eyes, shielded lamps are always installed in the upper part of rooms or corridors where normal air currents circulate contaminated air into an upper room/corridor ‘killing zone’. UVGI may also be installed in ventilation exhaust vents to provide supplemental air cleaning.
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Table 68.4 Characteristics of a respiratory isolation room 1,2 (airborne infection isolation, AII)
A room used for AII receives numerous air changes per hour (ACH); preferably 12 ACH but no less than 6 ACH. AII rooms are under negative pressure, such that the direction of the airflow is from the outside adjacent space, for example the corridor, into the room. A continuous negative air pressure (2.5 Pa (0.01 in. water gauge)) in relation to the air pressure in the corridor is maintained. The air in an AII room is preferably exhausted directly outside away from air intakes and traffic, but may be re-circulated provided that the return air is filtered through a high-efficiency particulate air (HEPA) filter. HEPA filters can be used in ventilation systems to remove droplet nuclei from the air. Ultraviolet germicidal irradiation (UVGI) units may also be installed in exhaust air ducts or near the ceiling to irradiate upper room air. The use of personal respiratory protection is also indicated for persons entering these rooms when caring for patients with TB (or other airborne transmitted infectious diseases). AII rooms are also used for patients with or suspected of having an airborne infection who also require cough-inducing or other aerosolgenerating procedures.
Courtesy of the Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005. MMWR 2005;54(RR-17):1–142. Available online at: http://www.cdc.gov/mmwr/ and 2. Centers for Disease Control and Prevention. Guidelines for environmental infection control in health-care facilities: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR 2003;52(RR-10):1–45. Available online at: http://www.cdc.gov/mmwr/ preview/mmwrhtml/rr5210a1.htm.
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The CDC recommends that all persons entering rooms where patients with known or suspected infectious TB are being isolated should use personal respiratory protection. PFRs should also be used by HCWs present during cough-inducing or aerosolgenerating procedures performed on such patients and by persons in other settings where administrative and engineering controls are not likely to protect them from inhaling infectious droplet nuclei. In England and Wales, NICE recommends that personal respiratory protection only be used by visitors and HCWs caring for people with suspected or known MDR-TB while that person is infectious and when assisting with aerosol-generating procedures.3,9,10
Respiratory protection programme A respiratory protection programme needs to be developed, implemented, and periodically re-evaluated in any healthcare facility in which personal respiratory protection is used. All HCWs who need to use respirators for protection against M. tuberculosis need to be trained in the safe and appropriate use of these devices. Face-seal fit testing and fit checking HCWs need to undergo fit testing to ensure the provided respirator adequately fits them. The need to receive full fitting instructions that include demonstrations and practice in how the respirator should be worn, how it should be adjusted, and how to determine whether it fits properly. HCWs need to be taught to check the fit before each use. Male HCWs with facial hair need to be advised that they will be unable to obtain an adequate facial seal when using disposable particulate filter respirators.
SUMMARY PERSONAL RESPIRATORY PROTECTION In some healthcare settings, administrative and engineering controls may not fully protect HCWs from infectious droplet nuclei.1–3,8,9 In these circumstances, special facemasks known as particulate filter respirators (PFRs) are used. This is known as personal respiratory protection and it is the third level in the hierarchy of controls used to prevent exposure to tubercle bacilli. Personal respiratory protection is not as effective as administrative and engineering controls but will provide additional protection when needed and when appropriately used. PFRs are different from surgical masks. Surgical masks are designed to prevent respiratory secretions of the person wearing the mask from entering the air. PFRs are designed to do the exact opposite, which is to filter the air before it is inhaled by the person wearing the respirator. PFRs are capable of filtering out particles with a diameter of 5 mm or smaller. In many developed countries, approved PFRs are certified by regulatory agencies, such as the National Institute for Occupational Safety and Health (NIOSH) in the USA. In Europe standards are laid down by the European Union (EU) parliament. NIOSH certifies the N-series of PFRs, particularly the N95 PFR for protection from healthcare-associated TB. The EU certifies the EN149 (Personal Protective Equipment) FFP series of PFRs, and in England the FFP3 PFR is recommended for protection against healthcare-associated TB.3
In this chapter we have explored general infection prevention and control practices which form the basis of current strategies for minimizing the risks for healthcare-associated infection in general and healthcare-associated TB in particular. These strategies are responsive to specific hazards for exposure to M. tuberculosis in each of our healthcare facilities which can be identified by conducting a risk assessment. The specific administrative and engineering control measures, and personal respiratory protection procedures that need to be incorporated into local strategies are adapted from a series of evidence-based guidelines issued by departments of health and professional organizations, such as the CDC in the USA and the NICE in England and Wales.1–3 As TB continues to be a serious threat, and as more and more persons develop active disease and seek treatment and care, it will remain a potential hazard to those healthcare practitioners who provide that care. Having well thought out evidence-based policies and procedures in place that provide guidance on safe work practices and ensuring that HCWs are trained to consistently incorporate this guidance into everyday clinical care is the first step in providing a safe environment for healthcare. In addition, HCWs need supervision and support to sustain adherence to policy and managers of healthcare facilities need to audit practice and reassess the risks for transmission of M. tuberculosis on a regular basis so that any identified risk is minimized and quality of care is continuously improved.
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REFERENCES 1. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Morb Mortal Wkly Rep 2005;54(RR-17):1–142. Available at URL: http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5417a1.htm 2. Centers for Disease Control and Prevention. Guidelines for environmental infection control in health-care facilities: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR Morb Mortal Wkly Rep 2003;52(RR-10):1–45. Available at URL: http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5210a1.htm 3. National Collaborating Centre for Chronic Conditions. Tuberculosis: Clinical Diagnosis and Management of Tuberculosis, and Measures for its Prevention and Control. London: National Institute for Health and Clinical Excellence, 2006. Available at URL:http://www.nice.org.uk/CG033 4. Pellowe CM, Pratt RJ, Harper P, et al. and the Guideline Development Team. Evidence-based
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5.
6.
7.
8.
guidelines for preventing healthcare-associated infections in primary and community care in England. J Hosp Infect 2003;55(Suppl 2):S1–S127. Available at URL:http://www.epic.tvu.ac.uk Pratt RJ, Pellowe CM, Wilson JA, et al. epic2: National evidence-based guidelines for preventing healthcare-associated infections in NHS hospitals in England. J Hosp Infect 2007;65(Suppl 1): S1–S64. Available at URL:http://www.epic.tvu. ac.uk Garner JS, Hospital Infection Control Practices Advisory Committee. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:53–80. Available at URL: http://www.cdc.gov/ncidod/hip/isolat/isolat.htm Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR Morb Mortal Wkly Rep 1994;43(RR-13): 1–132. Available at URL:http://www.cdc.gov/ mmwr/preview/mmwrhtml/00035909.htm Pratt RJ, Curran ET. Personal respiratory protection and tuberculosis: national evidence-based guidelines in England and Wales. Br J Infect Control 2006;7: 15–17. Available at URL:http://www. richardwellsresearch.com
9. Curran ET, Hoffman PN, Pratt RJ. Tuberculosis and infection control: a review of the evidence. Br J Infect Control 2006;7:18–23. Available at URL: http:// www.richardwellsresearch.com 10. Curry FJ. Tuberculosis Exposure Control Plan: Template for the Clinic Setting. National Tuberculosis Center, Institutional Consultation Services, 1999: 1–54. Accessed 25 March 2007. Available at URL:http:// www.nationaltbcenter.edu 11. Kent RJ, Uttley AHC, Stoker NG, Miller R, Pozniak AL. Transmission of tuberculosis in a British care centre for patients infected with HIV. BMJ 1994;309:639–640. 12. Jarvis WR. Nosocomial transmission of multidrugresistant Mycobacterium tuberculosis. Am J Infect Control 1995;23:146–151. 13. Di Perri G, Cruciani M, Danzi MC, et al. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 1989;334:1502–1504. 14. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Thorax 2000;55:887–901. Available at URL: http://thorax. bmjjournals.com/content/vol55/issue11/index. shtml#BTS%20GUIDELINES
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Nursing care of patients with tuberculosis Robert J Pratt and Johan van Wijgerden
INTRODUCTION In many regions of the world, people with TB are embarked on a perilous journey that frequently terminates in death, either following acute illness or at the end stage of chronic debilitating illhealth. Nurses are able to support patients during all phases of this journey and their interventions can make the defining contribution to the provision of good quality care which influences the likelihood of more positive patient health outcomes. The role of the nurse in providing person-centred care to patients with TB is reviewed in this chapter by using the experience of a patient case study. A problem-solving approach serves as a dynamic and holistic organizing structure to assess, plan, implement, and evaluate individualized nursing care for this patient. In addition, an international system of nursing diagnoses is illustrated as a framework for enhancing the clarity of the nursing process. This system also provides examples of how the most frequently identified healthcare needs and problems identified in patients with TB facilitate the development of a nursing care plan with appropriate patient-centred outcomes and associated evidence-based nursing interventions.
THE ROLE OF THE NURSE The international definition of nursing,1 shown in Box 69.1, describes a range of activities that illustrate the uniqueness and core essence of the contribution by nurses to meaningful and effective healthcare. Without competent nursing management, the care and treatment of people with TB will be substantially impoverished and their chances of recovery diminished. Patients with TB are cared for in a variety of settings, including acute care facilities, outpatient departments, TB and respiratory medicine clinics, and specialist primary and community care TB services. Many patients will need to access care in all of these environments at one time or another during the course of their illness. Thus, for example, patients are frequently admitted to hospital for investigation, diagnosis, and initiation of treatment and, following discharge, they receive continuing care from community and primary TB services. Most patients are predominantly cared for in the community. Nurses provide much of the ongoing care relevant to each patient during the different stages of their illness and in all healthcare settings. Furthermore, nurses in TB clinics and other services frequently manage and coordinate an indispensable hub of
multidisciplinary care and support. Nurses also act as advocates and guides for patients journeying through the complexities of modern multiagency healthcare services. In addition, through communication, nurses can instruct the patient, relatives, and the community in the nature of TB, thereby encouraging early presentation for diagnosis and compliance with anti-TB treatment regimens, and to reduce the stigmatizing effects of the disease, particularly in regions where TB is associated in local beliefs with HIV infection.
PERSON-CENTRED CARE The nursing process has evolved during the past several decades and is now used by nurses throughout the world as an organizing framework for providing individualized person-centred care. This process is cyclical and ongoing and is generally used in conjunction with various theoretical nursing models or philosophies.2 The stages of the nursing process are holistic, in the sense that each stage is intimately interconnected with the other stages and is explicable only by reference to the whole. This process, similar to those used in problem-solving and scientific reasoning, incorporates assessment, diagnosis, planning, implementation, and evaluation phases (Fig. 69.1).
NURSING ASSESSMENT There are two components to a comprehensive nursing assessment. The first component is a systematic collection of subjective (described by the patient) and objective (observed by the nurse) assessment data. This is done by taking a nursing health history and examining the patient. Detailed guidelines on conducting nursing health assessments are widely available,3 and Box 69.2 provides an abbreviated format of the assessment. The second component of the nursing assessment is an analysis of the data and its use in a meaningful way to formulate an easily understandable and precise nursing care plan. One way this can be done is by making use of nursing diagnoses to plan and evaluate patient-centred outcomes and associated nursing interventions.
NURSING DIAGNOSES Nursing diagnostic statements are clinical judgements about individual, family, or community responses to actual or potential health problems and life processes,4 and are the logical culmination of the
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4
Box 69.1 International definition of nursing
Table 69.1 Three-part PES diagnostic statement
Nursing encompasses autonomous and collaborative care of individuals of all ages, families, groups and communities, sick or well and in all settings. Nursing includes the promotion of health, prevention of illness, and the care of ill, disabled and dying people. Advocacy, promotion of a safe environment, research, participation in shaping health policy and in patient and health systems management, and education are also key nursing roles. International Council of Nurses.1
P (Problem)
E (Etiology)
S (Symptoms)
The nursing diagnosis (label); a concise term or phrase that represents a pattern of related cues
The related to factors, i.e. the related causes or contributor to the problem
Defining characteristics statement, summarizing symptoms identified during the nursing assessment
Systems examination
Assessment Nursing history
Nursing diagnosis
Rights were not granted to include this content in Nursing Interventions electronic media. Please refer to the printed book. process Evaluation Planning Outcomes
Implementation
Fig. 69.1 The nursing process. International Council of Nurses. Definition of Nursing. ICN website accessed January 10, 2007. [http://www.icn.ch/ definition.htm]
Box 69.2 Nursing assessment At interview, verifiable data from the primary source (patient) and secondary sources (family, healthcare professionals, medical records) are elicited. Nursing health history Biographical information Reasons for seeking healthcare Patient expectations Present illness or health concerns Health, family, environmental, and psychosocial history Spiritual health History of allergies, dietary restrictions, relevant medical history. Physical examination Vital signs records Other objective measurements made, e.g. height, weight, sputum, cough, diaphoresis Examination of all body systems in a systematic manner.
analysis of the assessment data. They include a description of the functional behaviours that can be improved through nursing interventions and the causative factors of those aspects of patient behaviour that nurses need to improve or influence. There are two ways to formulate a nursing diagnosis. A two-part system consists of the nursing diagnosis and the related to statement, with the latter listing those aetiological factors relevant to the diagnosis. A three-part
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system, known as the PES (problem–etiology–symptoms) system (Table 69.1), includes the above, plus a statement of the defining characteristics which are the various signs and symptoms identified during the nursing assessment and used to make the diagnosis. To take an example, a patient with active pulmonary TB could be diagnosed with hyperthermia related to infection, disease, dehydration, and an increased metabolic rate and with defining characteristics including fever (core body temperature elevated at least 0.8–1.1 C) above the person’s normal temperature (> 38 C), or hyperthermia (body temperature > 40 C) with flushed or hot skin, increased respiratory rate, and tachycardia. In another example, the analysis of the nursing assessment data may indicate a diagnosis of ‘ineffective therapeutic regimen management’, defined as a daily programme of life-incorporating treatment of the illness that fails to meet the necessary specific health goals.5 In the patient described in the case study presented below, the defining characteristics (signs and symptoms) associated with the diagnosis of ineffective therapeutic regimen management include choices of daily life style inadequate for meeting goals of antiretroviral and (potentially) anti-TB treatment, admission by the patient that he did not take action to include the treatment regimen in his daily routine, and his admission of difficulty with following the prescribed drug regimen. The related factors (aetiology) include a lack of understanding of his illness and treatment, the complexity of the drug regimen, homelessness, and a chaotic lifestyle. In the most widely used system, the North American Nursing Diagnosis Association-International (NANDA-International),5 provision is made for five categories of diagnosis, listed in Table 69.2. The formulation of a nursing diagnosis as a standardized statement for expressing the results of the assessment of the problems and needs of a patient provides a uniform way of identifying, describing, focusing on, and dealing with the problems and needs and is an ideal framework on which to base the nursing process. Once identified and documented, the nursing diagnosis provides direction for the remainder of the nursing process. Today, standardized nursing diagnostic statements continue to evolve into dynamic conceptual systems that guide the classification of nursing diagnoses into a widely used international one.5,6 By using nursing diagnoses and standardized descriptions of nursing interventions and patient outcomes, nurses around the world are enabled to use the same language to systematically document their work with patients, families, and communities.6
PLANNING CARE Following the assessment and the formulation of the nursing diagnosis, a plan of care is developed in partnership with the patient. As patients usually have multiple diagnoses, these must be
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Table 69.2 Categories of nursing diagnoses Category
Refers to statement about –
5
Example (diagnosis)
Actual diagnosis
A health problem that Fatigue due to advanced has been identified, i.e. TB and malnutrition actually exists and will benefit from nursing intervention Risk Health problems that the Ineffective airway diagnosis patient is at a higher than clearance related to normal risk of decreased energy as developing in the near manifested by an future ineffective cough were not granted to the include this in due to Possible Rights Health problem that Riskcontent for infection media. Please refer to theunderlying printed book. diagnosis electronic patient might actually TB related to have but which cannot immunosuppression be confirmed until more and advanced disease information is obtained state Syndrome A cluster of nursing Risk of the relocation diagnosis diagnoses seen together stress syndrome due to transfer to a long-term chronic infectious disease facility Effective therapeutic Wellness An aspect of the patient diagnosis at a high level of regimen management wellness due to excellent adherence to anti-TB therapy North American Nursing Diagnosis Association – International (NANDA-I). Nursing Diagnoses: definitions and classification, 2007– 2008. Philadelphia: NANDA; 2007. 343 pp.
prioritized when developing the care plans. Thus, for example, immediate severe respiratory problems which may be life-threatening have a greater priority than many other patient problems and needs. There are two aspects to the development of the care plan: formulating measurable outcomes and planning nursing interventions.
Outcomes Outcomes describe individual, family, or community states, behaviours, or perceptions measured along a continuum in response to nursing interventions.7 There are two methods of developing relevant and appropriate outcomes. They can be selected from the set of standardized patient outcomes in the Nursing Outcomes Classification,7 or, as demonstrated in the care plan described below, individualized patient outcome statements relevant to the nursing diagnosis can be developed. Outcomes incorporate a time frame for achievement and, as they are the criteria used for evaluation, an indication of how achievement will be measured is described in the care plan. Nursing interventions Once outcomes have been developed and agreed, nursing interventions that facilitate their achievement are planned and implemented. Planning and using nursing interventions based on good quality evidence of effectiveness is of importance to ensure that the desired outcomes of care are achieved. Identifying, appraising, and incorporating the best currently available research into evidence-based nursing practice promotes clinically effective quality care. As in the case of nursing diagnoses and outcomes, a comprehensive set of standardized nursing interventions, known as the Nursing Intervention Classification, has been developed,8 and is
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linked to both the NANDA-International diagnoses and the Nursing Outcomes Classification referred to earlier. Outcomes of care and associated nursing interventions that have been developed in collaboration with the patient provide a clear structure for the effective audit of nursing practice, facilitate better patient adherence to therapeutic regimens, and keep the patient at the centre of the care process.
IMPLEMENTATION AND EVALUATION The care plan is then implemented and all interventions and responses are carefully documented. The outcomes of care are evaluated on a regular basis and care is re-planned as necessary.
USING A NURSING CARE PLAN The use of a nursing care plan is best illustrated by a case study. The one presented here is based on the experience of Jason, a patient who requires in-patient care and further support in the community, and illustrates the development of a patient-centred nursing care plan that incorporates those diagnoses, outcomes, and interventions frequently identified and developed for patients with active pulmonary TB, the commonest form of the disease seen in clinical practice. More comprehensive examples of developing care plans by using nursing diagnoses, patient outcomes, and nursing interventions are described in standard nursing textbooks,4,5,7,8 and an online care plan constructor is available from the evolve website (http://evolve.elsevier.com/ackley/ndh).
CASE STUDY Jason is a 26-year-old homeless man who presented to the accident and emergency department of his local hospital complaining of a constant cough, haemoptysis, low-grade intermittent fever, and night sweats for the past month. He states that he has been progressively unwell for the past 6 months, during which time he has lost a considerable amount of body weight and has become increasingly fatigued and anxious. He smokes 40 cigarettes a day and states that he is an alcoholic. Jason has a past history of injecting drug use. Two years ago he was treated for pneumonia caused by the fungus Pneumocystis jirovecii. On testing, he was found to be infected with human immunodeficiency virus (HIV) and was started on antiretroviral treatment, but he stated that he rarely took his prescribed HIV medications and had not taken any medication for the past 2 months. Jason appeared acutely ill and he was admitted for investigation and treatment. His blood pressure was low, but within normal limits, and he had a low-grade fever and some dyspnoea. He was coughing and sounded congested and said he was too weak to cough up respiratory secretions. Because his presentation clearly suggested a respiratory infection, a chest radiograph was taken and a specimen of his sputum was sent to the laboratory for microscopy and culture. Blood samples were obtained for assessment of his plasma HIV RNA level (viral load) and CD4þ T-lymphocyte cell count. He was admitted to a respiratory isolation room and infection prevention precautions were taken to prevent nosocomial transmission of airborne microorganisms. On his second in-patient day, the laboratory reported a large number of acid-fast bacilli in his sputum, a peripheral blood CD4þ T-lymphocyte cell count of 400 cells/mm3 and a high HIV viral load. He was therefore diagnosed as having active HIV-related pulmonary TB and he was started on anti-TB therapy.
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Jason’s nursing assessment was completed and an analysis of the assessment data indicated the following initial nursing diagnoses: 1. ineffective therapeutic regimen management; 2. risk for infection; 3. fatigue; 4. impaired gas exchange; 5. ineffective airway clearance; 6. imbalanced nutrition; 7. hopelessness; and 8. ineffective health maintenance.
A discussion with Jason resulted in agreement on beneficial health outcomes and the related interventions needed to achieve these goals. These were then incorporated into an initial nursing care plan (Table 69.3). Because of potential problems with interactions between antiretroviral and anti-TB drugs, the physician decided not to recommence antiretroviral therapy until Jason had successfully completed his anti-TB treatment. The most frequent drug interactions are seen between rifamycins (rifampicin, rifabutin) used to treat TB and both protease inhibitors and non-nucleoside reverse transcriptase inhibitors
Table 69.3 Care plan Nursing diagnosis 1 Definition Defining characteristics
Related factors (aetiology) Outcomes (criteria for evaluation)
Interventions
Nursing diagnosis 2 Definition Related factors (aetiology) Outcomes (criteria for evaluation)
Interventions
Nursing diagnosis 3 Definition Defining characteristics
Related factors (aetiology)
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Ineffective therapeutic regimen management Pattern of regulating and integrating into daily living a programme for treatment of illness and its sequelae that is unsatisfactory for meeting specific health goals Choices of daily living ineffective for meeting goals of anti-TB treatment, the statement of the patient that he did not take action to include his antiretroviral treatment regimen in daily routine and that he had difficulty with following the prescribed drug regimen Limited understanding of the disease and its treatment, complexity of the drug regimen, homelessness, and chaotic lifestyle Patient will (time frame to be specified): Discuss reasons for non-adherence, e.g. satisfaction with current lifestyle and readiness for change, understanding of importance of treatment regimen, support from social services, adequate finances for travel to attend clinic appointments Accept and cooperate with the administration of his medications while in hospital and for community service arrangements for directly observed anti-TB therapy when discharged from hospital Attend all clinic follow-up appointments Sputum microscopy negative for AFB within 2 weeks of care plan being implemented Review self-management strategies and related outcomes Provide appropriate and relevant educational support to patient to reinforce his understanding of the need for adherence to his anti-TB therapy and antiretroviral treatment when it is recommenced Review methods of contacting health provider(s) for changes in medication regimen and/or method of incorporating the regimen into activities of daily living Help patient to arrange daily schedule to adhere to directly observed treatment (DOT) arrangements and to attend clinic follow-up appointments Refer patient to social services for relevant benefits and help with accommodation Refer patient to appropriate support groups, e.g. Alcoholics Anonymous (AA) for help with desired lifestyle changes Refer patient to HIV/AIDS support organization for group assistance in adherence to antiretroviral therapy when recommenced Record the effectiveness of managing the anti-TB drug regimen Risk for infection At increased risk for being invaded by pathogenic organisms (and opportunistic infections). Potential risk for nosocomial transmission of Mycobacterium tuberculosis HIV-related immunosuppression further exacerbated by active pulmonary disease process. Sputum microscopy positive for acid-fast bacilli, possibility of multidrug-resistant organisms, productive cough and poor cough hygiene, presence of pulmonary lesion on radiograph Respiratory isolation and infection control precautions effective in preventing nosocomial transmission of M. tuberculosis to healthcare personnel, patients, and visitors Decreasing infectivity resulting from anti-TB therapy Cooperation with consistent cough hygiene measures Implement respiratory isolation, i.e. assign to monitored negative pressure room Administer anti-TB therapy Provide appropriate and relevant educational support to patient to facilitate his understanding of the need for adhering to respiratory isolation and using cough hygiene measures Implement appropriate infection prevention precautions for airborne transmitted microorganisms (described in detail in Chapter 68) Fatigue An overwhelming and sustained sense of exhaustion and decreased capacity for physical and mental work at usual level Inability to restore energy even after sleep, lack of energy or inability to maintain usual level of physical activity, increase in rest requirements, tiredness, inability to maintain usual routes, complaints of an unremitting and overwhelming lack of energy, lethargic or listless, perceived need for additional energy to accomplish routine tasks, compromised concentration, lack of interest in surroundings, introspection, decreased performance, compromised libido, drowsiness, feeling of guilt for not keeping up with responsibilities, inability to concentrate, weakness Sleep deprivation (due to constant coughing and breathing difficulties), malnutrition, poor physical condition, disease state (active pulmonary TB), and advanced HIV disease
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Outcomes (criteria for evaluation)
Interventions
Nursing diagnosis 4 Definition Defining characteristics
Related factors (aetiology) Outcomes (criteria for evaluation)
Interventions
Nursing diagnosis 5 Definition Defining characteristics
Related factors (aetiology) Outcomes (criteria for evaluation)
Interventions
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Patient will (time frame to be specified): Identify potential factors that aggravate and relieve fatigue Report increased energy and improved well-being Use an energy conservation plan to offset fatigue Use an energy restoration plan to offset fatigue Assess severity of fatigue, activities and symptoms associated with increased fatigue, ability to perform activities of daily living (ADL) Evaluate adequacy of nutrition and sleep patterns Determine with colleagues whether there are physical or psychological causes of fatigue that could be treated, e.g. depression, medication effect Provide assistance with ADL as needed Gradually mobilize the patient as disease state improves Refer to nutritionist/dietitian for nutritional assessment Impaired gas exchange Excess or deficit in oxygenation and/or carbon dioxide elimination at the alveolar–capillary membrane Visual disturbances, dyspnoea, abnormal arterial blood gas levels, hypoxia, irritability, sleepiness, restlessness, hypo- or hypercapnia, tachycardia, cyanosis, abnormal skin colour (pale, dusky), hypoxaemia, headache on awakening, abnormal rate, rhythm, and depth of breathing, diaphoresis, abnormal arterial blood pH, nasal flaring Ventilation–perfusion imbalance, alveolar–capillary membrane changes Patient will (time frame to be specified): Demonstrate improved ventilation and adequate oxygenation as evidenced by blood gas levels within normal parameters for that patient Maintain clear lung fields and remain free of signs of respiratory distress Report understanding of oxygen supplementation and other therapeutic interventions Monitor: Respiratory rate, depth, and effort, including use of accessory muscles, nasal flaring, and abnormal breathing patterns Patient’s behaviour and mental status for the onset of restlessness, agitation, confusion, and lethargy Oxygen saturation continuously by means of pulse oximetry Arterial blood gas results Observe for: Cyanosis Signs of psychological distress, e.g. anxiety, agitation, insomnia Assist with deep breathing exercises and encourage patient to perform controlled coughing Administer humidified oxygen as ordered by the physician through an appropriate device, e.g. nasal cannula or Venturi mask (aim for oxygen saturation level of 90%) Teach the patient: How to perform pursed-lip breathing and controlled diaphragmatic breathing, and how to use the tripod position How to use pulse oximetry to note improvements in oxygenation with these breathing techniques The importance of not smoking tobacco Refer the patient to a physiotherapist for breathing exercises and controlled coughing Refer the patient to smoking cessation services to help the patient stop smoking tobacco Ineffective airway clearance Inability to clear secretions or obstructions from the respiratory tract to maintain a clear airway Dyspnoea, diminished breath sounds, orthopnoea, adventitious breath sounds (rales, crackles, rhonchi, wheezes), ineffective or absent cough, sputum production, cyanosis, difficulty vocalizing, wide-eyed, changes in respiratory rate and rhythm and restlessness Tobacco smoking; retained respiratory secretions, excessive mucus, secretions in bronchi, exudates in alveoli Patient will (time frame to be specified): Demonstrate effective coughing and clear breath sounds and be free of cyanosis and dyspnoea Maintain a patent airway at all times Relate to methods for enhancing secretion removal Understand the significance of changes in sputum to include colour, character, amount, and odour Identify and avoid specific factors that inhibit effective airway clearance Monitor: Breath sounds, respiratory rate, depth, and effort of breathing Patient’s behaviour and mental status and note the onset of restlessness, agitation, confusion, and lethargy Oxygen saturation continuously by means of pulse oximetry Arterial blood gas results Observe for sputum, noting colour, odour and, volume Assist with deep breathing exercises and encourage patient to perform controlled coughing Encourage the patient to use an incentive spirometer (Continued)
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Table 69.3
Care plan—(cont’d) Position patient to optimize respiration, e.g. head of bed elevated 45 and repositioned at least every 2 hours or, in the case of unilateral lung disease, alternate a semi-Fowler’s position with a lateral position (with a 10 –15 elevation and ‘good lung down’) for 60–90 minutes Provide postural drainage Refer patient to physiotherapist for postural drainage, percussion, and vibration as ordered by the physician Take infection control precautions to prevent nosocomial transmission of M. tuberculosis when assisting patient with airway clearance, i.e. patient to be in automatically monitored negative pressure isolation room and healthcare staff to use personal respiratory protection correctly (see Chapter 68) Assist with clearing secretions from pharynx by offering tissues and gentle suction of the oral pharynx if necessary Administer oxygen if and as ordered by the physician Administer prescribed medications, e.g. bronchodilators and inhaled steroids, and observe for side effects, e.g. tachycardia or anxiety Provide oral care every 4 hours (using a soft toothbrush) Encourage activity and ambulation as tolerated. If unable to ambulate the patient, turn in bed from side to side at least every 2 hours Imbalanced nutrition: less than body requirements Intake of nutrients insufficient to meet metabolic needs Body weight < 20% under ideal weight, pale conjunctival and mucous membranes, sore, inflamed buccal cavity, reported or evidence of lack of food, reported inadequate food intake less than recommended daily allowance (RDA), lack of interest in food, capillary fragility, diarrhoea, hyperactive bowel sounds, misinformation Inability to ingest or digest food or absorb nutrients because of biological, psychological, or economic factors Patient will (time frame to be specified): Progressively gain weight toward desired goal Achieve a weight within the normal range for height and age Recognize factors contributing to underweight Identify nutritional requirements Consume adequate amounts of food Be free of signs of malnutrition Monitor: For signs of malnutrition Weight, by weighing the patient daily in acute care and weekly in extended care under the same conditions State of oral cavity – provide good oral hygiene before and after meals Determine healthy body weight for age and height Refer patient to a dietitian for complete nutritional assessment if 10% under healthy body weight or if rapidly losing weight Observe the ability of the patient to eat (time involved, motor skills, visual acuity, and ability to swallow various textures of food) Provide companionship at mealtimes to encourage adequate nutritional intake Offer small quantities of food, served in an appetizing fashion, at frequent intervals Provide nutritional supplements as prescribed Administer antiemetics and analgesics as prescribed and as needed before meals Hopelessness Subjective state in which the patient sees limited or no alternatives or personal choices available and is unable to mobilize energy on his or her own behalf Passivity, decreased conversation, decreased emotions, verbal cues (e.g. saying ‘I can’t’, or sighing ‘I’ll never’ or ‘there is no future’), closing of eyes, anorexia, decreased responses to stimuli, increased/decreased sleep, lack of initiative, lack of involvement in care, passively allowing care, shrugging in response to speaker, turning away from speaker, reporting feeling lost, unable to cope, abandoned Abandonment, prolonged restriction of activity creating isolation, loss of beliefs in transcendent values/God, long-term stress, failing or deteriorating chronic physiological and/or psychological condition, negative life view, perception of demands that overwhelm personal resources Patient will (time frame to be specified): Discuss feelings and participate in care Make positive statements (e.g. ‘I can’ or ‘I will try’) Set themselves goals Make eye contact with, and focus on, the speaker Maintain appropriate appetite for age and physical health Sleep appropriate length of time for age and physical health Express concern for other people Initiate activity Explore patient’s definition of hope and assist in identifying sources of hope Monitor potential for suicide and, if appropriate, refer patient to psychiatric services Assist patient in identifying reasons for living Determine appropriate approach to supporting the patient based on the underlying condition or situation contributing to feelings of hopelessness, e.g. progressive chronic ill health, social circumstances, loneliness Assist with problem solving and decision making
Nursing diagnosis 6 Definition Defining characteristics
Related factors Outcomes (criteria for evaluation)
Interventions
Nursing diagnosis 7 Definition Defining characteristics
Related factors
Outcomes (criteria for evaluation)
Interventions
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Assist the patient to look at alternatives and to set goals important to him or her Encourage patient to participate in group activities Teach alternative coping strategies Refer patient to a relevant support group Use humour as appropriate Encourage the family and other people important to the patient to express their care, hope, and affection for the patient Ineffective health maintenance Inability to identify, manage, or seek out help to maintain health Ineffective family coping, perceptual–cognitive impairment (complete or partial lack of gross and/or fine motor skills), lack of significant alteration in communication skills (written, verbal, and/or gestural), unachieved developmental tasks, lack of material resources, dysfunctional grieving, disabling spiritual distress, inability to make deliberate and thoughtful judgements, ineffective individual coping Patient will (time frame to be specified): Discuss fear of health regimen or blocks to implementing it Follow mutually agreed healthcare maintenance plan Meet goals for healthcare maintenance Assess: The patient’s feelings, values, and reasons for not following the prescribed plan of care Family patterns, economic issues, and cultural patterns that influence adherence to the medical regimen Help the patient to determine how to arrange a daily schedule that incorporates the new healthcare regimen, e.g. taking medication, diet, clinic appointments, supervised therapy Refer the patient to social services for economic and housing support Identify relevant support group to provide adherence support for patient, i.e. a ‘buddy support system’ Help the patient choose a healthy lifestyle, e.g. cessation of cigarette smoking and alcohol abuse
Nursing diagnosis 8 Definition Related factors (r/t)
Outcomes (criteria for evaluation)
Interventions
Adapted from Ackley & Ladwig’s Nursing Diagnosis Handbook.4
used to treat HIV disease. Because of the increased risk of peripheral neuropathy, caution is also warranted if patients are taking isoniazid and the antiretroviral drugs stavudine or didanosine. Both rifampicin and isoniazid, as discussed in Chapter 59, are essential first-line antiTB drugs, making it difficult to effectively treat both TB and HIV disease simultaneously. In Jason’s case, it was felt safe to postpone re-starting antiretroviral therapy as his CD4þ T-lymphocyte cell count was over 350 cells/mm3. Had Jason had a CD4þ T-lymphocyte cell count between 100 and 200 cells/mm3 it is likely that his antiretroviral therapy would have resumed after 2 months of anti-TB treatment or as soon as possible if the CD4þ T-lymphocyte cell count was less than 100 cells/mm3.9 While this case report refers to HIV-related pulmonary TB, the same principles of nursing apply to all types of the disease, including non-pulmonary manifestations, with the latter also requiring specific management of, for example, orthopaedic, neurological, genitourinary, and dermatological problems in appropriate care settings.
CONCLUSIONS Although all patients are different, those with active TB frequently experience a range of common health problems. The nursing
REFERENCES 1. International Council of Nurses. Definition of nursing. Accessed 10 January 2007. Available at URL: http:// www.icn.ch/definition.htm 2. Fawcett J. Contemporary Nursing Knowledge: Analysis and Evaluation of Nursing Models and Theories, 2nd edn. Philadelphia: Davis, 2005. 3. Weber JR. Nurses’ Handbook of Health Assessment, 5th edn. Philadelphia: Lippincott Williams & Wilkins, 2004.
response to patients with these problems is not a haphazard activity but rather a systematically planned approach based on the analysis of good quality patient assessment data. This in turn drives the development of relevant nursing diagnoses, patient outcomes, and nursing interventions. The use of international classifications for nursing practice to depict patient phenomena and associated nursing interventions and outcomes provides a shared terminology to describe the elements of nursing practice. As TB occurs throughout the world, and as nursing science continues to evolve in different parts of the world, the principle of the nursing diagnoses as an organizing framework for caring for patients with this disease is ideal. It allows nurses wherever they work to compare practice across clinical settings, patient populations, geographical regions, or time. The nursing care plan described in this chapter is not meant to be all-inclusive but simply to demonstrate how it might be used in any patient setting. Further resources to support the use of nursing diagnoses are listed in the references. Preventing the nosocomial transmission of Mycobacterium tuberculosis in all healthcare environments is an important role for professional nurses. Evidence-based infection prevention and control measures for minimizing this risk are describe in detail in Chapter 68.
4. Ackley BJ, Ladwig GB. Nursing Diagnosis Handbook, 7th edn. St. Louis: Mosby Elsevier, 2006. 5. North American Nursing Diagnosis AssociationInternational (NANDA-I). Nursing Diagnoses: Definitions and Classification, 2007–2008. Philadelphia: NANDA, 2007. 6. International Council of Nurses. International Classification for Nursing Practice. Accessed 10 January 2007. Available at URL:http://www.icn.ch/icnp.htm 7. Moorhead S, Johnson M, Maas M (eds). Nursing Outcomes Classification (NOC), 3rd edn. St. Louis: Mosby, 2003.
8. McCloskey Dochterman J, Bulechek GM. Nursing Interventions Classification (NIC), 4th edn. St. Louis: Mosby, 2004. 9. Pozniak AL, Miller RF, Lipman MCI, et al. British HIV Association (BHIVA) treatment guidelines for TB/HIV infection 2005. Accessed 10 March 2007. Available at URL:http://www.bhiva.org
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Immunotherapy of tuberculosis Robert S Wallis and John L Johnson
INTRODUCTION The increase in global TB burden during the past decade has heightened interest in innovative approaches to shorten treatment and improve outcomes. There are several potential roles for immunotherapy in TB treatment in this context.
Improving treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB: by containing bacillary replication, immunotherapy could potentially prevent further emergence of resistance, thereby improving treatment outcomes. Ameliorating symptoms: tuberculosis results in tissue necrosis and fibrosis that destroys functioning lung tissue. Adjunctive immunotherapy that limited inflammation, necrosis, and fibrosis could reduce morbidity and mortality. Preventing deleterious immune activation in TB/HIV coinfection: in HIV coinfection, an additional role of immunotherapy might be to modulate a host immune response that otherwise promotes T-cell activation and HIV expression. Eliminating persisters: the development of new treatments capable of shortening TB treatment is a major objective of TB drug discovery.1 Immunotherapy that could enhance host responses against slowly replicating persistent tubercle bacilli, a subpopulation not effectively targeted by current therapy, could potentially shorten the required duration of TB treatment and decrease the risk of relapse. Alternatively, if host responses cannot effectively eradicate these persisting bacilli, but instead create the conditions leading to persistence, immunotherapy directed against the granulomatous host response might accelerate the response to treatment by increasing drug bioavailability and enhancing microbial susceptibility.
CYTOKINE REGULATION OF MACROPHAGE ACTIVATION Control of Mycobacterium tuberculosis infection occurs at three levels: the isolated macrophage, mixed macrophage and inflammatory cell infiltrates, and mature granulomas (Fig. 70.1). As intracellular pathogens, mycobacteria possess the capacity to replicate within the phagocytic cells that constitute the major effector arm of the cellular immune system. Resting human monocytes and macrophages are permissive of intracellular replication of M. tuberculosis.2 At this stage, the infection can be affected by factors reflecting innate (natural) immunity. In mice, resistance of resting
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macrophages to infection with most intracellular pathogens is controlled by the products of a gene on chromosome 1 identified as the bcg locus.3 Macrophages of Bacillus Calmette–Gue´rin (BCG)resistant strains demonstrate increased respiratory burst activity as assessed by peroxide production and enhanced capacity for inhibition of replication of Mycobacterium bovis BCG and Mycobacterium intracellulare.4 The human correlate of this gene may also play a role in determining TB susceptibility.5 Tumour necrosis factor (TNF), granulocyte–macrophage colony-stimulating factor (GM-CSF), and other macrophage cytokines act in an autocrine fashion to limit intracellular mycobacterial growth.6 These cytokines are produced by macrophages at the site of infection in response to mycobacterial lipoproteins and glycolipids. Other components of the innate immune response, such as natural killer (NK) cells, granulocytes, and antimicrobial peptides may also play a role in mycobacterial resistance.7,8 Macrophage activation for killing of intracellular M. tuberculosis is enhanced by interaction with antigen-specific T cells and local production of interferon (IFN)-g. The recruitment of these cells from the blood and their differentiation and expansion at the site of infection in the lung are critical events in mycobacterial immunity in which TNF, chemokines, interleukin (IL)-12, and IL-2 participate. Mice with targeted disruption of the IFN-g gene or the gene for the IFN-g receptor show increased susceptibility to M. tuberculosis and M. bovis BCG.9,10 Defects that prevent the clonal expansion and activation of IFN-g-producing T cells, such as deficiencies of IL-12 or IL-18, have similar effects.11,12 Mutations affecting the IFN-g or IL-12 receptors in humans also increase susceptibility to mycobacterial disease.13,14 Nitric oxide (NO), the production of which is induced by IFN-g, is thought to be the main anti-mycobacterial effector mechanism of activated macrophages.15 Other products of activated macrophages, including superoxide, IL-6, and calcitriol (1,25-dihydroxy-vitamin D3), also restrict intracellular mycobacterial growth.2,16,17 Calcitriol may act in part by simulating production of NO.18 Cytotoxic T cells contribute towards control of intracellular mycobacteria by a granule-dependent mechanism. Granulysin, a protein found in granules of cytotoxic T lymphocytes, reduces the viability of a broad spectrum of pathogenic bacteria, fungi, and parasites in vitro. Granulysin directly kills extracellular mycobacteria, and, in combination with perforin, decreases the viability of intracellular M. tuberculosis.19 However, cytotoxicity directed against host cells per se does not appear to be a major factor in the control of intracellular infection.20
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mØ
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is accompanied by increased production of the regulatory cytokines IL-10, transforming growth factor (TGF)-b, and prostaglandin E2, potentially opening other avenues for therapeutic immune intervention.27,28 Regulatory T cells (Treg), bearing the phenotype CD4+ CD25+ FoxP3+, may also be involved in inhibition of CD4 responses in TB, either through production of IL-10 and TGF-b or through other, undefined mechanisms.29,30
IMMUNE ACTIVATION AND AIDS/ TUBERCULOSIS CO-PATHOGENESIS
TNF
Capillary lumen
Fig. 70.1 Granuloma formation in the lung. The central region of multinucleated giant cells, mycobacteria, and necrotic debris (right) is surrounded by concentric rings of tightly apposed epithelioid cells and lymphocytes, with smaller numbers of neutrophils, plasma cells, and fibroblasts.
GRANULOMAS AND PERSISTENCE In most instances, however, it is believed that the human host response is unable to eradicate infection with M. tuberculosis. Granulomas therefore represent a stalemate between host and pathogen – an alternative strategy for physically containing an otherwise virulent pathogen in a microenvironment with reduced oxygen, pH, and micronutrients. In response, mycobacteria undergo profound alterations in metabolism, biosynthesis, and replication, leading to a semidormant state. This forms the basis of clinical latency in TB. The elucidation of the biology of these sequestered bacilli has become a critical area of research in TB. Karakousis et al.21 have examined the biology of dormancy using hollow semipermeable microfibres, which, when implanted subcutaneously in mice, become surrounded by granulomas. Mycobacteria contained by these lesions showed stationary colony-forming unit (CFU) counts, decreased metabolic activity, profoundly altered gene expression profiles, and decreased susceptibility to the bactericidal effects of isoniazid. Granulomas therefore present two contradictory roles in mycobacterial infection: a barrier to dissemination, yet also an impediment to treatment. Thus, alternative strategies for adjuvant immunotherapy might be targeted at the granuloma, maximizing drug penetration and bactericidal effect on persisters.22
CYTOKINE DYSREGULATION AND TUBERCULOSIS IMMUNOPATHOGENESIS Specific genetic defects involving the above pathways appear to account for only a small fraction of human TB cases. Nonetheless, there is substantial evidence of immune dysregulation in patients with active disease. Up to 25% have a negative tuberculin skin test on initial evaluation;23 this percentage is increased in those with disseminated or miliary disease.24 Up to 60% of patients demonstrate reduced responses to M. tuberculosis purified protein derivative (PPD) in vitro in terms of T-cell blastogenesis, production of IL-2 and IFN-g, and surface expression of IL-2 receptors.25,26 This
Coinfection with HIV is the most potent risk factor for active TB in a person latently infected with M. tuberculosis.31 Tuberculosis is often an early complication of HIV infection, occurring prior to other acquired immunodeficiency syndrome (AIDS)-defining illnesses. Prior to the introduction of HIV protease inhibitors, the diagnosis carried an expected mortality of 21% at 9 months, even in those subjects presenting without other AIDS-defining conditions.32 Death was infrequently due to active TB, however. More often, it resulted from other AIDS-related causes, occurring after the diagnosis of TB. Several studies indicate that the adverse interactions of M. tuberculosis and HIV are bidirectional, i.e. that TB affects HIV disease in addition to the better recognized converse interaction. Tuberculosis is characterized by prolonged antigenic stimulation and immune activation, even in HIV-infected subjects.33,34 Antigen-induced T-cell activation, and expression of proinflammatory cytokines TNF-a and other inflammatory cytokines in turn promotes HIV expression by latently infected cells.35,36Mycobacterium tuberculosis and its proteins and glycolipids directly stimulate HIV replication by mechanisms involving monocyte production of TNF-a.37 In the lung, TNF-a and HIV-1 RNA are both increased in bronchoalveolar lavage fluid of involved lung segments of patients with pulmonary TB and HIV-1 infection.38 Phylogenetic analysis of V3 sequences demonstrated that HIV-1 RNA present in bronchoalveolar fluid had diverged from plasma, indicating that pulmonary TB enhances local HIV-1 replication in vivo. These interactions appear to have significant clinical consequences. Plasma HIV viral load increases five- to 160-fold in HIV-infected persons during the acute phase of TB.39 New AIDS-defining opportunistic infections occur at a rate 1.4 times that of CD4-matched HIV-infected control subjects without a history of TB (95% confidence interval 0.94–2.11).40 AIDS/TB cases also have a shorter overall survival than control AIDS patients without TB ( p ¼ 0.001), as well as an increased risk for death (odds ratio 2.17). Thus, although active TB may be an independent marker of advanced immunosuppression in HIV-infected patients, it may also act as a co-factor to accelerate the clinical course of HIV infection, potentially offering opportunities for immunebased interventions.
TREATMENT AND TESTING STRATEGIES To summarize, protective host responses against M. tuberculosis are dependent on T-helper (Th)-1 responses mediated primarily by interactions of CD4+ T lymphocytes and macrophages. IL-2 and IFN-g are crucial cytokines produced by antigen-responsive T cells that activate macrophages to inhibit intracellular mycobacterial growth and may also act indirectly to enhance specific cytotoxic Tcell and NK cell responses. Other cytokines such as TGF-b enhance
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fibrosis and scarring near tuberculous lesions and result in loss of functional pulmonary parenchyma. These observations have led to the hypothesis that administration of endogenous IFN-g or IL-2 and other agents might augment immune responses in active TB, improve or accelerate clearance of tubercle bacilli, and improve clinical outcomes. The availability of highly purified recombinant cytokines, increasing rates of MDR-TB, and successful experience with adjunctive therapy with human cytokines in cancer therapy and the treatment of other infectious diseases has led to strong interest in their possible role in the therapy of human mycobacterial diseases. Current approaches to the immunotherapy of TB centre on promoting Th-1 responses by administration of Th-1 cytokines or immunomodulators, inhibition of macrophage-deactivating cytokines such as TGF-b, and inhibition of proinflammatory cytokines by specific or general cytokine inhibitors such as corticosteroids, thalidomide, or pentoxifylline. The design of clinical trials to test these new treatments (both chemotherapy and immunotherapy) poses several unique challenges. Studies of adjuvant TB immunotherapy have, for the most part, been conducted using surrogate markers indicating relapse risk, and in patients with MDR-TB (in whom the outcome of standard treatment is poor). Delayed sputum culture conversion and reduced rate of decline in log sputum CFU counts during the first month of treatment are recognized indicators of increased relapse risk in TB.41,42
INTERFERON IFN-g was first studied as adjunctive treatment in patients with non-tuberculous mycobacterial infections. In lepromatous leprosy, intradermal therapy with low-dose IFN-g resulted in increased local T-cell and monocyte infiltration, HLA-DR (Ia) antigen expression, and decreased bacillary load.43 In another study, twiceor thrice-weekly therapy with 25–50 mg/m2 of subcutaneous IFN-g was administered to seven non-HIV-infected patients with disseminated Mycobacterium avium complex infection who had failed
to respond to antibiotic therapy.44 Within 8 weeks of beginning IFN treatment, all seven patients had significant and sustained clinical improvement. However, a similar study in patients with advanced AIDS revealed no benefit.45 High-dose systemic therapy with IFN-g is associated with frequent side effects including fatigue, myalgias, and malaise. Treatment with aerosolized IFN-g has been studied in an attempt to decrease these systemic side effects and deliver therapy directly to the site of disease in the lung. An uncontrolled trial of therapeutic IFN-g in patients with MDR-TB without overt disorders of IFN-g production or responsiveness was reported by Condos and colleagues in 1997.46 In this study, five patients with MDR-TB were administered 500 mg IFN-g thrice weekly by aerosol for 1 month in addition to their previous chemotherapy. Sputum smears became negative in four of the five patients after 1 month of IFN-g treatment and the time until positive culture in automated detection systems (MGIT) increased. Smears reverted to positive within 1 month after treatment was stopped, however. Interferon-a is an immunomodulatory cytokine produced by mononuclear phagocytes stimulated by bacteria and viruses. IFN-a modulates differentiation of T cells towards the Th-1 phenotype, induces production of IFN-g and IL-2, and inhibits proliferation of Th-2 cells. Two small studies have examined a possible role for IFN-a in TB treatment. A randomized open-label trial in 20 HIV-seronegative TB patients in Italy studied the effects of aerosolized IFN-a 3 million units thrice weekly during the first 2 months of TB treatment.47 Patients treated with IFN-a had earlier improvement in fever, sputum bacillary burden by quantitative microscopy after 1 week of treatment, and pulmonary consolidation after 2 months compared with patients receiving placebo. In another pilot study, IFN-a2b (3 million units weekly) was administered subcutaneously for 3 months as an adjunct to chemotherapy to five patients with chronic MDR-TB.48 Two of the five patients became consistently sputum culture negative over a 30month follow-up period. However, other studies have not confirmed this modest measure of success (Table 70.1).49–51
Table 70.1 Clinical trials of adjunctive IFN for treatment of drug-resistant and multidrug-resistant (MDR) pulmonary tuberculosis Citation
Study population
n
Regimen
Outcome
Condos et al.
MDR-TB
5
500 mg IFN-g thrice-weekly by aerosol nebulizer for 1 month
Palmero et al.48
MDR-TB
5
3 MU IFN-a2b SC once weekly for 3 months
Giosue` et al.49
MDR-TB
7
Suarez-Mendez et al.50
Drug-resistant (n = 4; resistant to HS (2) and H (2)) and MDR (n = 4) TB MDR-TB
8
3 MU IFN-a thrice weekly by aerosol for 2 months 1 MU IFN-g IM daily, then thrice weekly IM for 6 months
Sputum smears became negative in 4 of the 5 patients after 1 month of IFN-g treatment and time to positive culture decreased. Sputum smears became positive in 4 of the 5 patients 1 month after adjunctive IFN-g was stopped 2 of the 5 patients became smear and culture negative long term; 1 patient became smear negative but culture positive; 2 patients showed no improvement Transient improvement in sputum smears, minimal effect on CFU counts Sputum smears and cultures became negative in all patients after 3 months of treatment and remained negative after 6 months. Results difficult to interpret due to simultaneous change in chemotherapy
46
Koh et al.51
6
2 MU IFN-g thrice weekly by aerosol for 6 months
Sputum smears remained positive in all subjects. Cultures were negative after 4 months in 2 subjects but became positive again after 6 months of IFN-g therapy. Five patients had radiological improvement
MU, million units; SC, subcutaneous; IM, intramuscular; CFU, colony-forming units.
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The largest, most rigorous trial of IFN in MDR-TB to date was initiated by Intermune in 2000.52 It was designed as a randomized, placebo-controlled, multicentre trial of inhaled adjunctive IFN-g for patients with chronic MDR-TB. The trial was halted prematurely due to lack of efficacy, after review by an independent safety monitoring board. Unfortunately, its findings have never been published. A study of adjunctive aerolized or subcutaneous (SC) IFN-g (200 mg aerosol or SC thrice weekly for 4 months versus standard short-course chemotherapy) in patients with drug-susceptible, cavitary pulmonary TB was recently initiated in South Africa. Preliminary data reported from this ongoing study showed that sputum acid-fast bacilli (AFB) smears became negative in all treatment groups by 12 weeks and that patients treated with IFN-g converted their sputum earlier.53 Recent basic research on the potential therapeutic role of IFN in TB has indicated that IFN-g-induced genes such as IP-10 and iNOS are already upregulated in the lung in patients with TB, and that therapeutic aerosol IFN-g has relatively little additional effect.54 These findings would appear to indicate that the modest mycobactericidal capacity of lung macrophages cannot be effectively augmented by therapeutic IFN.
INTERLEUKIN-2 Early clinical trials with IL-2 in patients with leprosy and leishmaniasis, and other serious infections due to intracellular pathogens, demonstrated that IL-2 immunotherapy may be useful in controlling these infections.55 In leprosy patients, IL-2 administration led to enhanced local cell-mediated immune responses and resulted in more rapid and extensive reduction in Mycobacterium leprae bacilli than multidrug chemotherapy alone.56 IL-2 at low doses of 10 mg (180,000 IU) twice a day for 8 days led to body-wide infiltration of CD4+ T cells, monocytes, and Langerhans cells in the skin and a decline in the total body burden of M. leprae.57 The presumed mechanism of this anti-bacterial effect is via the destruction of oxidatively incompetent dermal macrophages and the extracellular liberation of bacilli and their subsequent uptake and destruction by newly emigrated and oxidatively competent monocytes from the circulation. Several clinical trials have examined IL-2 as an adjunct to TB treatment. A pilot study of IL-2 was performed in 20 TB patients in Bangladesh and South Africa to evaluate its safety, and microbiological and immunological activities.58 The patient population was diverse, and included new, partially treated, and chronic MDR cases. Patients received 30 days of twice-daily intradermal injections of 12.5 mg (225,000IU) of IL-2 in addition to combination chemotherapy. Patients in all three groups showed improvement of clinical symptoms during the 30-day treatment period. Results of direct sputum smears for AFB demonstrated conversion to negative following IL-2 and chemotherapy in all of the newly diagnosed patients and in five of seven patients with MDR-TB. Patients receiving IL-2 did not experience clinical deterioration or any significant side effects. A randomized clinical trial of 35 patients with MDR-TB in South Africa compared daily or pulse IL-2 therapy with placebo.59 Patients received the best available combination chemotherapy based on individual drug-susceptibility testing results. Twelve patients received 12.5 mg (225,000 IU) IL-2 intradermally twice daily. Nine patients received pulse IL-2 therapy (twice-daily intradermal injection of 25 mg (450,000 IU) IL-2 daily for 5 days,
70
followed by 9 days off IL-2 treatment, for three cycles), and 14 subjects received placebo. Immunotherapy or placebo was given in conjunction with combination chemotherapy during the first 30 days of the study. The total dose of IL-2 in both active treatment groups was identical. Pulse IL-2 therapy did not appear to have any microbiological effect. However, five of eight patients receiving daily IL-2 treatment who were smear positive on entry had reduced or cleared sputum mycobacterial load compared with two of seven subjects receiving pulse IL-2 and three of nine subjects in the placebo group. Chest radiograph improvement after 6 weeks of anti-TB treatment was present in seven of 12 patients receiving daily IL-2 compared with two of nine patients on pulse IL-2 treatment and five of 12 patients receiving placebo. The number of circulating CD25+ (low-affinity IL-2 receptor-bearing T cells) and CD56+ (NK) cells was significantly increased in patients receiving daily IL-2 but not in the pulse IL-2 or placebo arms. No significant side effects related to IL-2 treatment were observed. One patient developed mild influenza-like symptoms during two cycles of pulse IL-2 treatment. Patients receiving IL2 developed mild self-limited local induration and pruritus at injection sites. All patients receiving IL-2 treatment completed the study. The results of these studies suggest that IL-2 administration in combination with conventional combination chemotherapy is safe in patients with TB and may potentiate the antimicrobial cellular immune response to TB. Results from another trial of adjunctive IL-2 treatment in 203 previously treated patients from China showed significantly improved sputum culture conversion after 1 and 2 months of treatment and improved radiographic resolution at the end of TB treatment.60 One study of IL-2 has been conducted in newly diagnosed, non-MDR-TB cases. This randomized, double-blind, placebocontrolled trial of the effect of IL-2 on sputum culture conversion was conducted by the CWRU TB Research Unit in 110 nonHIV-infected Ugandan adults with fully drug-susceptible, newly diagnosed smear-positive pulmonary TB.61 IL-2 or placebo was administered at the same dose and schedule as the daily treatment group in the South Africa trial. Although IL-2 was well tolerated, it did not increase the rate of sputum culture conversion after 1 and 2 months of treatment, the primary study endpoints. Instead, time to culture conversion to negative was prolonged and quantitative sputum CFUs during the first month of treatment were greater in patients receiving IL-2 (Fig. 70.2). This was not due to lack of biological activity of IL-2, as treated subjects had a greater proportion of CD4 cells expressing the IL-2 receptor CD25 as had occurred in previous trials. Together, these studies suggest that adjunctive IL-2 is safe in patients with pulmonary TB, but appears to accelerate the microbiological response to chemotherapy only in patients with MDR disease, in whom chemotherapy is otherwise suboptimal. In patients with drug-susceptible disease, the observed antagonism with strongly bactericidal therapy is consistent with IL-2 promoting bacterial sequestration and dormancy by granulomas. The potential role of adjunctive anti-granuloma therapy in TB patients with drugsusceptible disease is further discussed below.
GM-CSF GM-CSF is a growth factor that increases the number of circulating white blood cells and enhances neutrophil and monocyte function. It is widely used in oncology in the management of patients with leucopenia and bone marrow failure. Early studies demonstrated that GM-CSF
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1
2
IL-2 Placebo
83 72
24 15
% culture positive
6 Sputum log CFU/ml
Month
5 4 IL-2 Placebo
3 2 1
0
7
14 Days
21
28
Fig. 70.2 Deleterious effect of IL-2 on sputum culture conversion in drug-susceptible pulmonary TB (n = 110). Adapted from Johnson et al.61
stimulated the killing of several intracellular pathogens including Leishmania species, Trypanosoma cruzi, Candida albicans, and M. avium complex.6,62–64 Recombinant human GM-CSF also was shown to decrease the in vitro replication of M. tuberculosis in human monocyte macrophages.65 These observations led to interest in its potential use in patients with TB. In a randomized, placebo-controlled phase II trial assessing the safety and activity of 1 month of twice-weekly subcutaneous GM-CSF 125 mg/m2 in 31 patients with newly diagnosed pulmonary TB conducted in Brazil, a trend towards faster bacillary clearance in the sputum was observed during the first 8 weeks of treatment in patients receiving GM-CSF in addition to standard chemotherapy.66 No patients had to discontinue GM-CSF treatment. Mild local skin reactions and leucocytosis, which resolved within 3 days, were the most frequent side effects in patients receiving GM-CSF. Fever and increased pulmonary necrosis on chest radiograph were not observed. The results of this small phase II study suggest that adjunctive GM-CSF is reasonably well tolerated by patients with TB and warrants further study, possibly in patients with drug-resistant or MDR-TB.
INTERLEUKIN-12 Interleukin-12 is a pivotal cytokine that enhances host responses to intracellular pathogens by inducing IFN-g production and Th-1 responses. Patients with congenital abnormalities of IL-12 receptors are highly susceptible to serious mycobacterial and salmonella infections.67,68 Administration of IL-12 to SCID or CD4+ T-celldepleted mice infected with M. avium enhances IFN-g production and had modest activity against M. avium.69 Recombinant IL-12 also has been shown to upregulate M. tuberculosis-induced IFN-g responses in human peripheral blood mononuclear cells and alveolar macrophages.70,71 Because of these properties, interest in a possible role for IL-12 immunotherapy in TB has been balanced by concerns about its non-specific mechanism of action and potential toxicity. A trial of IL-12 immunotherapy in TB in the Gambia has been completed, but its findings have not yet been reported.
THALIDOMIDE Thalidomide (a-N-phthalimidoglutarimide) is a synthetic derivative of glutamic acid initially released as a sedative in Europe in 1957 but withdrawn from most countries 4 years later after recognition of its serious teratogenic effects. In 1965 an Israeli dermatologist prescribed
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thalidomide as a sedative for six patients with lepromatous leprosy and erythema nodosum leprosum (ENL).72 ENL is a serious reaction characterized by painful nodules, fever, malaise, wasting, vasculitis, and peripheral neuritis. All six patients improved within hours. This observation spurred a series of studies by other researchers to investigate its underlying mechanisms. It is now recognized that thalidomide has complex antiinflammatory, immunological, and metabolic effects. Its activity has been attributed, at least in part, to its ability to inhibit TNF-a synthesis in vitro and in vivo.73,74 Thalidomide also inhibits neutrophil phagocytosis, monocyte chemotaxis, and angiogenesis, and, to a lesser degree, inhibits lymphocyte proliferation to antigenic and mitogenic stimuli.75–77 Thalidomide inhibits HIV-1 replication in the U-1 monocytoid cells and peripheral blood mononuclear cells (PBMCs) from patients with advanced AIDS.78,79 These studies indicate potential clinical roles of thalidomide to limit TNF-related clinical toxicities and to reduce cytokine-related HIV expression. The side-effect profile of thalidomide varies considerably among different patient groups. Aside from its teratogenic effects, the major toxicity of thalidomide is a peripheral polyneuropathy that occurs in 20–50% of patients. It is predominantly sensory, and can be irreversible. Other side effects include sedation, orthostatic hypotension, xerostomia, and rash. Thalidomide was approved in 1998 for use in the USA for the treatment of severe erythema nodosum leprosum and more recently for use in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma. Because of its teratogenicity and neurological toxicity, its use has been reserved for conditions refractory to other medical therapy and is strictly regulated in women of child bearing age. Patients on chronic therapy must be followed closely for neurological toxicity. Adjunctive immunotherapy with thalidomide was studied in a double-blind placebo-controlled trial of 39 HIV-infected adults with and without active TB.80 Patients with active TB treated with thalidomide had decreased plasma TNF-a and HIV-1 viral levels and greater weight gain than patients in the placebo group. Thalidomide also has been evaluated as adjunctive therapy for TB meningitis, a severe form of TB that often has serious sequelae. The inflammation in the subarachnoid space is believed to play a central pathophysiological role in the cerebral oedema, vasculitis, and infarction typically seen in this form of TB. Levels of TNF-a and other inflammatory cytokines are increased in the cerebrospinal fluid in patients with tuberculous meningitis and correlated with disease progression and brain injury in an animal model of tuberculous meningitis.81 Rabbits treated with the combination of thalidomide and anti-TB drugs are protected from death compared with animals treated only with anti-TB drugs.82 Based on these promising pre-clinical data, a randomized, placebo-controlled trial of adjunctive thalidomide in non-HIVinfected children with tuberculous meningitis was initiated in children with severe TB meningitis. Following promising results in a pilot study in children with TB meningitis,83 a double-blind, placebo-controlled randomized clinical trial of high-dose thalidomide (24 mg/kg/day orally for 1 month) was initiated in South Africa in children with severe (stage 2 and 3) tuberculous meningitis receiving standard chemotherapy plus corticosteroids.84 Enrolment in this trial was stopped after 47 patients were enrolled after excess adverse events and all four deaths occurred in patients in the thalidomide group. Frequent side effects included rash, hepatitis, and thrombocytopenia; two patients had severe neurological deterioration. Motor
CHAPTER
Immunotherapy of tuberculosis
ANTI-GRANULOMA STRATEGIES TNF is essential for the formation and maintenance of granulomas. Neutralization of TNF in experimental animals interferes with the early recruitment of inflammatory cells to the site of M. tuberculosis infection and inhibits the orderly formation of granulomas.85 In addition, TNF blockade also reduces the microbicidal activity of macrophages and NK cells. As a result, animals deficient in TNF are highly susceptible to granulomatous infections.86 Recent studies also indicate that the risk of TB is increased several-fold in individuals with polymorphisms in TNF promoter regions,87 and is substantially increased in patients treated with TNF antagonists for chronic inflammatory conditions such as rheumatoid arthritis.88 These observations indicate that adjunctive anti-TNF therapy in TB may have several beneficial effects. Blockade of the proinflammatory effects of TNF may reduce inflammation at the site of infection and promote resolution of symptoms. Disruption of granulomas may facilitate tissue sterilization, by eliminating dormancy and promoting drug penetration. Lastly, in HIV/TB coinfection, TNF blockade may prevent cytokine-driven HIV expression and T-cell apoptosis and sequestration. Two controlled clinical trials have examined the effects of potent anti-TNF therapies on microbiological outcomes in TB. Both were conducted in HIV-1-infected cases with relatively preserved TB immune responses (based on the presence of high CD4 counts and cavitary lung disease). Their main objective was to examine the role of TNF in the acceleration of HIV disease progression due to TB; as such, their main endpoints were CD4 cell count and plasma HIV RNA load. However, all three studies prospectively collected data on microbiological and clinical endpoints reached during TB treatment as an indicator of safety.
Etanercept (soluble TNF receptor) A phase I study examined the response to treatment in 16 subjects given adjunctive etanercept 25 mg subcutaneously twice weekly for eight doses, beginning on day 4 of TB treatment.89 Responses were compared with 42 CD4-matched controls. Sputum culture conversion occurred a median of 7 days earlier in the etanercept arm (p = 0.04) (inverted triangles, Fig. 70.3). Etanercept was well tolerated. There were no serious opportunistic infections. CD4 cell counts rose by 96 cells/mL after 1 month of etanercept treatment ( p ¼ 0.1 compared with controls). This effect may have been due to inhibition of apoptosis, or to the release of sequestered T cells from lymph nodes or other sites.90 The etanercept arm also showed trends towards superior resolution of lung infiltrates, closure of lung cavities, improvement in performance score, and weight gain; these approached statistical significance despite the small number of treated subjects. There were no TB relapses in either treatment arm. No effect on HIV RNA was apparent, indicating factors other than TNF may drive HIV expression in AIDS/TB. High-dose methylprednisolone A substantially greater microbiological effect was observed in a phase II placebo-controlled study in 189 subjects of prednisolone 2.75 mg/kg/day for the first month of standard TB chemotherapy.91
1.0 Proportion culture positive
function and mean IQ 6 months after treatment did not differ between patients receiving adjunctive thalidomide and those receiving placebo. TNF levels in the cerebrospinal fluid and blood were not affected by thalidomide treatment. Based on these results the investigators recommended that adjunctive high-dose thalidomide not be used in tuberculous meningitis.
70
Control Etanercept Prednisolone
0.8 0.6 0.4 0.2 0 0
30
60
90 Days
120
150
180
Fig. 70.3 Acceleration of sputum culture conversion by etanercept (soluble TNF receptor) and high-dose methylprednisolone (2.75 mg/kg/ day) in pulmonary TB. Each symbol represents an individual subject. Both treatments differed from control subjects by Kaplan–Meier analysis (p ¼ 0.04 and 0.001, respectively). From Wallis22 and Mayanja-Kizza et al.91
This daily dose had been selected based on a phase I study to determine the weight-adjusted dosage required to reduce TB-stimulated TNF production by half. The dose was tapered to 0 during the second month; the average subject received a cumulative dose of over 6500 mg methylprednisolone. Although there is extensive experience in the use of corticosteroids to ameliorate symptoms in TB, no previous studies have examined the microbiological effects of doses of this magnitude. Fifty per cent of prednisolone-treated subjects converted to sputum culture negative after 1 month versus 10% in the placebo arm (upright triangles, Fig. 70.3, p = 0.001). The magnitude of this effect is greater than has been reported in any other studies of adjunctive TB immunotherapy. No serious opportunistic infections occurred. However, early serious adverse events, consisting of expected gluco- and mineralocorticoid toxicities (hypertension, oedema, hyperglycaemia, and one death due to hypertensive crisis) occurred significantly more often in the prednisolone arm. Two other prospective randomized trials of adjunctive corticosteroids given at lower doses have observed similar, albeit smaller, effects on the kinetics of sputum culture conversion.92,93 Several studies of AIDS/TB support the hypothesis that chemotherapy may be more effective in the absence of a strong granulomatous host response. These are reviewed in Wallis.22 Together, these findings appear to indicate a substantial potential benefit for anti-TNF therapy in TB. However, it also appears that, for corticosteroids to be effective in this context, they must be given in very high doses, and that these doses are not well tolerated. Additional studies of anti-granuloma adjunctive immunotherapy, such as infliximab (anti-TNF antibody) or other targeted therapies, are warranted.
THERAPEUTIC VACCINES In 1890 Koch demonstrated that intradermal injection of tuberculous guinea pigs with old tuberculin led to rapid necrosis and sloughing of tuberculous lesions – the ‘Koch phenomenon’. Nonetheless, immunotherapy with tuberculin was subsequently administered to TB patients with mixed results. Interest in therapeutic vaccines declined following the development of modern anti-TB chemotherapy; however, recognition of the limitations of current combination chemotherapy, such as its relatively long 6-month
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duration and increasing rates of MDR-TB, led to renewed work in this area. Two types of vaccines have been studied in this context: environmental mycobacteria and DNA vaccines.
HEAT-KILLED MYCOBACTERIUM VACCAE Mycobacterium vaccae is a rapidly growing environmental mycobacterium that has low pathogenicity for humans.94Mycobacterium vaccae was originally isolated from the soil in an area of Uganda where BCG vaccination had been shown to be protective against leprosy. Heat-killed preparations of M. vaccae have been studied as an adjunct to standard anti-TB drug therapy for over a decade. Mycobacterium vaccae expresses antigens common to many mycobacteria.95 Heat-killed M. vaccae preparations have been hypothesized to work in TB by restoring host recognition of shared mycobacterial antigens, and by promoting Th-1 responses important to host defences against intracellular pathogens. However, such mechanisms have generally not been evident in clinical trials, even in those in which a beneficial effect on sputum microbiology was observed.96 In recent work in a murine model of allergic airway disease M. vaccae has been shown to activate regulatory (suppressive) T cells (Treg) that act via production of IL-10 and TGF-b.97 In that model, the M. vaccae-induced Treg cells suppressed deleterious allergic Th-2 responses. Modulation of Th-1 or Th-2 responses by M. vaccae-induced Treg in TB has not yet been reported. Because heat-killed M. vaccae is inexpensive, is simple to administer, and could potentially be implemented by TB control programmes in developing countries, there has been great interest in performing controlled trials to evaluate its potential role in TB treatment. In most trials, M. vaccae has been administered as an intradermal injection of an autoclaved preparation given within the first few days to first month after the initiation of standard chemotherapy. The heat-killed vaccine has been demonstrated to be safe in HIV- and non-HIV-infected adults. Side effects due to M. vaccae have been mild and infrequent. Forty per cent of subjects in an earlier trial developed a local scar similar to a BCG vaccination scar.98 In early studies, heat-killed preparations of M. vaccae showed activity as an adjunct to anti-TB chemotherapy. In studies from the Gambia and Vietnam the proportion of TB cases cured was increased and mortality decreased among those treated with heatkilled M. vaccae immunotherapeutic agent.99 Other studies in Nigeria, Romania, and Iran also suggested activity in TB patients with drug-susceptible and drug-resistant TB.100–103 These studies suffered from methodological problems including insufficient sample sizes, non-random treatment allocation, high losses to follow-up, and the use of various TB drug treatment regimens, as noted in a Cochrane review.104 Subsequent randomized, double-blind, placebo-controlled clinical trials did not confirm the earlier results. Three studies in Malawi, South Africa, Uganda, and Zambia examined the role of immunotherapy with heat-killed M. vaccae in a rigorous fashion. HIV- and non-HIV-infected adults with smear-positive pulmonary TB received one dose of M. vaccae or placebo early after beginning standard anti-TB treatment. Treatment with M. vaccae immunotherapy did not affect mortality or consistently affect sputum culture conversion after 2 months of treatment, radiographic
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clearance of disease, closure of cavities, weight gain, improvement in clinical symptoms, or the outcome of anti-TB treatment.96,105– 107 The data from these three rigorous trials in over 1500 patients showed no consistent benefit from immunotherapy with M. vaccae administered early during treatment to patients with drug-susceptible pulmonary TB.104 The use of adjunctive immunotherapy with M. vaccae also has been studied in patients with MDR-TB where treatment options are limited. In a randomized clinical trial from China in patients with MDR-TB, sputum conversion, cavity closure, and relapse were significantly better in patients treated with multiple doses of M. vaccae administered every 3–4 weeks for 6 months in addition to susceptibility-directed anti-TB chemotherapy.108 The vaccine administered in this study was prepared locally. These results are interesting but require confirmation.
OTHER THERAPEUTIC VACCINES Recent studies using a plasmid DNA encoding the M. leprae 65-kDa heat shock protein (hsp65) as an adjunct to combination chemotherapy in mice infected intracheally with H37Rv or MDR-TB accelerated bacillary clearance and was effective in disease due to MDR strains.109,110 Interestingly, corticosteroid administration after combined treatment with drugs and the DNA-hsp65 vaccine did not result in regrowth of H37Rv growth and reactivation of TB, suggesting that the adjunctive DNA vaccine may prevent the development or improve the clearance of slowly metabolizing, persistent bacilli – properties desirable of an immunotherapeutic agent that might allow shortening of the duration of anti-TB treatment.
CONCLUSIONS The evolution of M. tuberculosis as an intracellular pathogen has led to a complex relationship between it and its host, the human mononuclear phagocyte. The products of M. tuberculosis-specific T-lymphocytes, particularly IFN-g, are essential for macrophage activation for intracellular mycobacterial killing and/or sequestration of viable mycobacteria in granulomas. However, some cytokines, including products of both lymphocytes and phagocytic cells, may contribute to disease pathogenesis, by enhancing mycobacterial survival and by causing many of the pathological features of the disease. In HIV-associated mycobacterial infections, cytokines may mediate accelerated progression of HIV disease. The objectives of adjunctive immunotherapy for TB therefore are complex. In some situations, such as multidrug-resistant disease, clearance of bacilli may be enhanced by administration of IL-2, IL-12, or IFN-g, or possibly by using inhibitors of the deactivating cytokines TGF-b and IL-10. In other circumstances, it may be desirable to reduce the non-specific inflammatory response using inhibitors of TNF-a such as pentoxifylline, prednisone, or soluble TNF receptor. In MDR-TB, immunotherapy may play an important role in preventing the subsequent emergence of resistance to less active second-line anti-TB drugs. Further clinical trials are needed to define the role for immunotherapy of TB and other mycobacterial infections.
CHAPTER
Immunotherapy of tuberculosis
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a comparison of two treatment regimens and placebo. Tuber Lung Dis 1997;78(3–4):195–203. Chu NH, Zhu LZ, Yie ZZ, et al. [A controlled clinical study on the efficacy of recombinant human interleukin-2 in the treatment of pulmonary tuberculosis]. Zhonghua Jie He He Hu Xi Za Zhi 2003;26(9):548–551. Johnson JL, Ssekasanvu E, Okwera A, et al. Randomized trial of adjunctive interleukin-2 in adults with pulmonary tuberculosis. Am J Respir Crit Care Med 2003;168:185–191. Ho JL, Reed SG, Wick EA, et al. Granulocytemacrophage and macrophage colony-stimulating factors activate intramacrophage killing of Leishmania mexicana amazonensis. J Infect Dis 1990;162(1): 224–230. Reed SG, Grabstein KH, Pihl DL, et al. Recombinant granulocyte-macrophage colonystimulating factor restores deficient immune responses in mice with chronic Trypanosoma cruzi infections. J Immunol 1990;145(5):1564–1570. Smith PD, Lamerson CL, Banks SM, et al. Granulocyte-macrophage colony-stimulating factor augments human monocyte fungicidal activity for Candida albicans. J Infect Dis 1990;161(5):999–1005. Denis M, Gregg EO, Ghandirian E. Cytokine modulation of Mycobacterium tuberculosis growth in human macrophages. Int J Immunopharmacol 1990;12:721–727. Pedral-Sampaio DB, Netto EM, Brites C, et al. Use of Rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial. Braz J Infect Dis 2003;7(4):245–252. Altare F, Durandy A, Lammas D, et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 1998;280(5368): 1432–1435. de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 1998;280(5368):1435–1438. Silva RA, Pais TF, Appelberg R. Evaluation of IL-12 in immunotherapy and vaccine design in experimental Mycobacterium avium infections. J Immunol 1998;161(10):5578–5585. Barnes P, Zhang M, Jones B. Modulation of Th1 responses in HIV infection and tuberculosis (TB). Int Conf AIDS 1994;10:126. Fenton MJ, Vermeulen MW, Kim S, et al. Induction of gamma interferon production in human alveolar macrophages by Mycobacterium tuberculosis. Infect Immun 1997;65:149–156. Sheskin J. Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther 1965;6:303. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991;173:699–703. Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces tumor necrosis factor production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995;1(4): 384–397. Barnhill RL, Doll NJ, Millikan LE, et al. Studies on the anti-inflammatory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytes. J Am Acad Dermatol 1984;11:814–819. Keenan RJ, Eiras G, Burckart GJ, et al. Immunosuppressive properties of thalidomide. Inhibition of in vitro lymphocyte proliferation alone and in combination with cyclosporine or FK506. Transplantation 1991;52:908–910.
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77. D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:4082–4085. 78. Makonkawkeyoon S, Limson Pobre RN, Moreira AL, et al. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1993;90:5974–5978. 79. Peterson PK, Gekker G, Bornemann M, et al. Thalidomide inhibits lipoarabinomannan-induced upregulation of human immunodeficiency virus expression. Antimicrob Agents Chemother 1995; 39:2807–2809. 80. Klausner JD, Makonkawkeyoon S, Akarasewi P, et al. The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection. J Acquir Immune Defic Syndr Hum Retrovirol 1996;11:247–257. 81. Tsenova L, Bergtold A, Freedman VH, et al. Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. Proc Natl Acad Sci USA 1999;96:5657–5662. 82. Tsenova L, Sokol K, Freedman VH, et al. A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitisassociated death. J Infect Dis 1998;177:1563–1572. 83. Schoeman JF, Springer P, Ravenscroft A, et al. Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role. J Child Neurol 2000;15(8):497–503. 84. Schoeman JF, Springer P, van Rensburg AJ, et al. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. J Child Neurol 2004;19(4):250–257. 85. Kindler V, Sappino AP, Grau GE, et al. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 1989;56:731–740. 86. Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2(6):561–572. 87. de Oliveira MM, da Silva JC, Amim LH, et al. Single nucleotide polymorphisms (SNPs) of the TNF-a (-238/-308) gene among TB and non TB patients: Susceptibility markers of TB occurrence? Jornal Brasileiro Pneumologia 2004;30(4):461–467. 88. Wallis RS, Broder M, Wong J, et al. Reactivation of latent granulomatous infections by infliximab. Clin Infect Dis 2005;41:S194–S198. 89. Wallis RS, Kyambadde P, Johnson JL, et al. A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1associated tuberculosis. AIDS 2004;18(2):257–264. 90. Andrieu JM, Lu W, Levy R. Sustained increases in CD4 cell counts in asymptomatic human immunodeficiency virus type 1-seropositive patients treated with prednisolone for 1 year. J Infect Dis 1995;171:523–530. 91. Mayanja-Kizza H, Jones-Lopez EC, Okwera A, et al. Immunoadjuvant prednisolone therapy for HIVassociated tuberculosis: A phase II clinical trial in Uganda. J Infect Dis 2005;191(6):856–865. 92. Bilaceroglu S, Perim K, Buyuksirin M, et al. Prednisolone: a beneficial and safe adjunct to antituberculosis treatment? A randomized controlled trial. Int J Tuberc Lung Dis 1999;3(1):47–54. 93. Horne NW. Prednisolone in treatment of pulmonary tuberculosis: a controlled trial. Final report to the Research Committee of the Tuberculosis Society of Scotland. BMJ 1960;5215:1751–1756.
94. Hachem R, Raad I, Rolston KV, et al. Cutaneous and pulmonary infections caused by Mycobacterium vaccae. Clin Infect Dis 1996;23(1):173–175. 95. Stanford JL, Paul RC. A preliminary report on some studies of environmental mycobacteria. Ann Soc Belg Med Trop 1973;53(4):389–393. 96. Johnson JL, Kamya RM, Okwera A, et al. Randomized controlled trial of Mycobacterium vaccae immunotherapy in non-human immunodeficiency virus-infected Ugandan adults with newly diagnosed pulmonary tuberculosis. The Uganda-Case Western Reserve University Research Collaboration. J Infect Dis 2000;181(4):1304–1312. 97. Zuany-Amorim C, Sawicka E, Manlius C, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002;8(6):625–629. 98. Stanford JL, Bahr GM, Rook GA, et al. Immunotherapy with Mycobacterium vaccae as an adjunct to chemotherapy in the treatment of pulmonary tuberculosis. Tubercle 1990;71:87–93. 99. Stanford JL, Grange JM. New concepts for the control of tuberculosis in the twenty first century. J R Coll Physicians Lond 1993;27(3):218–223. 100. Etemadi A, Farid R, Stanford JL. Immunotherapy for drug-resistant tuberculosis [letter]. Lancet 1992;340(8831):1360–1361. 101. Corlan E, Marica C, Macavei C, et al. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 2. Chronic or relapsed disease. Respir Med 1997;91(1):21–29. 102. Corlan E, Marica C, Macavei C, et al. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis in Romania. 1. Newly-diagnosed pulmonary disease. Respir Med 1997;91(1):13–19. 103. Onyebujoh PC, Abdulmumini T, Robinson S, et al. Immunotherapy with Mycobacterium vaccae as an addition to chemotherapy for the treatment of pulmonary tuberculosis under difficult conditions in Africa. Respir Med 1995;89(3):199–207. 104. de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis (Cochrane Review). The Cochrane Library, Issue 1. Oxford: Update Software; 1999. 105. Durban Immunotherapy Trial Group. Immunotherapy with Mycobacterium vaccae in patients with newly diagnosed pulmonary tuberculosis: a randomised controlled trial. Lancet 1999; 354(9173):116–119. 106. Johnson JL, Nunn AJ, Fourie PB, et al. Effect of Mycobacterium vaccae (SRL172) immunotherapy on radiographic healing in tuberculosis. Int J Tuberc Lung Dis 2004;8(11):1348–1354. 107. Mwinga A, Nunn A, Ngwira B, et al. Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial. Lancet 2002;360(9339): 1050–1055. 108. Luo Y, Lu S, Guo S. [Immunotherapeutic effect of Mycobacterium vaccae on multi-drug resistant pulmonary tuberculosis]. Zhonghua Jie He He Hu Xi Za Zhi 2000;23(2):85–88. 109. Silva CL, Bonato VL, Coelho-Castelo AA, et al. Immunotherapy with plasmid DNA encoding mycobacterial hsp65 in association with chemotherapy is a more rapid and efficient form of treatment for tuberculosis in mice. Gene Ther 2005;12(3):281–287. 110. Lowrie DB. DNA vaccines for therapy of tuberculosis: where are we now? Vaccine 2006; 24(12):1983–1989.
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71
Current controversies and unresolved issues in adult tuberculosis Jose´ A Caminero
INTRODUCTION Tuberculosis is certainly the disease that has provoked the most damage to mankind throughout history. It has caused death and disease for perhaps more than 3 million years and, as a rule, has affected the poorest strata of the society.1 A long coexistence with man has endowed Mycobacterium tuberculosis, the causal agent, with the best adaptation among all known human pathogens. Therefore, it has remained in a quiescent state within a large number of individuals, generating neither symptoms nor disease, but surviving and awaiting more suitable conditions to attack.2 Today, it is estimated that onethird of the global population – more than 2,000 million people – live with this microorganism, known as Koch’s bacillus, and represent the largest reservoir of healthy, infected carriers for any given infectious disease.3 It is disconcerting that at the onset of a new millennium and after so many significant developments of the past century, TB remains a major infectious disease due to the number of healthy infected persons in the world, as well as to the 8 million people living with the disease, and to the 2 million deaths it still causes each year.3 A number of reasons explain this worrying situation, but ahead of all is the enormous inequality in the global distribution of wealth which constantly increases the fraction of people living in extreme poverty, the most suitable condition for TB dissemination.2 Moreover, the burden of acquired immunodeficiency syndrome (AIDS) has further degraded the situation in areas where TB had not been effectively controlled.2–4 Tuberculosis is perhaps the disease most written about in the history of medicine.2,5 However, a significant amount of TB research carried out during the past decades either has yielded knowledge applicable only to wealthy countries,2,5 which endure the smallest share of the burden (industrialized countries contribute only 6% of the global cases of TB3), or has been insufficiently verified. Moreover, a portion of new research has challenged previously well-accepted knowledge about TB. Some of these controversial issues remain of great interest, fully justifying a chapter analysing the most important. It is hoped that this chapter, addressing six different topics (Table 71.1), can elucidate some doubts on each of the treated subjects.
ANNUAL RISK OF INFECTION WITH MYCOBACTERIUM TUBERCULOSIS The epidemiology of TB can be understood by using a model based on its pathogenesis, from exposure to latent infection to
overt TB, and to death.6,7 Our knowledge of the epidemiology of TB has, however, moved in the opposite direction, from the description of mortality, later to morbidity and finally to understanding the role of latent infection.7 In 1934, Muench proposed a means of deriving average annual rates of infection incidence from observed infection prevalence, using among others the example of infection with M. tuberculosis. In 1957, Nyboe formulated the simplest model for estimating expected prevalence (P) of infection from a known constant risk (R) by age and calendar year. This has become the standard approach for deriving the average annual risk from prevalence of infection. It was, however, the work of the Tuberculosis Surveillance and Research Unit (TSRU) that developed a model of the dynamics, i.e. taking calendar changes in the risk of infection into account to ascertain changes from a series of tuberculin skin test prevalence surveys. The work of the TSRU resulted in the recognition of the central role of incidence and prevalence of infection in the epidemiology of TB.7 Because notifications to the World Health Organization (WHO) had been very poor in providing information on the global epidemiology of TB,8 the WHO decided to ascertain the risk of infection in various regions to get a better handle on changes in transmission of M. tuberculosis. Such information was available from these countries up to the mid-1980s. The analyses showed that the risk of infection declined in many regions, albeit to a very different extent, from several percentage points each year to virtually no change.9 This often slow decline was not particularly surprising as national TB programmes were either non-existent or chaotic at best.7 When the International Union against Tuberculosis and Lung Disease (the Union) initiated its model programmes in collaboration with some of the poorest countries in the world, measuring the impact of a country-wide case-finding and chemotherapy programme on changes in the risk of infection among school children was to be an integral part. In collaboration with the Union, Tanzania was the first country to implement what is now known as the directly observed treatment, short-course (DOTS) strategy.10 The results of the tuberculin skin test surveys were presented at TSRU meetings but were never published in the formal biomedical literature.7 Several major obstacles were encountered when attempting to measure the extent of the impact of the national control programme on transmission. First, the coverage with Bacillus Calmette-Gue´rin (BCG) vaccination made it necessary to exclude more than half of the eligible children from analysis as the most obvious source of non-specific reaction, thus making the sample non-representative for the target population. Second, the observation of a staggering amount of non-specific
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Table 71.1 Some current controversies and unresolved issues in adult tuberculosis 1. 2. 3. 4.
Annual risk of infection with M. tuberculosis Unresolved issues on the nature of M. tuberculosis latent bacilli Current controversies and unresolved issues in the diagnosis of TB Treatment of multidrug-resistant TB: evidence and controversies a. Confirmation of diagnosis in suspected MDR-TB patients: the real value of drug susceptibility testing (DST) b. Number of drugs required to treat a patient with MDR-TB c. Length of parenteral drug administration or of the initial phase of treatment d. Contribution of surgery to the treatment of MDR-TB patients e. The optimal regimen for MDR-TB: standardized versus individualized regimens 5. Cost-effectiveness of TB control strategies among immigrants and refugees 6. The dream of a vaccine against TB. New vaccines: improving or replacing BCG?
reactions made it virtually impossible to disentangle the underlying prevalence of infection with M. tuberculosis in the test population from cross-reactions due to infection with environmental mycobacteria.11 Third, the growing impact of human immunodeficiency virus (HIV) on TB morbidity seemingly overpowered any reduction in transmission accomplished by the control programme.12 Additionally, the test population of children is chosen for their accessibility in schools but also to obtain insight into transmissions more recent than those found in older population segments. This selection has in turn two more disadvantages. First, the younger the test population, the lower the expected prevalence of infection and thus the poorer the predictive value of a positive test result. Second, while the approach may show how excess transmission arising from HIV-associated TB affects the youngest population, it fails to show how HIV infection could affect TB directly and indirectly in the age groups most at risk for HIV infection, as nothing can be known about the extent of those already infected nor about those still at risk of becoming infected.7
RELATING RISK OF INFECTION TO BURDEN OF DISEASE Styblo13 proposed a study of the relation between disease incidence and infection risk, showing some constant relation in the prechemotherapy-era settings. This was expanded in a later study by Murray et al.14 The weakness of the latter paper lies in its admission that there were actually some studies only on prevalence and that the incidence was estimated by dividing the former by 2, a somewhat circular argumentation. If risk of infection were driven by the incidence then intervention with curative chemotherapy would be futile, as the expected immediate impact of case-finding and chemotherapy is on person-time of infectiousness in the community, not on incidence: the incidence in two populations might be the same, but the risk of infection may vary greatly depending on how long each incident case is allowed to transmit. Yet, despite this apparent shortcoming in epidemiological reasoning, the erroneous notion that information about the risk of infection makes it possible to estimate disease incidence stubbornly persists in some prominent publications.15 The major impediment to determining the prevalence of infection (and thus deriving the risk of infection) is related to the varying and unpredictable specificity of the tuberculin skin test in various settings, driven by the frequency of non-specific sensitization to
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environmental mycobacteria and the type and extent of BCG vaccination.11 In such settings, the use of intuitively defining a cut-off point that ‘balances’ errors from lack of sensitivity with errors from lack of specificity becomes arbitrary. Similarly, assuming a symmetric distribution around the true mean of the diameter of tuberculin skin test reaction sizes from true tuberculous infection becomes a doubtful undertaking.11,16 Estimation with such techniques is further hampered by often observed terminal digit preference. To address some of these issues, models employing mixture analysis to estimate underlying distributions have been successfully used to estimate the prevalence of infection with M. tuberculosis both among BCG-unvaccinated and -vaccinated subjects, albeit the experience is limited.7
RISK OF INFECTION, WHAT IT CAN AND WHAT IT CANNOT ACCOMPLISH Theoretically, determination of change in infection risk is the most informative indicator for change in M. tuberculosis transmission patterns in a community. The technical, logistic and financial problems associated with carrying out representative tuberculin skin test surveys might, however, be a major impediment in many settings. Determining infection risk does not make is possible to estimate disease incidence in a community. If carried out among children, it will also allow little insight into the impact HIV exerts on a population.7
UNRESOLVED ISSUES ON THE NATURE OF MYCOBACTERIUM TUBERCULOSIS LATENT BACILLI One of the most remarkable features of M. tuberculosis is its capacity to generate latent infection. Estimations suggest that, once infected, only 10% of the hosts develop TB. These data reveal how mankind has adapted to this infection. It is believed that 5% of the infected population develop the disease after 2–5 years while the rest suffer it at some point during their lives.2 The former is known as ‘primary’ TB and usually affects children and immunosuppressed hosts, whereas the latter is known as ‘postprimary’ TB. For years, postprimary TB has been related to those cases of TB found in countries with a low risk of infection, and mostly to the elder population (> 65 years old). The use of molecular markers has shown that this idea needs to be reviewed. In fact, reinfection represents a large percentage of postprimary cases.17 Furthermore, in this form TB reactivation has been over-emphasized mainly because of two facts: lack of knowledge about the degree and duration of immunity conferred by M. tuberculosis infection; and the conflation of infected people (i.e. a positive tuberculin test but with no lung radiograph images) with people whose incidence of TB resolved without any antibiotic treatment. When only the concentration of bacilli is considered, the possibility of retaining M. tuberculosis bacilli seems to be higher in the latter group. The first clinical evidence of latent TB infection (LTBI) was obtained with the discovery of the first anti-mycobacterials. Soon after, chemoprophylaxis studies provided some idea about the nature of latency.18 Since susceptibility to anti-mycobacterials requires some level of metabolism and cell growth, these trials suggested that many bacilli involved in LTBI are constantly growing. More evidence came from the natural history of pulmonary TB in humans.2 The postprimary pulmonary TB also accepts the presence of dormant bacilli in constant relation with the immune system, waiting to reactivate due to immunosuppression. Nevertheless,
CHAPTER
Current controversies and unresolved issues in adult tuberculosis
other authors such as Canetti were sceptical about this idea because, in most cases, the primary complex is sterile within 5 years.19 Since this author considered the metastatic foci to be a part of the primary complex and thus suffer its same fate, and taking into account that the bacillary concentration would be even lower in the metastatic foci than in the original foci, he believed that an exogenous reinfection would be the origin of postprimary pulmonary TB. Some authors have recently discovered the presence of M. tuberculosis DNA in human lung parenchyma inside endothelial and epithelial cells, or fibrocytes, and mainly outside granulomas which they believe to be responsible for the maintenance of LTBI.20 Without considering the limited significance of detecting DNA by ‘in situ’ hybridization in tissue, there is a paramount problem. The turnover of pulmonary cells ranges between 28 and 125 days.21 If it is accepted that latent bacilli are reclusive within this niche, latency is limited as some energy would be required to periodically invade younger parenchymal cells. Therefore, latent bacilli must deal with this dynamic nature of the pulmonary parenchyma. There are only two possibilities: either to constantly disseminate and reactivate following the murine model, or to keep dormant inside the necrotic material of a fibrotic granuloma where the movement of macrophages would be limited for a long time until being finally reabsorbed (that is, if they do not calcify or become a scar).21 Obviously, this resuscitation would have to be very fast, before being drained out by the host. Experimental data from the ‘in vitro’ model (i.e. from bacilli submitted to stationary nonstressed culture) have shown that up to 4–5 months under the most ideal conditions are needed for reactivation.21 At this point bacilli would be drained out of the lungs. In consequence, the idea of latent bacilli waiting for immunosuppression should be changed to a situation of a constant trend of bacilli to disseminate in order to reach an adequate environment for reactivation.22 If this reactivation takes place in an area where bacilli may grow quickly, such as the apex of the lungs, and where there is a lack of immunity, then a cavitary lesion (and thus pulmonary TB, which is the evidence of LTBI) may develop. The diagnosis of LTBI is based on the tuberculin test. The existence of live bacilli is not necessary to retain a strong immune memory, because the cells of the immune system live for long periods of time and many people with LTBI have already killed the bacilli; in this case, many LTBI bacilli will never reactivate.21 Secondly, infection with M. tuberculosis triggers protective immunity. It has been estimated that BCG vaccination induces immunity for 15–20 years, therefore suggesting a similar period of protection after M. tuberculosis infection. Considering the current hypothesis that the constant ‘escape’ of bacilli from granulomas before fibrosis is the primary source of bacteria,21 reactivation would never occur after a specific time period unless the host suffered a immunosuppressive episode. Another question is whether the immune system would be able to stop bacillary growth in the upper zones of the lungs with high oxygen partial pressure. The answer may be found in the classic literature. Since calcified primary lesions have also been detected in the upper zones of the lung it seems clear that the immune system would be able to stop bacillary growth at this point.21 In conclusion, latent M. tuberculosis is a complex mixture of both slow metabolism and dormant bacilli (probably depending on the severity of the environmental stress suffered).21 In both cases, the fate of latent bacilli is determined by the dynamic physiology of the tissue where they remain. Thus it seems feasible to suggest that there are only two ways to remain latent until later reactivation: constant reactivation once the stressful conditions have disappeared
71
(e.g. when bacilli leave the foamy macrophages), and dormancy inside necrotic tissue while waiting for late drainage and then resuscitation in a short period of time before definitive removal from the host.21 In both cases, it seems important that reactivation takes place without any specific immunity against it and to reach a privileged zone where the bacilli can grow as much as possible to generate a strong inflammatory response that in turn will induce liquefaction and cause a cavitary lesion to form. Since no cases of quick resuscitation of dormant bacilli have occurred, a prolonged state of LTBI may not be assumed to be longer than about 10 years, which is the usual time period for ‘primary’ TB.
CURRENT CONTROVERSIES AND UNRESOLVED ISSUES IN THE DIAGNOSIS OF TUBERCULOSIS Pulmonary TB, the most important type of TB from a public health point of view, can be diagnosed by its symptoms, chest radiography, sputum smear microscopy and cultivation of M. tuberculosis. A percentage of patients, however, are not confirmed bacteriologically and are only diagnosed on the basis of high clinical and radiograph suspicion and response to anti-TB drugs.2 The gold standard for TB diagnosis is the cultivation of M. tuberculosis. In some cases, the diagnosis of TB becomes even more problematic due to several factors associated with immunosuppression in patients who are HIV-infected or in those with latent infection or extrapulmonary TB. Because of its non-specific clinical presentation, diagnosis of TB is also problematic in children.23 Recent advances in the field of molecular biology and progress in the understanding of the molecular basis of drug resistance in M. tuberculosis have provided new tools for rapid diagnosis by molecular methods;23 however, the high cost of most of these techniques and their requirement for sophisticated equipment or highly skilled personnel have precluded their implementation on a routine basis, especially in low-income countries.23 Other non-conventional approaches recently proposed include the search for biochemical markers, detection of immunological response and early detection of M. tuberculosis by methods other than colony counting. Several new diagnostic approaches have been proposed for TB and several others will surely appear in the near future. The most important consideration for new diagnostic methods is that they should be as good as or better than the currently existing tools and at the same time be adequate for low-resource countries where the burden of TB is greater. For example, nucleic acid amplification (NAA) methods, especially the commercial kits that have the advantage of being well standardized and reproducible, have been shown to be highly sensitive and specific in smear-positive samples; however, these values are much lower in smear-negative samples or in extrapulmonary specimens where the usefulness of these new tools would be much more desirable. The cost is another important consideration, since at the current prices these commercial kits are still out of reach for most TB diagnostic laboratories in low-resource countries. Other molecular procedures call for the use of sophisticated, expensive equipment and highly skilled personnel available only in developed countries or in central laboratory facilities in TB-endemic countries. As long as these constraints are not properly addressed, expensive commercial kits making use of NAA techniques will remain restricted to developed countries or academic and research laboratories with the appropriate funding never in the hands of the TB control programmes.23
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Concerning serological approaches for the diagnosis of TB none of the several tests proposed until now using a variety of mycobacterial antigens have been shown to be predictive enough to warrant their routine use as a diagnostic test for TB.23,24 Apparently, tests using a cocktail of antigens rather than a single more specific antigen have given better results. The new enzyme-linked immunosorbent assay (ELISA)-based tests such as the QuantiFERON-TB test and the new enzyme-linked immunospot tests like the T SPOT-TB assay measuring the production of interferon-g by activated T cells are promising;25,26 however, more studies are needed in different settings to assess their positive and negative predictive values and their usefulness as a diagnostic tool in certain populations, such as those immunosuppresed by HIV infection or other diseases and in children. The cost of these tests, since they are also available as a commercial kit, will have an impact on the feasibility for their implementation on a routine basis in the future.23 The phage-based tests have also been evaluated in different settings either as a commercial kit or as the in-house method. The low sensitivity obtained in some of these studies could have been due to low infectivity of the phages which also can be affected by the age and condition of the samples.27 On the other hand, in the studies where the phage-based methods have shown an increased sensitivity as compared with direct microscopy and culture, the volume of sample used was up to five times higher than that used for culture. It seems that, in their current format, the phage-based assays are not ready as a tool for improving the diagnosis of TB; however, they seem to be appropriate for rapid rifampicin resistance detection.23 Many studies in the search for newer and rapid TB diagnostic methods are done with the thinking of finding the ‘magic bullet’ that would allow diagnosis of TB in a matter of hours or on the spot. Maybe it is not the way, and we should not rule out simple and pragmatic approaches that are closer to what can feasibly be implemented in TB diagnostic laboratories in high-endemic countries.23 For example a simple technique as described by Mejı´a et al.28 and based on the rapid detection of microcolonies of M. tuberculosis under a standard microscope made it possible to detect more than 60% of the positive samples within the first 10 days, and, after 2 weeks, more than 80% of the samples tested positive with the microcolony method compared with 10% on Lo¨wenstein–Jensen. Other recent ¨ ngeby et al.29 using the reduction approaches like that described by A of nitrate should be explored as a rapid diagnostic tool. Culture media incorporating potassium nitrate and rifampicin could be used directly on decontaminated sputum samples to detect not only M. tuberculosis but also rifampicin-resistant bacilli at the same time. The same approach could be used with the recently described colorimetric methods, incorporating coloured indicators in the medium and inoculating directly with decontaminated sputum samples.23 A final consideration is that any new method or approach, sophisticated or not, commercial or in-house, should be evaluated in welldesigned and controlled clinical trials and tested in high-endemic, low-resource settings where the implementation and use of these methods are more needed to contribute to the improvement of TB control.23
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS: EVIDENCE AND CONTROVERSIES In the past decade, multidrug-resistant TB (MDR-TB, defined as resistance to at least isoniazid (INH) and rifampicin (RMP)) has
730
become an epidemiological issue of first priority at the global level. Case management needs to be simplified and standardized, as in many countries MDR-TB cases cannot receive individualized attention from specialist physicians. However, the difficulties lie not only in the absence of controlled trials to validate specific recommendations, but also in the very different and even contradictory results found in the literature. It is therefore essential to analyse these discrepancies before developing rational, uniform recommendations.30 Five issues are analysed in this topic (Table 71.1).
CONFIRMATION OF DIAGNOSIS IN SUSPECTED MULTIDRUG-RESISTANT TUBERCULOSIS PATIENTS: THE REAL VALUE OF DRUG SUSCEPTIBILITY TESTING The main predictor of resistance to a particular drug is the demonstration of its prior use in monotherapy for more than 1 month.30–32 To obtain this evidence it is essential to be meticulous in obtaining the history of anti-TB treatment in all patients suspected of MDR-TB.2,30,31 If the treatment history is taken meticulously, it can identify not only the errors that caused many of the failures, but also those drugs with potential efficacy, despite prior use, if they were prescribed in sound associations and led to culture conversion in the past.30 Another approach to obtaining the resistance pattern is drug susceptibility testing (DST) against first- and second-line drugs. DST has several weaknesses, including delays in results, usually > 3 months after sampling (when carried out by conventional methods on solid media), and failure due to insufficient growth of cultures.31,33 It is also important to realize that, although the in vitro and in vivo correlation of DST is very reliable for INH and RMP, this is not the case for other anti-TB drugs.31,33 It should be pointed out that although drug resistance, as detected by DST, reflects the ineffectiveness of a drug in culture media, it does not necessarily correspond to the lack of efficacy of the drug in a new regimen.31,33 Despite its drawbacks, however, DST should be performed systematically against first-line drugs for all patients; it is adequate for INH and RMP, but less so for streptomycin (SM) and ethambutol (EMB),31,33,34 for which the susceptibility results are more reliable than the resistance results,33 while for pyrazinamide (PZA) the BACTEC radiometric system is most reliable. The clinical reliability of other probes for pyrazinamide (pyrazinamidase test) has been not studied. DST of second-line drugs should not be carried out systematically on account of difficulty, cost and poor reliability.30,31,33–35 Even in wealthier countries, where multiple methods are available for performing DST for second-line drugs, interpretation of the results requires cautious analysis by experienced staff.30,33,36 Today, it appears that the DST results for some second-line drugs, such as kanamycin and ofloxacin/ciprofloxacin, may be of great help, as long as they are carefully compared with the patient’s treatment; however, DST results of other second-line drugs have proved to be of very poor reliability.30,33
NUMBER OF DRUGS REQUIRED TO TREAT A PATIENT WITH MULTIDRUG-RESISTANT TUBERCULOSIS One of the most controversial issues in the debate around MDR-TB in recent years is the number of drugs required to treat a patient with multidrug resistance,30,31,37 mainly because of the absence of controlled trials to compare different regimens. As a result, expert opinion prevails and perspectives differ according to personal experience. Thus, significant discrepancies are found in the guidelines published by the scientific societies, and divergences have emerged over time. A comprehensive critical review of the literature highlights good
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Current controversies and unresolved issues in adult tuberculosis
studies from the pre-RMP period, showing that treatment with only three drugs may ensure very favourable clinical outcomes in patients with resistance to SM, INH and para-aminosalicylic acid (PAS) (Table 71.2).30 These studies showed success rates of 75–97%, three of them demonstrating success rates of more than 90%.38–41 On the other hand, other studies from the RMP period (Table 71.3) have demonstrated good outcomes with more than four drugs, with success rates of 44–46% to 82%.30,42–46 However, only the study by Leimane et al.,47 showing a success rate of 66%, compares the results with the number of drugs received by the patients. This excellent study, which finds a correlation between inferior results and the administration of five or fewer drugs, was performed in Latvia, a setting with very high rates of MDR-TB, where most of the patients, including those with no history of previous TB treatment, harbour bacillary resistance to many drugs other than INH and RMP. Given that the main goal in making recommendations is to ensure that they are suitable for the majority of patients, it could be concluded that:30 1. the use of three effective second-line drugs could be sufficient (natural resistant mutants per drug > 1 105) from a bacteriological point of view; 2. in the field, however, some drugs often have compromised efficacy or very weak action; 3. for this reason, under NTP conditions, a second-line drug regimen should include at least four drugs; and 4. occasionally, when several drugs exhibit compromised efficacy or very weak action, it may be justified to prescribe more than four drugs.
71
LENGTH OF PARENTERAL DRUG ADMINISTRATION OR OF THE INITIAL PHASE OF TREATMENT No clinical trials have compared the efficacy of regimens with different lengths of parenteral drug administration in patients with drug resistance. Considering that the site of action of SM may be exclusively extracellular, it would be estimated to be of low efficacy once cultures have become negative. However, Crowle et al.48 demonstrated that SM also has intracellular activity. If these findings in vitro correspond also to effects in vivo, and if other injectable agents behave like SM, this group of drugs would be likely to remain effective even after culture conversion. For this reason, recommendations about the length of administration of injectable drugs should be decided in the context of the other drugs in the regimen, the patient’s bacteriological status and close monitoring of adverse effects.
CONTRIBUTION OF SURGERY TO THE TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS PATIENTS Despite the absence of randomized trials assessing the role of surgery in the treatment of patients with MDR-TB, virtually all available guidelines and specific recommendations on the subject include a mention of surgery, albeit a very secondary role,2,49,50 and it is recommended only in patients meeting the three following conditions: 1. a fairly localized lesion; 2. an adequate respiratory reserve; and 3. a lack of sufficient available drugs (two or three with very weak action) to design a regimen potent enough to ensure cure.
Table 71.2 Outcome of tuberclosis patients with bacillary resistance to isoniazid, streptomycin and para-aminosalicylic acid, treated with only three SLD, in the pre-rifampicin period Reference
Country
Years
No. of a patients
Followup period
Cured/ completed treatment
Efficacy of the regimen b (%)
Tousek
Czechoslovakia
1959–62
55
45 (82%)
96
Zierski
Poland
1958–62
32
31 (97%)
97
Fischer
USA
1960–2
146
24 months 9 months 4 years
122 (83%)e
88f
Kass Pines
USA UK
1960–2 1961–3
74 12
58 (79%) 9 (75%)
81g 90
Somner
UK
1960–2
22
4 years 24 months 5 years
20 (91%)
100
Kassh
USA
1962–4
24
277 days
23 (96%)
96
Died
Defaulters/ withdrew/ c lost
Failures/ nond responders
8 (14%)
2 (4%)
Poor outcome associated
1 (3%) 37 (25%)e
27 (18%)
16 (21%) 1 (8%)
2 (17%) 1 (4.5%)
1 (4.5%) 1 (4%)
a
Number of MDR-TB patients with outcome known in the study. Efficacy of the regimen: cured þ completed treatment/cured þ completed treatment þ failures þ non-responders. c Patients not taking the drugs regularly are included. d Including the relapses known in patients cured previously. e Sputum conversion after 120 days of treatment. Thirty patients (20.5%) relapsed during the period observation. Only seven failures. The final number of cured cases is not divulged in the article. f Of the 68 living patients whose culture status was known as of January 1966, 60 (88%) remained consistently non-infectious. g By January 1964 60 (81%) of the patients were known to be still culture negative. h The only study using ethambutol in the regimen. Adapted from Caminero JA30. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis 2006; 10:829-37 b
731
Country
Years
Treatment
Median drug resistant
No. of a patients
New MDR
Cured/ completed treatment
Efficacy of the regimen b (%)
Died
Defaulters/ withdrew/ lost
Failures/ c nonrespond
Poor outcome associated
Leimane
Latvia
2000
Individualized
4
204
55 (27%)
135 (66%)
76
14 (7%)
26 (13%)
29 (14%)
Mitnick
Peru
1996–9
Individualized
6
75
Palmero
Argentina
1996–9
Individualized
4.1
141
55 (73%)
83
5 (7%)
14 (19%)
1 (1%)
64 (45%)
60
27 (19%)
28 (20%)
7 (5%)
50 (35.5%)
298
136 (46%)
52
32 (11%)
34 (11%)
96 (32%)
6
171
75 (44%)
56
8 (4.6%)
22 (13%)
59 (34%)
Standardized Individualized
7 4
130 83
107 (82%) 63 (76%)
98 82.5
6 (4.6%)
14 (11%) 20 (24%)
2 (1.5%) 11 (13%)
Individualized Individualized
5 4.4
39 158
32 (82%) 121 (77%)
97 90
6 (14%) 7 (4%)
17 (11%)
1 (2.5%) 13 (8%)
Sua´rez
Peru
1997–9
Standardized
Goble
USA
1973–83
Individualized
IOM TB Park
Vietnam Korea
1990–5 1993–6
Geerligs Tahaoglu
Netherlands Turkey
1985–8 1992–9
Narita
USA
Van Deun Chan
Bangladesh USA
1994–7
Individualized
4.8
81
46 (57%)
100
1997–9 1984–98
Standardized Individualized
6
58 139
40 (69%) 71 (51%)
93 64.5
26 (32%) 8 (14%) 16 (11%)d
9 (11%) 7 (12%) 21 (15%)
3 (5%) 39 (28%)#
a
Number of MDR-TB patients with outcome known in the study. Efficacy of the regimen: cured þ completed treatment/cured þ completed treatment þ failures þ non-responders. c Including the relapses known in patients cured previously. d Six patients died from TB after relapses. BMI, body mass index. Adapted from Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis 2006; 10:829-37 b
Previous MDR treatment 5 drugs 3 months Resist. Of. BMI < 18.5 Low haematocrit Low BMI No admission to hospital No. drugresistant Resistance to 5 drugs > No. drugs received previously Male sex Age > 45 > No. drugs received previously Older age Previous treatment with ofloxacin Treatment on an outpatient basis No surgery Younger No quinolones
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732 Table 71.3 Outcome of the multidrug-resistant tuberculosis patients in the most important articles published in the rifampicin period
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Current controversies and unresolved issues in adult tuberculosis
Surgery should therefore only be considered for the management of MDR-TB for patients fulfilling these three conditions, and it should be performed by experienced surgeons with the support of efficient postoperative care units.51 These conditions exist in few countries in the world, most of them industrialized.
THE OPTIMAL REGIMEN FOR MULTIDRUG-RESISTANT TUBERCULOSIS: STANDARDIZED VS INDIVIDUALIZED The guidelines of scientifically advanced societies in high-income countries have always advocated individualized case management.49,52 With an abundance of resources at their disposal, various authors have published recommendations based on individualized criteria for the selection of the best possible regimen for each patient.50,53,54 The main principles of this individualization are selection of treatment based on the DST results and elaboration of aggressive therapeutic regimens in settings that allow close follow-up of patients by skilled professionals. Several published studies have reported the efficacy of this strategy (Table 71.3).45,47,51,55,56 However, as a highly expensive approach, it is difficult to implement in the majority of middle- and low-income countries, which bear the highest burden of MDR-TB.3,30 As use of second-line drugs in many countries has been very limited in the past, in these countries susceptibility to these drugs can be accepted despite DST results.30,31 Standard treatment regimens for these MDR-TB patients facilitate their management, reduce the number of specialist physicians needed and reduce the overall cost of treatment by five to 10 times. In light of these advantages, various authors have advocated standard management, but again, only under specific conditions.30,31,57 The efficacy of this strategy has been confirmed by reports in the literature.57,58 To begin to resolve this controversy and simplify the management of MDR-TB, the cases could be divided into three treatment categories:30,59 1. Initial MDR-TB in patients with no history of anti-TB treatment (or who have received treatment for less than 1 month): it appears more judicious to recommend that contacts of MDR-TB cases be treated with the same regimen as their index cases, adapting later in regards to the DST result. 2. MDR-TB cases who have received only first-line drugs in the past: these patients could be treated with standardized regimens consisting of second-line drugs, selecting at least four new drugs and following a rational classification of these drugs. 3. MDR-TB cases who have received both first- and second-line drugs in the past: the management of these patients poses the most difficult problem, as they have often suffered from a regrettably lengthy sequence of therapeutic errors, which are very often hard to determine due to the multiple regimens and drugs administered over the past years,. The only solution in these cases is individualized management.
COST-EFFECTIVENESS OF TUBERCULOSIS CONTROL STRATEGIES AMONG IMMIGRANTS AND REFUGEES Today, in regions of the world with a relatively low incidence of TB, such as Western Europe, Canada, and the USA, more than half of all new active TB cases occur among residents born in
71
South and Central America, Asia, Africa and Latin America.3 This can result in significant transmission within certain foreign-born communities in these countries.60 However, restriction fragment length polymorphism (RFLP) studies have detected relatively little TB transmission from foreign-born residents to the general population.61 The estimated proportion of active TB cases among the native-born that can be attributed to transmission from the foreign-born may be as low as 2% or 11%, or as much as 17%.60 In one US study, foreign-born TB patients were more likely to have acquired TB from US-born individuals than vice versa.62 Many active TB cases among the foreign-born are attributable to reactivation of latent TB infection. Reactivation rates are highest during the first 2–5 years following migration.60 In some cases, however, active TB cases are the result of new infection acquired after migration, as demonstrated in an analysis conducted in the Netherlands of TB cases among Moroccanorigin residents.63 Despite the large proportion of active cases attributable to foreign-born residents, the public health impact is relatively low, as TB transmission from foreign-born occurs largely within specific ethnic communities.60 Although mass screening of the general population had no appreciable impact on the incidence of smear-positive cases, overall morbidity or mortality several decades ago,64 almost all highincome industrialized countries continue to utilize chest radiograph screening for detection of active TB among applicants for permanent residence.60 Screening for a disease is justified if that disease is relatively common and treatable. The ideal screening test should be inexpensive, be easy to administer, cause no discomfort to the patient and offer both high sensitivity and specificity.60 As shown in Table 71.4, only a small proportion of permanent resident applicants evaluated through TB screening programmes are found to have active pulmonary TB at the time of evaluation.60 The prevalence is higher among refugees from high-incidence countries, although still less than 1%.60 On the other hand, the prevalence of latent infection with chest radiograph abnormalities (inactive TB and/or apical fibronodular disease) is substantially higher – with estimates ranging from 3% to 5%.60 Latent infection without chest radiograph abnormalities is even more common, with prevalence estimates between 35% and 42%.60 When considering the most cost-effective approach to control of TB in foreign-born migrants, it is important to remember that cost-effectiveness is affected by the perspective of the analysis (government, private payer, patient, society), costs of services (evaluations, tests, hospitalization, transportation) and effectiveness of available interventions. Existing TB screening programmes for migrants to low-TB-incidence countries have used chest radiographs to detect active TB in permanent resident applicants. Because of the very low prevalence of active TB in this population and the low positive predictive value of the chest radiograph, radiographic screening for active TB at entry has minimal impact and is not cost-effective. The major potential benefit of screening at entry is the detection of individuals with latent TB infection and abnormal chest radiographs, but only if they receive preventive therapy. This means the screening programme must have the capacity to provide treatment for LTBI. Given the current recommended standard of INH treatment for 9 months, substantial infrastructure is necessary to ensure adequate compliance, and to ensure that adverse events, which can rarely be fatal, are detected and managed promptly. This increases the expense
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Table 71.4 Prevalence of tuberculosis among migrants to low-incidence countries Authors
Population
Prevalence (%) Active tuberculosis
Blum et al. (1993)73 Markey et al. (1986)74 Pitchenik et al. (1982)75 Nolan and Elarth (1987)76 Dasgupta et al. (2000)77
Latent TB infection With chest radiograph abnormalities
Without abnormalities
Amnesty programme adjustments for illegal migrants from Mexico in USA Port of entry screening of all immigrants to UK
0.08
5
42
0.04
0.1
Not available
Haitian refugees in USA
0.65
Southeast Asian refugees in USA
0.8
5.6
35.7
Permanent resident applicants in Canada
0.15
2.6
Not available
Adapted from Dasgupta and Menzies.60
more costly than chest radiograph or tuberculin skin testing, so their utility and cost-effectiveness remain unclear at this time.60 Effective TB screening strategies are also needed for all other entrants, as well as for permanent residents who return home to their high-incidence countries. A screening programme designed to address all of these potential sources of TB infection is likely to be complex and expensive. A more effective use of resources may be comprehensive contact tracing within foreign-born communities through local primary care networks.60 The ideal long-term TB control strategy would be global investment for improving TB control in high-incidence countries. If successful, this could result in a global reduction in TB incidence
and complexity of any screening programme. Nevertheless, detection and treatment of inactive TB through chest radiographs will be more cost-effective than detection of latent infection through tuberculin skin testing, but neither are highly cost efficient (Table 71.5).60 Replacement of chest radiograph screening with sputum culture would offer a small improvement in cost-effectiveness, but would not detect latent infection. Tests of cell-mediated immune response and seroassays involving cocktails of antigens are emerging technologies that may offer the potential to both detect and differentiate active and LTBI. However, these new technologies have not been evaluated for screening purposes and at the present time are generally
Table 71.5 Total cost per active tuberculosis case detected using different screening tests, in a hypothetical cohort of 1,000 immigrants, with 1% prevalence of active tuberculosis TST
Cost to screen 1,000 persons ($) Number of cases of active TB detected Number of false-positive tests Costs of work-up after positive testd ($) Total cost for screening ($) Total cost per active case detected ($)
7,000 8 470c 92,254 99,254 12,407
Chest radiograph
22,000 7 238 47,285 69,285 9,898
a
Sputum TB culture 1
3
50,000 8.2 19.8 5,404 55,404 6,757
150,000 9 19.8 5,558 155,558 17,284
Sputum TB PCR (1)
Serology
CMI
75,000 7.3 19.8 5,230 80,230 10,990
19,000b 5.5 99 20,169 39,169 7,122
45,000b 6.5 178 35,609 80,609 12,401
Adapted from Dasgupta and Menzies.60 All costs in Canadian $. CMI, cell-mediated immune response; PCR, polymerase chain reaction; TST, tuberculin skin test. a Sputum TB culture includes cost of sputum induction, but does not include acid-fast bacilli smear. b Serology and CMI: includes cost for drawing blood samples ($10). c Assume that prevalence of positive TST would be 50%. d Average costs was $193 for evaluation of persons with positive screening test in a chest specialist clinic.77 Does not include overhead, administration or patient costs.
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Current controversies and unresolved issues in adult tuberculosis
which would reduce the risk of TB among human migrants travelling from high- to low-TB-incidence regions. Such a strategy would be more humanitarian and may be more cost-effective than current approaches to TB control among these migrants.60
THE DREAM OF A VACCINE AGAINST TUBERCULOSIS. NEW VACCINES: IMPROVING OR REPLACING BCG? The development of an effective TB vaccine seemed implausible until only a few years ago.65 The current TB vaccine, BCG, is a live vaccine that protects against severe childhood forms of disease, miliary and extrapulmonary TB including the often fatal TB meningitis. It also confers protection against leprosy. The WHO recommends BCG vaccination in areas of high TB prevalence and incidence. BCG vaccination is currently compulsory in at least 64 countries and administered in more than 167.66 Indeed, BCG remains the most widely used vaccine in the world. BCG is an inexpensive vaccine that has been given to more than 2.5 billion people since 1948. It has a long-established safety profile and has outstanding adjuvant activity, eliciting both humoral and cellmediated immune responses. It can be given at birth or any time thereafter and a single dose can produce long-lasting immunity. It has also been licensed as a treatment for bladder cancer. Moreover, an investigation of the long-term efficacy of BCG vaccine, a 60-year follow-up study in American Indians and Alaska natives, has shown remarkable results that the efficacy of BCG vaccine persists for 50–60 years, suggesting that a single dose of BCG vaccine can give life-long protection.67 The level of protection conferred by BCG is very variable: it differs according to the form of pulmonary TB and can be affected in those cases in which TB is associated with AIDS. The efficacy of BCG vaccines against pulmonary TB varies between populations, showing no protection in Malawi but 50– 80% protection in the UK.68 The reasons for the failure of BCG have been widely debated, and remain a topic of active research. Natural exposure to environmental mycobacteria is thought to exert an important influence on the immune response, and this may mask or otherwise inhibit the effect of BCG vaccination in tropical countries. This type of phenomenon has been proposed as a plausible explanation for the north–south gradient in the effectiveness of BCG.69 Anyway, BCG fails to protect against adult pulmonary TB in countries in which it is endemic. After more than 80 years of using BCG as a vaccine against TB, there is now an urgent need for new vaccines offering better protection than BCG. In the past 10 years of work with experimental laboratory models, many vaccine candidates have been developed.65 They include protein or DNA subunit vaccines, modified BCG and attenuated M. tuberculosis. Some of these candidates are now being tested for safety and immunogenicity in human volunteers. For the first time phase I clinical trials of new TB vaccine candidates have started. These new trials mainly involve subunit vaccines including TB antigens: the idea is to improve BCG immunity by boosting with vaccines consisting of subunits or attenuated vaccinia virus expressing TB antigens. However, effective vaccination against TB presents diverse and complex challenges. For example, TB infection can become reactivated years later and infection does not guarantee resistance to a subsequent second infection.65
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A truly effective TB vaccine may, therefore, have to elicit an immune response that is greater than that induced by natural infection.65 In addition, various different populations must be protected: they include those vaccinated with BCG and those infected with M. tuberculosis or with HIV. The goal is a new generation of vaccines effective against the respiratory forms of TB. In a first step, good candidate vaccines able to boost BCG and thereby improve protection could be a reality in the middle term. Tuberculosis vaccine candidates able to replace the currently used BCG and/or make the eradication of TB feasible can only be expected in the long term. Indeed, these goals may require safe live vaccines.65 Then, although the efficacy of the BCG vaccine continues to be discussed, live attenuated BCG is still the only vaccine in use for the prevention of TB in humans. This is because it is effective against the severe forms of TB and its use is preventing a large number of deaths that would otherwise be caused by TB each year. The choice of the BCG strain to be used for vaccination is a very important issue. It is currently difficult to determine which strain should be used, and further detailed analysis of the genomics and immunogenicity of BCG substrains may provide an answer to this important question.65 The WHO and the Union could then use the BCG substrains giving the best protection, and recommend them for future vaccination worldwide. Research to develop improved TB vaccines seems to be at a decisive moment. More than 200 vaccine candidates have been proposed as the result of work over recent years in experimental laboratory models, and some are now approaching clinical testing.70 The transition from laboratory to clinical trials has a wide range of strategic and technical implications. In particular, facilities and funding need to be provided for the production of any successful vaccine appropriate for clinical use. After the Madrid Conference in March 1995 ‘Definition of a Coordinated Strategy towards a New TB Vaccine’ organized by the WHO and the Union, a joint effort involving diverse governmental organizations in Europe (FP5 and FP6 Framework Programmes) and the USA by the National Institutes of Health and recently the AERAS Foundation was established. For the first time, after 80 years of widespread use of BCG, evaluations of new TB vaccine candidates in humans are available. The development of a new vaccine conferring better protection than BCG, and able to replace it, nevertheless remains a challenge for the scientific community.65 If eradication of TB is to be possible and affordable, appropriate new vaccines must be found. Subunit vaccines have potential advantages over live mycobacterial vaccines in terms of safety and quality control of the manufactured vaccine and are good candidates for improving the effect of BCG. However, in order to confer the complex immunity required to protect against TB, it is possible that more than single antigens will be necessary.65 Progress to date with live attenuated M. tuberculosis vaccines indicates that it is possible to design strains that are highly attenuated, even in immunodeficient animals. These ‘classical’ vaccine candidates must mimic natural infection as closely as possible without causing disease.71M. tuberculosis mutant vaccine candidates must induce long-term cellular immune responses, essential for effective protection against TB. New live vaccines should be stored lyophilized and current technology allows monitoring of any possible variation of genomic composition by comparative hybridization experiments using DNA microarrays.72
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REFERENCES 1. Gutierrez MC, Brisse S, Brosch R, et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog 2005;1:e5:1–7. 2. Caminero Luna JA. A Tuberculosis Guide for Specialist Physicians. Paris: Imprimerie Chirat, 2004. 3. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO/ HTM/TB/2006.362. Geneva: World Health Organization, 2006. 4. Dlodlo R, Fujiwara PI, Enarson DA. Should tuberculosis treatment and control be addressed differently in HIV-infected and -uninfected individuals? Eur Respir J 2005;25:751–757. 5. Caminero JA, Torres A. Controversial topics in tuberculosis. (Editorial). Eur Respir J 2004;24:895. 6. Rieder HL. Opportunity for exposure and risk of infection: the fuel for the tuberculosis pandemic. (Editorial). Infection 1995;23:1–4. 7. Rieder HL. Annual risk of infection with Mycobacterium tuberculosis. Eur Respir J 2005; 25:181–185. 8. Bulla A. Worldwide review of officially reported tuberculosis morbidity and mortality (1967–1971–1977). Bull Int Union Tuberc Lung Dis 1981;56:111–117. 9. Cauthen GM, Pio A, ten Dam HG. Annual risk of tuberculous infection. Bull World Health Organ 2002;80:503–511. 10. Enarson DA. Principles of IUATLD Collaborative Tuberculosis Programmes. Bull Int Union Tuberc Lung Dis 1991;66:195–200. 11. Rieder HL. Methodological issues in the estimation of the tuberculosis problem from tuberculin surveys. Tuber Lung Dis 1995;76:114–121. 12. Chum HJ, O’Brien RJ, Chonde TM, et al. An epidemiological study of tuberculosis and HIV infection in Tanzania, 1991–1993. AIDS 1996;10:299–309. 13. Styblo K. The relationship between the risk of tuberculous infection and the risk of developing infectious tuberculosis. Bull Int Union Tuberc Lung Dis 1985;60(3–4):117–119. 14. Murray CJL, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990;65(1):6–24. 15. World Health Organization. Tuberculosis Handbook. WHO/TB/98.253:1–222. Geneva: World Health Organization, 1998. 16. Arnadottir T, Rieder HL, Tre´bucq A, et al. Guidelines for conducting tuberculin skin test surveys in high prevalence countries. Tuber Lung Dis 1996; 77(suppl):1–20. 17. Caminero JA, Peno MJ, Campos-Herrero MI, et al. Exogenous reinfection with tuberculosis on a European island with a moderate incidence of disease. Am J Respir Crit Care Med 2001;163:717–720. 18. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuberc Res 1969;17:28–106. 19. Canetti G. Re´activation engege`ne et re´infection exoge`ne. Leur importance relative dans l’e´closion de la tuberculose primaire. Bull Int Union Tuberc 1972;47:122–129. 20. Herna´ndez-Pando R, Jeyanathan M, Mengistu G, et al. Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection. Lancet 2000;356:2133–2138. 21. Cardona PJ, Ruiz-Manzano J. On the nature of Mycobacterium tuberculosis-latent bacilli. Eur Respir J 2004;24:1044–1051. 22. Cardona PJ, Gordillo S, Amat I, et al. Catalaseperoxidase activity has no influence on virulence in a murine model of tuberculosis. Tuberculosis 2003; 83:351–359. 23. Palomino JC. Nonconventional and new methods in the diagnosis of tuberculosis: feasibility and applicability in the field. Eur Respir J 2005;26: 339–350.
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24. Caminero JA, Rodriguez de Castro F, Carrillo T, et al. Value of ELISA using A60 antigen in the serodiagnosis of tuberculosis. Respiration 1994;61: 283–286. 25. Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB Gold Test for detecting Mycobacterium tuberculosis infection, United States. MMWR Morb Mortal Wkly Rep 2005;54(RR-15):49–55. 26. Richeldi L. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med 2006;174:736–742. 27. Mbulo GMK, Kambashi BS, Kinkese J, et al. Comparison of two bacteriophage tests and nucleic amplification for the diagnosis of pulmonary tuberculosis in sub-Sahran Africa. Int J Tuberc Lung Dis 2004;8:1342–1347. 28. Mejia GI, Castrillon L, Trujillo H, et al. Microcolony detection in 7H11 thin layer culture is an alternative for rapid diagnosis of Mycobacterium tuberculosis infection. Int J Tuberc Lung Dis 1999;3:138–142. 29. A¨ngeby KAK, Klintz L, Hoffner SE. Rapid and inexpensive drug susceptibility testing of Mycobacterium tuberculosis with nitrate reductase assay. J Clin Microbiol 2002;40:553–555. 30. Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis 2006;10:829–837. 31. Caminero JA. Management of multidrug-resistant tuberculosis and patients in retreatment. Eur Respir J 2005;25:928–936. 32. Mitchison DA. The segregation of streptomycinresistant variants of Mycobacterium tuberculosis into groups with characteristic levels of resistance. J Gen Microbiol 1951;5:596–604. 33. Kim SJ. Drug-susceptibility testing in tuberculosis: methods and reliability of results. Eur Respir J 2005;25:564–569. 34. Canetti G. The J. Burns Amberson lecture. Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 1965;92:687–703. 35. Tuberculosis Division International Union against Tuberculosis and Lung Disease. Tuberculosis bacteriology—priorities and indications in high prevalence countries: position of the technical staff of the Tuberculosis Division of the International Union against Tuberculosis and Lung Disease. Int J Tuberc Lung Dis 2005;9:355–361. 36. Kim SJ, Espinal MA, Abe C, et al. Is second-line antituberculosis drug susceptibility testing reliable? (Correspondence). Int J Tuberc Lung Dis 2004;8: 1157–1158. 37. Caminero JA, de March P. Statements of ATS, CDC, and IDSA on treatment of tuberculosis. (Correspondence). Am J Respir Crit Care Med 2004;169:316–317. 38. Pines A. Treatment of pulmonary tuberculosis with cultures resistant to two or more drugs: a series of 44 patients. Tubercle 1965;46:131–142. 39. Zierski M, Zachara A. Late results in re-treatment of patients with pulmonary tuberculosis. Tubercle 1970;51:172–177. 40. Somner AR, Brace AA. Late results of treatment of chronic drug-resistant pulmonary tuberculosis. BMJ 1966;1:775–778. 41. Kass I. Chemotherapy regimens used in retreatment of pulmonary tuberculosis. Part II. Observations on the efficacy of combinations of ethambutol, capreomycin and companion drugs, including 4–4 diisoamyloxythiosemicarbanilide. Tubercle 1965; 46:166–177. 42. Palmero DJ, Ambroggi M, Brea A, et al. Treatment and follow-up of HIV-negative multidrug-resistant tuberculosis patients in an infectious diseases reference hospital, Buenos Aires, Argentina. Int J Tuberc Lung Dis 2004;8:778–784. 43. Sua´rez PG, Floyd K, Portocarrero J, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359: 1980–1989.
44. Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328:527–532. 45. Park SK, Kim CT, Song SD. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampicin. Int J Tuberc Lung Dis 1998;2:877–884. 46. Geerligs WA, van Altena R, de Lange WCM, et al. Multidrug-resistant tuberculosis: long-term treatment outcome in the Netherlands. Int J Tuberc Lung Dis 2000;4:758–764. 47. Leimane V, Riekstina V, Holtz TH, et al. Clinical outcome of individualised treatment of multidrugresistant tuberculosis in Latvia: a retrospective cohort study. Lancet 2005;365:318–326. 48. Crowle AJ, Sbarbaro JA, Judson FN, et al. Inhibition by streptomycin of tubercle bacilli within cultures human macrophages. Am Rev Respir Dis 1984;130:839–844. 49. American Thoracic Society, Centers for Disease Control and Prevention, Infectious Disease Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662. 50. Mukherjee J, Socci A, Acha J, et al. The PIH Guide to Management of Multidrug-Resistant Tuberculosis. International edn. Boston: Partners in Health; 2003. 51. Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrugresistant tuberculosis. Am J Respir Crit Care Med 2004;169:1103–1109. 52. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998;53:536–548. 53. Iseman MD. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993;329: 784–791. 54. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment fo multidrugresistant tuberculosis. Lancet 2004;363:474–481. 55. Mitnick C, Bayona J, Palacios E, et al. Communitybased therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003;348:119–128. 56. Tahaoglu K, To¨ru¨n T, Sevim T, et al. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001;345:170–174. 57. Van Deun A, Hamid Salim MA, Kumar Das AP, et al. Results of a standardised regimen for multidrugresistant tuberculosis in Bangladesh. Int J Tuberc Lung Dis 2004;8:560–567. 58. International Organization for Migration Tuberculosis Working Group. Outcome of secondline tuberculosis treatment in migrants from Vietnam. Trop Med Intern Health 1998;3:975–980. 59. World Health Organization. Guidelines of the Programmatic Management of Drug-Resistant Tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization, 2006. 60. Dasgupta K, Menzies D. Cost-effectiveness of tuberculosis control strategies among immigrants and refugees. Eur Respir J 2005;25:1107–1116. 61. Dahle UR, Sandven P, Heldal E, et al. Continued low rates of transmission of Mycobacterium tuberculosis in Norway. J Clin Microbiol 2003; 41(7):2968–2973. 62. Jasmer RM, Ponce dL, Hopewell PC, et al. Tuberculosis in Mexican-born persons in San Francisco: reactivation, acquired infection and transmission. Int J Tuberc Lung Dis 1997;1(6): 536–541. 63. Bwire R, Nagelkerke N, Keizer ST, et al. Tuberculosis screening among immigrants in The Netherlands: what is its contribution to public health? Neth J Med 2000;56(2):63–71. 64. Toman K. Tuberculosis—case-finding and chemotherapy: Questions and answers. Geneva: World Health Organization, 1979. 65. Martı´n C. The dream of a vaccine against tuberculosis; new vaccines improving or replacing BCG? Eur Respir J 2005;26:162–167.
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Current controversies and unresolved issues in adult tuberculosis 66. World Health Organization. Global Tuberculosis Programme and Global Programme on Vaccines. Statement on BCG revaccination for the prevention of tuberculosis. WHO Wkly Epidemiol Rec 1995;70:229–231. 67. Aronson NE, Santosham M, Comstock GW, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives. A 60-year follow-up study. JAMA 2004;291:2086–2091. 68. Black GF, Weir RE, Floyd S, et al. BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomized controlled studies. Lancet 2002; 359:1393–1401. 69. Brandt L, Feino Cunha J, Weinreich Olsen A, et al. Failure of the Mycobacterium bovis BCG vaccine: some
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species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun 2002;70: 672–678. McShane H, Pathan AA, Sander CR, et al. Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis 2005;85:47–52. Young D, Dye C. The development and impact of tuberculosis vaccines. Cell 2006;124:683–687. Behr MA. BCG—different strains, different vaccines? Lancet Infect Dis 2002;2:86–92. Blum RN, Polish LB, Tapy JM, et al, Results of screening for tuberculosis in foreign-born persons applying for adjustment of immigration status. Chest 1993;103(6):1670–1674.
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74. Markey AC, Forster SM, Mitchell R, et al. Suspected cases of pulmonary tuberculosis referred from port of entry into Great Britain, 1980–3. BMJ 1986;292: 378–379. 75. Pitchenik A, Russell B, Cleary T, et al. The prevalence of tuberculosis and drug resistance among Haitians. N Engl J Med 1982;307(3): 162–165. 76. Nolan C, Elarth A. Tuberculosis in a Cohort of Southeast Asian Refugees.A five-year surveillance study. Am Rev Resp Dis 1983;137(4):805–809. 77. Dasgupta K, Schwartzman K, Marchand R, et al. Comparison of cost effectiveness of tuberculosis screening of close contacts and foreign-born populations. Am J Resp Crit Care Med 2000;162(6): 2079–2086.
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Laboratory systems and strategies for tuberculosis John C Ridderhof and Armand Van Deun
INTRODUCTION Laboratories play a critical role in diagnosing, monitoring and treating TB – all significant in an effective TB control programme. A positive TB diagnosis is considered certain only if the diagnosis is laboratory confirmed, and patient classifications and treatment management have depended largely, and often solely, on bacteriology.1,2 However, in many high-prevalence and resource-limited countries, reliance on smear microscopy as the most effective and practical tool for diagnosis and control of TB has helped contribute to a growing disparity in the quality and availability of laboratory testing compared with countries with sufficient resources. Industrialized countries, especially in Europe and North America, have embraced and supported new technologies that provide rapid detection, identification, and drug-susceptibility testing of Mycobacterium tuberculosis.3 These enhanced diagnostic capabilities have helped control TB, when combined with good treatment programmes and effective public health disease control strategies.4,5 In contrast, many countries with high TB prevalence, but few resources for diagnosing, treating and controlling the disease, still struggle to provide high-quality microscopy.6 Moreover, culture and drug-susceptibility testing (DST) are rarely available outside the TB national reference laboratory and are mainly used only for epidemiological monitoring of drug resistance. Poorly managed TB programmes and laboratory systems have hindered progress towards more consistent testing and treatment world-wide, and progress is now further hampered by the additional burden of the human immunodeficiency virus (HIV) epidemic and multidrugresistant (MDR) TB. Although strengthening laboratory services and technology has been given higher priority on the TB agenda, for example introducing programmes such as the new Stop TB Strategy,7,8 this reprioritization has not yet resulted in increased allocation of resources for TB testing in many countries. More global guidance, research and programmes focused on capacity building are needed to provide access to and use of existing diagnostics, and to develop and implement new technologies. A different situation exists in industrialized countries. Industrialized countries have implemented technologies such as fluorescence microscopy, liquid cultures for isolation and DST, and have developed molecular amplification methods for detecting TB and any possible drug resistance. These diagnostic methods, although effective, are expensive, labour-intensive and relatively slow in producing test results, in comparison with technological developments in other areas of microbiology such as direct detection of organisms with polymerase
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chain reaction. These developments have sparked renewed interest in developing new diagnostics and examining successful models for implementing modern diagnostic methods in low-income countries. The Foundation for Innovative and New Diagnostics (FIND) is supporting a world-wide initiative to apply a systematic approach to research and development of new diagnostics.9 One danger in only addressing diagnostic methods and funding for supplies is that system requirements could be neglected. These include needs for well-trained staff, quality management systems and other organizational structures that support higher standards of practice found in industrialized countries. In settings with sufficient resources, the clinician expects and advocates for certain diagnostic tests. The pressure to provide newer technologies is accompanied by expectations for quality that have not only medical care but legal implications (i.e. false-positive test results have led to law suits). By contrast, in many low-income countries, the clinician is aware of deficiencies in the laboratory system and may treat empirically (i.e. physician treats for TB based on recognized symptoms as opposed to actual test results) due to a lack of trust in laboratory results.10 Unfortunately, this reduces the incentive to upgrade technologies and services, and to implement quality standards that strengthen the laboratory system. Problems associated with MDR-TB and recent outbreaks of extensively drug-resistant (XDR) TB have highlighted the need to increase capacity for culture and DST.11 Culture and DST, however, are much more complex than microscopy; thus, countries and international organizations are being forced to examine the critical elements needed to significantly scale up laboratory capacity. There is also a corresponding interest in determining how national TB programmes (NTPs) can work with other programmes and agencies to build effective laboratory networks that integrate services and leverage scarce resources in the midst of a growing private sector. Scaling up services for culture and DST, and optimizing microscopy might succeed if the technology and system requirements of TB laboratory services are integrated into a general initiative to upgrade the country’s laboratory network.12 Many countries and international organizations recognize that improving the quality of TB laboratory networks is required to continue progress in TB control. This chapter will focus on some of the critical technical and organizational challenges with microscopy, culture, DST and corresponding safety issues. Successful laboratory services will also be examined with a focus on both historical and new perspectives in laboratory strategy, human resources considerations, research, quality management systems and the structure of the laboratory network. All are necessary components for strengthening laboratory capacity.
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Laboratory systems and strategies for tuberculosis
LABORATORY METHODS: STRENGTHS AND WEAKNESSES MICROSCOPY In most countries, especially those with the highest burden of disease, the Ziehl–Neelsen (ZN) smear remains the first test given and the only one accessible to a large part of the population for years to come. Reaching the best possible sensitivity is essential and requires diligence and appropriate technique. Numerous examples exist where the testing sensitivity is low because of neglecting to adhere to details in the guidelines and lack of regular laboratory onsite evaluation, even in the absence of HIV coinfection. Concerns that the ZN smear has lower sensitivity when used on HIV-infected patients have stimulated interest in practical methods for improving microscopy.13,14 Industrialized countries use centrifugation-concentrated smears and fluorescent microscopy, a combination that could provide higher sensitivity also in low-income, high-HIV-prevalent countries, but requires more resources.15 A strategy using simple bleach digestion and concentration, not requiring high-force centrifugation, has been intensively studied for more than 10 years. However, doubts about the correct use of and indications for this approach remain, requiring further operational research.16–18 Also, the use of fluorescence microscopy is still not widespread, but for other reasons. There is no doubt about fluorescence microscopy’s greater efficiency and increased sensitivity.19 That said, for a wide variety of reasons, of which poor acceptance may be most important, this expensive equipment is rarely used in low-income countries, even in clearly overloaded laboratories where its advantages are obvious. The new light-emitting diode (LED) lamp fluorescence systems are simpler and less costly, and are a potential catalyst to the final breakthrough of this technology in countries with a high prevalence of HIV. Considering the tedious nature of acid-fast bacilli (AFB) microscopy, internal and external quality assessment (EQA) programmes are necessary to monitor smear preparation, staining and interpretation, and to ensure that all microscopy centres achieve an acceptable level of performance. The implementation of EQA for microscopy also strengthens laboratory networks and contributes to quality improvement.20 Systematic review by a laboratory expert is a critical component to strengthening network management, but can be limited by funding and staff requirements (i.e. transportation and supervision). In integrated health systems, one solution is to broaden the scope of onsite supervision to include reviewing and monitoring other testing services (e.g. HIV, malaria, chemistry and haematology). An integrated onsite evaluation of laboratory services could inevitably lead to a reduced focus on TB, but is more efficient and cost-effective, considering limited human resources. Integrated review is also the standard for laboratory accreditation in industrialized countries.
CULTURE AND DST The use of culture and DST is standard diagnostic practice in industrialized countries, but at the other extreme most lowresource countries still cannot provide culture for priorities that include drug resistance surveillance (DRS), extrapulmonary and childhood TB and suspicion of MDR-TB. There is continued
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debate on whether providing culture for routine detection of TB cases in the high-prevalence setting is cost-effective and feasible.21 Enhanced culture capacity would benefit both patients and the TB control effort with higher sensitivity than the now widely used harsh decontamination methods and inoculation on egg media. These controversies aside, many countries with high TB prevalence have not yet developed capacity for accurate and reliable culture for DRS and diagnosis of MDR-TB. The scarcity of data on drug resistance in most of the high-prevalence countries demonstrates that countries have not sufficiently addressed the priorities of surveillance and diagnosing drug resistance, and so are unable to even consider using limited culture services for routine diagnosis of TB.22 NTPs must first adopt and enforce policies for appropriate use of limited culture capacity so that priority requests are met and TB laboratory services are extended throughout the country, as opposed to in selected urban areas.23 In the past it has proven extremely difficult and time-consuming to introduce efficient culture in laboratories at the national level and the challenges go much farther than scarcity of equipment and adequate budgets for supplies. Infrastructure and staffing constitute enormous barriers, as do problems with continuity and other factors that have become common among poor and sometimes politically unstable countries, making a quick transfer of technology impossible. Resources also remain extremely scarce to provide technical assistance internationally. Only within the past few years has a handful of experts been employed full-time by the major TB organizations, leaving much work to be done by the remaining number of volunteer temporary consultants. One large body of work is a huge backlog of policy documents to be developed, such as guidelines, standard operating procedures, equipment specifications and training modules. The update of guidelines and procedures started very recently, and has so far only been completed for part of the microscopy-related materials. It is alarming that, although laboratory services have been identified as the main stumbling block for major areas of the expanded directly observed treatment, short-course (DOTS) strategy, adequate funding for guidance at the international level is still not available.
NUCLEIC ACID AMPLIFICATION TESTS (NAATs) Using NAATs for drug resistance holds immediate promise for scaling up laboratory capabilities. The use of direct specimen NAAT testing for rifampin resistance provides a rapid diagnosis of TB that needs to be treated with second-line drugs, and avoids the difficulty of accomplishing rapid and accurate DST with culture methods. Testing services can also be centralized with direct specimen testing with NAATs without the transportation cold chain systems required for culture.24 Although NAAT testing has inspired great interest and promise for detecting drug resistance and cost and determining which high-risk patients will benefit most from early detection, there are still issues, especially in areas of low MDR-TB prevalence.25 Quality issues must be addressed for any laboratory test, and false-positive cultures as well as NAATs are well documented in the literature.26–28 There should be additional support, in terms of training, EQA programmes, and guidelines for standard practices to ensure accurate results that will encourage programmes to allocate resources to expand services for DST and NAATs.
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PROGRAMME STRATEGIES AND REQUIREMENTS BACKGROUND In low-income countries, emphasis is appropriately put on smearpositive patients to prevent and control TB transmission.29 This emphasis, however, often leads to excessively repressive attitudes regarding diagnosis of other forms of the disease. Since their initial development by Dr Karel Styblo, modern TB programmes have aimed to control the disease by means of detection and cure in microscopy-positive cases, without creating drug resistance.30 It has taken many years to expand the DOTS strategy to most countries and to increase the number of TB patients cured. Making the use of microscopy and identification of smear-positive cases a priority has its roots also in the limited funding and high drug prices of recent times, and in the difficult conditions in the sub-Saharan African countries from where most of the early programmes derived.31 For these reasons more demanding bacteriological tests, such as culture, were slow to be adopted. Moreover, drug resistance was not initially tested during individual patient management for several reasons:
The successively employed standard regimens for new and retreatment cases would cure all patients except those with MDR-TB (TB bacilli resistant to isoniazid and rifampicin). Using thioacetazone, and later ethambutol, rather than rifampicin as a companion drug to isoniazid in the continuation phase of the standard regimen for new cases made it possible to avoid creating new resistance to the main drugs to a very large extent. Steering therapy based on drug resistance test results was tried initially, but proved to be unrealistic and subsequently unnecessary because the outcome of individualized treatment was not improved and effective treatment of MDR-TB was considered impossible.32
Emphasizing prevention, but not diagnosis or treatment of serious drug resistance, proved correct as shown by continuously low or decreasing MDR-TB levels in programmes following this strategy.33 If not for the HIV epidemic, control of transmission would have perhaps succeeded. However, in most countries this strategy also led to neglect of laboratory services and non-support of microscopy network activities, such as training and supervision. Many factors have changed since the initial development of TB control strategies and these changes exacerbated the acute inadequacy in laboratory services. Fortuitously, TB has since been declared a global emergency, which led to an exponential increase in funding. This funding was used to scale up activities and led clinicians to focus on target populations for case detection but not exclusively detection of smear-positive cases. In addition, the HIV epidemic has dramatically increased the demand for laboratory services, particularly in Africa. The relatively frequent paucibacillary disease found in HIV-infected persons has generated a need for highly sensitive microscopy and culture. From a treatment perspective, establishing parity in drug pricing and promising quick results has led to an almost complete replacement of other drugs by rifampicin-throughout regimens that have a higher risk for acquired drug resistance.34,35 Frighteningly high levels of MDR-TB exist in several hot spots.22 A fast rise to at least moderately high prevalence is expected soon in many other areas
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where MDR-TB’s effective treatment is even more difficult.36,37 With the advent of the fluoroquinolones, effective MDR-TB treatment has indeed become possible, but it is accompanied by the danger of misuse of second-line drugs. Recent reports on extensive drug resistance demonstrate the impact of misusing second-line drugs (i.e. XDR-TB, MDR-TB also resistant to the injectable anti-TB drugs and fluoroquinolones).38
NEW STRATEGIES Tuberculosis control programmes in poor countries continue to emphasize bacteriological detection and diagnosis, at least for pulmonary TB. Algorithms generally prescribe a series of three sputum specimens for microscopy, which can still allow rapid diagnosis for the majority of spontaneously presenting cases in populations with little or no HIV coinfection. However, the expanded DOTS strategy foresees rapid expansion of culture services, particularly for improved diagnosis of TB in countries with a high prevalence of HIV, TB in children and extrapulmonary TB.23,39 Feasibility and effectiveness of this expanded strategy still need to be shown.21 Another controversial point is the collection strategy. The yield of the third sputum is too low to justify this strategy wherever it has been examined,40 and reliance on highquality morning sputa, as opposed to spot sputa, might be more rewarding than modifications of technique to increase sensitivity of microscopy and culture (e.g. in the HIV/TB coinfected patient). New World Health Organization (WHO) recommendations for the use of two sputum specimens, when quality measures are in place and there is a high laboratory workload, allow programmes the flexibility to address country and regional needs.41 In industrialized countries, DST is often performed on all isolates from TB patients for epidemiological monitoring, individual case management and legal back-up. This approach is neither feasible nor affordable elsewhere. Also, because of the scarcity of rapid and accurate DST, this approach might not be useful or desirable for individual patients, except in a few countries with a serious MDR-TB problem. Although there is a call for expansion of DST to all cases, in the average TB control programme DST is still exclusively used for epidemiological investigation and increasingly also for MDR-TB diagnosis. Diagnosis for MDR-TB involves screening of high-risk groups such as treatment failures, relapses while on the retreatment regimen and cases of known MDRTB.42 Systematic screening of other groups, such as first-line treatment failures and relapses, should be decided upon in the local context and will depend mainly on the prevalence of MDR-TB within these groups. MDR-TB patients are rare, particularly in the poorest countries, where testing is most difficult to perform correctly and with good coverage. Such difficulties lead unavoidably to poor predictive values of resistant results in the absence of accurate patient selection. The same is true for second-line drugs in countries where these drugs have hardly been misused. Resistance is then very rare, and thus testing for individual patient management may be unrewarding. In fact, until methods and performance become more accurate, it might even be undesirable because of the unavoidably low predictive value of a resistant result.43 Deciding not to test for individual patient management could be a considerable operational advantage, provided that standardized second-line treatment regimens for MDR-TB are identified. Unfortunately, research in this field has been badly neglected for far too long, possibly because of unrealistically high expectations on further development of laboratory services.
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Although recommended since the early days of TB testing and treatment programmes, systematic follow-up of drug resistance among failure and relapse cases has rarely been implemented. This approach could nevertheless be the most efficient strategy for early detection and monitoring of MDR-TB and tracking the TB control programme’s impact on drug resistance trends.44 Instead, more difficult random surveys among new cases have been emphasized by the Global Project for Drug-Resistance Surveillance.45 As a result, available epidemiological data mainly concern point prevalence among new cases, and reliable data on trends from lowincome countries hardly exist. Although such information certainly has value in estimating the extent of the drug resistance problem, it responds insufficiently to current priorities (i.e. avoidance of drug resistance under programme conditions and MDR-TB treatment). The choice of drugs tested should also be considered. Typically, isoniazid, rifampicin, ethambutol and streptomycin are all tested, but with a 6-month rifampicin primary treatment regimen, virtually only resistance to this drug is decisive for treatment outcome. Besides monitoring of rifampicin resistance, the expansion of MDR-TB treatment calls for the testing of its key drugs, fluoroquinolones and injectables as well.
QUALITY MANAGEMENT SYSTEM AND NETWORK REQUIREMENTS HUMAN RESOURCES Highly skilled laboratory scientists are needed to manage microscopy networks and referral laboratories for culture and DST. However, there is a paucity of them and those who are skilled are often employed by private organizations and research institutions which tend to pay far better than publicly funded positions. This is true particularly in African countries where the human resources crisis has been fuelled by the HIV epidemic and the more highly skilled laboratory staff are in search of greater opportunities to relocate to more industrialized countries. At the same time that there is competition for skilled laboratory scientists, governments and worker unions are increasingly restricting laboratory work to certified technicians, which only makes the shortage worse. Moreover, in many cultures there is still serious fear and stigma associated with contracting TB, and working with sputum is almost universally disliked. This is also a service that, unlike many others, has remained free of charge to the patient so revenues to support staff are low. Recruitment of fully qualified TB laboratory workers is, thus, a challenge. If culture and DST for TB are further expanded, it seems likely that little technician time will be devoted to AFB microscopy. At the peripheral level, the shortage of trained laboratory technicians has already led countries to train and employ a new cadre of individuals who have little formal laboratory education. After brief on-the-job training, these people can perform on the level of formally trained laboratory technicians when administering simple, but vitally important tests such as AFB microscopy and HIV rapid tests, provided these individuals work under proper supervision and are supported by training programmes and routine EQA.46,47 Such cadres could be ideal for easy-to-learn but challenging tasks, such as AFB microscopy; however, the highly educated persons might be more attracted to tasks they consider closer to their intellectual level. Lack of human resources is a serious problem that often also exists at an intermediate level (i.e. regional or provincial laboratories).
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This is the essential level for implementing labour-intensive parts of laboratory network management, such as training, EQA and supervision. However, most often such tasks are usually left to often overburdened technicians of the regional hospital laboratory. Experience from laboratories in many countries trying to accomplish the difficult job of rechecking smears, without appointing the additional staff needed, has shown that it cannot work without some form of compensation (e.g. pay, reduction of routine work by introduction of fluorescence microscopy, a vehicle for supervision). Since allowances for supervision are often the only incentive available, sometimes the time spent on supervision exceeds the time spent doing the routine important testing tasks. Training good laboratory supervisors, who not only know the guidelines verbatim but are capable of providing supportive supervision, problem identification and problem solving, is badly needed even for simple tests like AFB microscopy. To achieve better integration and motivation of laboratory staff who often work in isolation and under very difficult conditions, managers of TB control programmes should make an effort to educate their general supervisors on the basics of AFB microscopy. They should also have them include a visit to the clinic microscopy laboratory as a standard element of their supervision. Training and education of laboratory technicians (or technologists) varies by country, with some programmes offering a 2- to 3-year diploma, as opposed to a formal undergraduate degree. Scaling up culture and DST will require that new competencies and policies be added to the curriculum of laboratory technology to ensure that graduates have the skills to do increasingly specialized work. One of the greatest gaps that occurs in both high- and low-resource countries, but is more pronounced in low-resource countries, is the lack of training and education programmes for laboratory managers and leaders. Whereas in many high-resource countries doctorate degrees are required to direct a laboratory, in many African countries it is rare to find TB laboratory staff at the national level with graduate degrees. Doctorate degrees granted within the country are usually focused on research (e.g. PhD, EdD), with little or no training in laboratory management and no orientation on career opportunities in diagnostic laboratory services. This is in contrast to medical degrees that provide training and curriculum designed entirely around patient care and healthcare delivery. Laboratory management and network management are just beginning to be addressed through new mentoring and training programmes to provide the leaders who will be responsible for scaling up new technologies and programmes.
LABORATORY NETWORK Healthcare systems in many countries are either evolving or are under pressure to evolve to include private providers, integrated services and new organizational models. Expanding and strengthening TB laboratory networks will require taking into account the evolution of health systems and the reluctance to invest in new systems that do not represent integrated service delivery. Most high-resource countries have a large private healthcare system, including laboratories that provide high-quality care and services. Many issues concerning quality of care can be attributed to laboratory quality standards and regulations, mandatory reporting of TB and other infectious diseases, and private/public initiatives, in addition to the availability of resources.48,49 In contrast, many countries with high TB prevalence still struggle to monitor quality in government-provided healthcare and the expanding availability of private laboratories. If funding is available, testing the poor in the
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private sector becomes possible, although often at greater expense. However, supporting and maintaining AFB microscopy is even less popular with private providers. So unless the programme is successful at truly changing the habits of private physicians, access to private sector testing will remain temporary. Tuberculosis cultures, and particularly rapid automated culture systems, are developed in the private sector more often than in the public sector. Provided long-term prospects make the investment worthwhile, the NTPs and national reference laboratories (NRLs) must develop strategies to enrol private laboratories in EQA programmes and require reporting and referral of TB cases. The NTPs and NRLs are unlikely to establish and sustain programmes that only monitor TB testing in private laboratories. The NTPs will probably have to work in partnership with other disease control and health programmes to lobby for national laboratory standards and organizational resources to implement regulations. Interest is growing in defining and striving for the optimum alignment of laboratories to effectively provide service. This requires examining the organization of TB laboratory services in relation to the NTPs and the general health services. Some countries may have the NRLs report directly to the NTPs, even though the NRLs could be located at a separate hospital or facility. In the past, the NRLs have typically reported directly to the NTPs to ensure that laboratory activities and services were focused on the needs of the programme. One of the disadvantages of having TB NRLs structurally and organizationally separate from other laboratories is that frequently the NRLs are relatively small in terms of staff and service support. Locating the TB NRLs in a larger integrated NRL facility or organization provides the advantages of shared support services such as staff, equipment, supplies and larger facilities. This arrangement also provides more interaction between laboratory peers who share various ranges of technical expertise. Integrated NRLs can also benefit from sharing quality assurance, information technology and specimen transportation functions. For many countries the intermediate-level laboratories must be integrated because there is insufficient staff and infrastructure to justify separately managed and supported facilities for different testing services. Many countries cannot accumulate the human and other resources required for quality assurance and other tasks at this level when focusing on a single programme. The major drawback of locating a TB section in an integrated NRL is ensuring that laboratory activities are focused on supporting NTP needs and goals. In some situations, the laboratory requirements for NTPs could greatly exceed those of the general services or other programmes. This need leads to difficulties in integrating services and meeting programme needs. All sectors of the healthcare system should be involved in a process to decide on the best structure for expanding and improving laboratory services.50 To be efficient, a microscopy network must be sufficiently decentralized to be readily accessible, but not so much that it becomes uncontrollable (e.g. for supplies and quality assurance). The rule of thumb is a population of 50,000–150,000 per microscopy laboratory, but this must be seen as highly flexible. A far larger population can be adequately and efficiently served by one large-volume laboratory in a densely populated urban area, particularly when using fluorescence microscopy, whereas only a few thousand people may need a laboratory in forest or semi-desert areas. Poor quality or broken microscopes are a frequent problem of microscopy networks, together with bad-quality immersion oil, which leads to microscope damage.51 Even if periodic rechecking is not possible, surveying all AFB-smear laboratories with
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panels, during a visit or sent by postal mail, followed by correction of microscope problems, will go a long way to improving quality. Low-income countries have minimal experience with culture networks because culture has almost exclusively been used to obtain an isolate for DST in the context of drug resistance surveys. However, reports from middle-income countries, such as Peru and Cuba, with fairly advanced-to-extensive culture networks, show that these cultures contribute only between 5% and 10% to case detection. In large part, this must be because the requirements for high yield of culture were not being fulfilled (i.e. exclusive use of solid media of unknown quality, harsh decontamination methods necessary because of delayed processing, lack of internal quality control). Although this does not affect the yield of microscopy, a major limiting factor for culture is transport delay of specimens, which is an additional factor to be considered when deciding on the density of a culture network. The expanded Stop TB Plan calls for one culture facility per 5 million people by 2015. In most high-prevalence countries only urban populations would be effectively covered geographically. However, considering the high demands of culture facilities on infrastructure, utilities and skilled staff, this would already be a remarkable achievement, serving a priority population in terms of TB and HIV prevalence, intensity of transmission and drug resistance. In high-prevalence areas, DST can remain more limited, with increased diagnosis of MDR-TB and better surveillance. This does not require a dense network of DST laboratories. Even very large countries can be served by a few very large facilities. Considering the difficulty of continuously providing high-quality DST results, centralized, well-equipped, -staffed and -controlled DST services are, in fact, preferred. For surveillance, it is always possible to isolate strains in the periphery, for instance on acidified media, and to forward these strains for DST.52 There are high hopes that rapid testing for MDR-TB will prove to be best using transport-insensitive NAATs at an advanced facility in the capital, and even abroad.53
LABORATORY SAFETY Safety regulations are very strict in TB laboratories in industrialized countries, requiring a biosafety level 3 (BSL3) designated facility for work with strains. This is consequently a growing concern for laboratory staff in high-prevalence countries where such facilities are rarely affordable. Those who work with culture and DST, and increasingly those only involved with AFB microscopy, request safety measures that are difficult and costly to provide. The NRLs and NTPs are responsible for addressing safety concerns through a combination of training and education to help promote risk assessment and safe practices. Experience has shown that laboratory staff often lack basic knowledge of transmission routes and a differentiation of practices taking into account assessment of risk levels. Reasonable and rational safety improvements in equipment, supplies and facilities should be supported, but there are still serious questions and concerns in this area. Microscopy carries a negligible risk if direct smears are prepared with careful technique in wellventilated areas.54,55 Rather than purchase biological safety cabinets (BSCs) that are very difficult to maintain, microscopy centres may want to purchase simple air extraction cabinets or fan boxes. These are relatively inexpensive and efficiently exhaust air without filters, provided they have sufficient extraction power.56 When properly installed, these devices provide a level of protection that also reassures technical staff. In fact, there is no reason why they could not
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be used also for simple culture. Aerosol creation is minimal, except in the case of accidents with grown cultures. This type of cabinet, equipped with a backflow stop mechanism and exhausted above the upper floor, gives more guarantee of negative pressure and complete expulsion of infectious particles than the sophisticated class II BSCs. As with class I cabinets, the challenge is to conduct proper and regular maintenance to ensure perfect functionality of filters that are replaced before they get completely clogged; thus, these machines become hazards rather than sources of protection. As countries expand culture capacity, there will be a need for guidance and policy decisions on minimum safety standards that are affordable and sustainable. Sophisticated class II BSCs, which protect decontaminated products, are needed for laboratories performing identification and DST. They are also considered to be one of several prerequisites for successful introduction of liquid cultures. However, a liquid DST system has been used successfully for rapid diagnosis of MDR-TB from fresh smear-positive sputa, containing contamination by use of antibiotic cocktails, as recommended by Mitchison et al.,57 despite manipulations in a class I type cabinet.58 Moreover, this system used virtually unbreakable universal containers, which were heated before opening, thus reducing the risk for technicians to a very low level. These factors should also be considered for determining the chosen method among the multitude of rapid, liquid media-based DST methods described.59,60
QUALITY ASSURANCE, QUALITY CONTROL AND EXTERNAL QUALITY ASSESSMENT Poor quality assurance of testing services remains a major problem, not only for culture, DST and NAAT methods, but first and foremost for microscopy. In addition to good internal controls, effective EQA is necessary to ensure accurate testing and particularly to improve test sensitivity. Until further evidence is obtained on the appropriateness of more complicated methods such as fluorescence microscopy and concentration techniques and until new diagnostics are tested, this will be the only way to enhance case detection by microscopy for years to come.61 Internally, quality assurance must first of all be set up for ZN or fluorescence microscopy staining solutions which are increasingly identified as major sources of error. The issue is further compounded by older WHO and International Union against Tuberculosis and Lung Disease (IUATLD) technical guidelines, which require practical improvements and currently leave no margin for error.62–64 Additionally, there is an increasing reliance on locally manufactured, ready-made staining solutions of unknown quality. The international guidelines for effective EQA programmes were issued only a few years ago,65 and their implementation has been slow in most countries. The major obstacle is lack of staff; EQA requires dedicated staff for onsite supervisory visits in addition to rechecking a relatively large workload of smears at higher levels.28,66 Progress is also hampered by poor understanding and comprehension of the guidelines, even among laboratory consultants. Many countries have not fully or correctly implemented rechecking: and some regions continue to use older methods of unblinded rechecking that have been demonstrated to be ineffective and misleading.67,68 Panel tests (sending out smears with known results prepared by a central laboratory) are considered less efficient because they correlate well with capacity, but not always with routine performance, and are less reliable. However, they will still be more rewarding than rechecking in countries not able
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or willing to invest what is needed for the latter (i.e. sufficient manpower and meticulous execution). Proven programmes that measure performance of microscopy and DST do exist.69 Culture performance is often more difficult to measure. Existing EQA programmes do not necessarily measure the sensitivity of performance. Universal guidelines for quality assurance of culture are still under development. Mainly, internal controls (i.e. of medium sterility and growth-supporting quality) and monitoring (i.e. contamination and false-negative rates) must be used. EQA of decontamination and culture itself might not be feasible because of extreme lability of samples during transport. The low yield of culture in some settings is clearly shown by surveillance for drug resistance where laboratories might have difficulties isolating M. tuberculosis from smear-positive specimens. It is only possible to guess at the quality of DST without EQA, but so far few DST laboratories or even NRL in high-prevalence countries participate in panel testing, originating from the Center for Disease Control and Prevention in Atlanta or the (WHO/ IUATLD) Global Project for TB Drug Resistance Surveillance. This activity and linking national TB reference laboratories to a Supra-National TB Reference Laboratory (SRL) for technical assistance and rechecking of routine DST is hampered by lack of funding for the SRL. So far, rechecking DST has almost exclusively been done in the context of surveys, and it is not always clear how the results have been used.70 A minimal requirement would be rechecking all resistant strains (at least those resistant to rifampicin or isoniazid), plus at least about 100 susceptible strains.45 Quality problems cannot be solved by EQA alone and one must consider the total quality management systems that include all the components of documents, records, personnel, standards, facilities and quality control. One critical difference in many industrialized countries is the presence of laboratory regulations or accreditation programmes.71,72 Until such time that countries regulate performance against national laboratory standards there should be consideration in the TB community to develop an accreditation process for NRLs.
RESEARCH Tuberculosis laboratories play a key role in research, especially operational research, supporting evidence-based decisions to guide not only laboratory practice but also areas of fundamental importance to TB programmes, such as the efficacy of standard treatment regimens. To be meaningful for programme applications, research should be performed in the field in low-resource settings so there are conditions of utilities, equipment, supplies and staffing replicating the situation in most high-burden countries. Research performed in academic research centres with human and material resources that differ from public sector services in low-resource countries are useful initially for providing proof of principle, but results might not always be reproducible under programme conditions. Operational research is still needed to improve diagnostic methods and techniques, even the most basic ones such as smear microscopy. Because of the potentially huge impact, research might be needed even more urgently to test the appropriateness of existing programme guidelines, or to simplify procedures after uprooting longstanding dogma. Many NRLs are interested in research although few also have the capacity to carry out the more demanding research of large international projects without compromising their daily routine activities of NTP service delivery
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and network guidance. A downside to taking on research is that the research agenda often takes precedence over routine tasks because of prestige and financial incentives. Hence, a major concern is to ensure that the NRL and other institutions balance research activities with NTP priority initiatives to monitor and support the laboratory network.
CONCLUSION In most resource-poor countries, expanding and strengthening laboratory systems for quality-assured microscopy, culture and DST services must and can be done – but not overnight, and probably not all at the same time. Great care should thus be taken not to overstretch the scarcest resources (i.e. the staff responsible for implementation of these changes). Priorities must be set, and, although introduction of diagnostic culture and detection of MDR-TB cannot wait until microscopy reaches perfection, their expansion should be gradual and not at the cost of deterioration of important processes such as microscopy EQA. Gradual expansion logically means that first the NRL should be proficient in basic techniques, before starting to train and supervise others. To avoid wasting donor money and limited country resources there should be guidance in purchasing suitable laboratory equipment. Whatever the targets set, the process is going to be lengthy. It would be better to be done slowly, but correctly, now that global funds and other resources are finally available at the country level. A fast gain, however, may be possible, introducing improved microscopy techniques (i.e. appropriate, user-friendly and robust fluorescence microscopy systems). The Global Plan to Stop TB calls for 800 new culture and DST facilities at an estimated cost of $700 million to reach the year 2015 goals and the Global Fund for TB, HIV, and Malaria can help with these costs.7 For phasing in culture and drug resistance testing, techniques and patients will have to be carefully selected for individual diagnosis; use for epidemiological monitoring must be optimized starting with the international guidelines for drug resistance surveillance. Liquid cultures are highly desirable but remain controversial if they are performed using automated machines rather than manually. They also carry very high infrastructure and system requirements, including safety. For these
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pulmonary tuberculosis patients in Rwanda. Int J Tuberc Lung Dis 2007;11:189–194. Sanders M, Van Deun A, Ntakirutimana D, et al. Rifampicin mono-resistant Mycobacterium tuberculosis in Bujumbura, Burundi: results of a drug resistance survey. Int J Tuberc Lung Dis 2006;10:178–183. Shah NS, Wright A, Bai GH, et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007;13:380–387. Stop TB Partnership. The Global Plan to Stop TB 2006–2015. Geneva: World Health Organization, 2006. Mase SR, Ramsay A, Ng V, et al. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis 2007;11:485–495. Strategic and Technical Advisory Group for Tuberculosis (STAG-TB). Seventh meeting, 11–13 June 2007. Report on session 10 c/d. Available at URL: http://www.who.int/tb/events/stag_report_2007.pdf. World Health Organization. Guidelines of the Programmatic Management of Drug-Resistant Tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization, 2006. Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies. Int J Tuberc Lung Dis 2006;10:829–837. Van Deun A, Hamid Salim A, Rigouts L, et al. Evaluation of tuberculosis control by periodic or routine susceptibility testing in previously treated cases. Int J Tuberc Lung Dis 2001;5: 329–338. World Health Organization. Guidelines for the Surveillance of Drug Resistance in Tuberculosis. WHO/TB/2003.320. Geneva: World Health Organization, 2003. Van Deun A, Portaels F. Limitations and requirements for quality control of sputum smear microscopy for acid-fast bacilli. Int J Tuberc Lung Dis 1998;2(9):756–765. San Antonio-Gaddy M, Richardson-Moore A, Burstein GR, et al. Rapid HIV antibody testing in the New York State Anonymous HIV Counseling and Testing Program: experience from the field. J Acquir Immune Defic Syndr 2006;43(4):446–450. Shinnick TM, Lademarco M, Ridderhof JC. National plan for reliable tuberculosis laboratory services using a systems approach: recommendations from CDC and the Association of Public Health Laboratories Task Force on tuberculosis laboratory services. MMWR Morb Mortal Wkly Rep 2005;54 (RR6):1–15. Kusznierz GF, Latini OA, Sequeira MD. Quality assessment of smear microscopy for acid- fast bacilli in the Argentine tuberculosis laboratory network, 1983–2001. Int J Tuberc Lung Dis 2004; 8(10): 1234–141. Garrett, L. The challenge of global health. Foreign Affairs 2007;Jan/Feb. Lumb R, Van Deun A, Kelly P, et al. Not all microscopes are equal. Int J Tuberc Lung Dis 2006;10:227–229. Rieder HL, Van Deun A, Kam KM, et al. Priorities for Tuberculosis Bacteriology Services in Low-Income Countries, 2nd edn. Paris: International Union against Tuberculosis and Lung Disease, 2007: 1–120. Drobniewski FA, Watterson SA, Wilson SM, et al. A clinical, microbiological and economic analysis of a national service for the rapid molecular diagnosis of tuberculosis and rifampicin resistance in Mycobacterium tuberculosis. J Med Microbiol 2000; 49:271–278. Working Group on Sputum Smear Microscopy, IUATLD. The laboratory diagnosis of tuberculosis by sputum microscopy: a review of current practice. Unpublished. Kim SJ, Lee SH, Kim IS, et al. Risk of occupational tuberculosis in National Tuberculosis Programme laboratories in Korea. Int J Tuberc Lung Dis 2007;11:138–142.
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56. Smithwick R. Laboratory Manual for Acid-Fast Microscopy, 2nd edn. Atlanta: Department of Health, Education, and Welfare; Center for Disease Control, 1976. 57. Mitchison DA, Allen BW, Carrol L, et al. A selective oleic acid albumin agar medium for tubercle bacilli. J Med Microbiol 1972;5:165–175. 58. Hamid Salim A, Aung KJM, Hossain MA, et al. Early and rapid microscopy-based diagnosis of true treatment failure and MDR-TB. Int J Tuberc Lung Dis 2006;10:1248–1254. 59. Moore DAJ, Evans CAW, Gilman RH, et al. Microscopic-observation drug-susceptibility assay for the diagnosis of TB. N Engl J Med 2006;355: 1539–1550. 60. Palomino JC, Martin A, Camacho M, et al. Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2002;46: 2720–2722. 61. Addo KK, Dan-Dzide M, Yeboah-Manu D, et al. Improving the laboratory diagnosis of TB in Ghana: the impact of a quality assurance system. Int J Tuberc Lung Dis 2006:10(7):812–817. 62. World Health Organization. Laboratory Services in Tuberculosis Control. Part II: Microscopy. WHO/ TB/98.258. Geneva: World Health Organization, 1998. 63. International Union Against Tuberculosis and Lung Disease. Technical guide. Sputum examination for tuberculosis by direct microscopy in low income countries. Paris: International Union Against Tuberculosis and Lung Disease, 2000. 64. Van Deun A, Hamid Salim A, Aung KJM, et al. Performance of variations of carbolfuchsin staining of sputum smears for AFB under field conditions. Int J Tuberc Lung Dis 2005;9:1127–1133. 65. Aziz M, et al. External Quality Assessment for AFB Smear Microscopy. World Health Organization, Centers for Disease Control and Prevention, APHL, KNCV and IUATLD. Washington, DC: APHL, 2002. 66. Aziz M, Bretzel G. Use of a standardized checklist to assess peripheral sputum smear microscopy laboratories for tuberculosis diagnosis in Uganda. Int J Tuberc Lung Dis 2002;6(4):340–349. 67. Nguyen Thi Ngoc Lan, Wells CD, Binkin NJ, et al. Quality control of smear microscopy for acid-fast bacilli: the case for blinded re-reading. Int J Tuberc Lung Dis 1999;3:55–61. 68. Martinez A, Balandrano S, Parissi A, et al. Evaluation of new external quality assessment guidelines involving random blinded rechecking of acid-fast bacilli smears in a pilot project setting in Mexico. Int J Tuberc Lung Dis 2005;9:301–305. 69. Laszlo A, Rahman M, Espinal M, et al. Quality assurance program for drug susceptibility testing of Mycobacterium tuberculosis in the WHO/IUATLD Supranational Reference Laboratory Network: five rounds of proficiency testing, 1994–1998. Int J Tuberc Lung Dis 2002;6:748–756. 70. MacArthur A Jr, Gloyd S, Perdiga˜o P, et al. Characteristics of drug resistance and HIV among tuberculosis patients in Mozambique. Int J Tuberc Lung Dis 2001;5:894–902. 71. Martin R, Hearn TL, Ridderhof JC, et al. Implementation of a quality laboratory system approach for laboratory practice in resourceconstrained countries. AIDS 2005;19(suppl 2): S59–S65. 72. Ridderhof JC, Van Deun A, Kam KM, et al. The role of laboratories and laboratory systems in effective TB control. Bull World Health Organ 2007;85(5):354–35.
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Priorities in tuberculosis research Keertan Dheda, Philip C Onyebujoh, Mahnaz Vahedi, and Alimuddin I Zumla
INTRODUCTION Although most TB cases can be cured with 6 months of appropriate multidrug treatment, TB kills about 1.8 million people each year. This failure is due to several reasons: control efforts have been hampered by suboptimal case finding and diagnosis (Fig. 73.1), a treatment regimen that is lengthy and has several drugs, poor adherence to treatment, development of drug resistance and coinfection with human immunodeficiency virus (HIV). The only available TB vaccine is ineffective in most countries. The main diagnostic method is sputum smear microscopy and has in practice a 50% yield. No new classes of anti-TB drugs have been researched for more than 40 years. It is obvious that new tools are required to control TB, and research into new drugs, diagnostics and vaccines has taken off in a big way during the past decade, and continues to build momentum. Working groups on new diagnostics, drugs, immunomodulators and vaccines convened by the STOP TB Partnership have set out to develop new improved tools for the detection, treatment and prevention of TB disease, drug resistance and latent infection. Research led by a number of international organizations and academic institutions is now pointing toward the discovery of new drug compounds, immunotherapeutics, immune markers of disease, diagnostics and vaccines. The revised Global TB Control Plan, of the World Health Organization (WHO) Stop TB Partnership announced in March 2006, has six elements, the sixth of which is enabling and promoting research for new tools and programme performance.1 Current UNDP/UNICEF/World Bank/WHO Special Programme in Research and Training, Scientific Working Group recommendations for priority research into TB are grouped into several areas (Table 73.1):2,3 1. improved diagnostics for TB, multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB; 2. improved clinical management of TB, MDR- and XDR-TB in HIV-infected and -uninfected individuals; 3. social, economic and behavioural research and the Global TB Agenda; 4. immunopathogenesis and vaccine studies; 5. operational and implementation research; 6. improved programme performance and capacity building; 7. epidemiological research in national TB programmes; and 8. cross-cutting issues. The main emphasis is currently on development of newer drugs, immunotherapeutics, diagnostics and vaccines for improved outcomes
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in the clinical management of TB in HIV-infected and uninfected individuals. There are several other areas in which further research is required, and these are discussed later in this chapter.
IMPROVED DIAGNOSTICS FOR TUBERCULOSIS One of the most frustrating challenges in TB management has been the lack of a specific, sensitive, inexpensive and rapid point of care test for the diagnosis of TB.4,5 For individual patients, the cost, complexity and potential toxicity of 6 months of standard TB treatment demands certainty in diagnosis. For communities, the risk of transmission from undetected cases requires widespread access to diagnostic services and early detection. Unfortunately, current diagnostic services in most TB-endemic settings fail both the individual and the community. Patients are commonly diagnosed after weeks to months of waiting, at substantial cost to themselves, and at huge cost to society as TB goes unchecked. Many patients are missed altogether, and contribute to the astonishing number of annual deaths from TB world-wide. Some of this failure could be corrected by better implementation of existing standards of clinical and laboratory practice. The WHO and its member states have made great gains in the expansion of the directly observed treatment, short-course (DOTS) strategy to control TB, with an important rise in rates of cure.6–8 Improving case detection rates has proven more difficult, largely because of limitations of existing diagnostic technologies. As many as 3 million cases of TB each year present as sputum smear-negative pulmonary disease and extrapulmonary disease, for which sputum smear microscopy is inadequate. As an indicator of the difficulty of implementing quality microscopy services, fewer than 45% of predicted incident smear-positive cases of TB are currently detected and notified (Fig. 73.1B). Paediatric TB and MDR- and XDR-TB pose additional diagnostic challenges not addressed by sputum-smear microscopy. Diagnostics need to be driven by the reality of health systems infrastructure (Fig. 73.2); well-engineered, simplified tests are needed at the point of care, at district hospital laboratories and at central laboratories (Fig. 73.3).4,5 Different diagnostic strategies – including sputum concentration methods, fluorescence microscopy, improved mycobacterial culture system – also need to be evaluated for their impact on case detection. Diagnostic algorithms, including the use of empiric antibiotic trials to exclude TB, need to be carefully reassessed and improved. Implementation research can also assess the potential of integrating health services at district and healthcare
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2002
2001
2000
1999
Year
1989
Rate per 100,000 population
0
1988
0
1987
25
1986
B
50
1985
A
50
1984
2.2 other
75
100
1983
2.7 other
Global case notification rate
150
1982
Not notified 4.7 million
100
Countries
1981
2.0 smear positives
Notified to public health authorities: 4.1 million
1.9 smear positives
Global case notification rate for smear-positive pulmonary TB is not improved by DOTS expansion alone
1980
Global caseload of new TB cases stratified by smear and notification status
Number of countries implementing DOTS
200
Fig. 73.1 Global case notification rates. (A) Despite geographic extension of the DOTS programme the gap between notified and estimated numbers of TB cases, an astounding 4.4. million cases, has not narrowed significantly over the past several years. (B) Inadequate case detection is a major constraint on TB control. Table 73.1 Tuberculosis research priorities Research priority area
Specific activities
1. Improved diagnostics for TB
2. Improved clinical management of TB in HIV-infected and -uninfected individuals a. New drug research b. New immunotherapeutics research c. More effective shortened drug treatment regimens d. More effective drug and adjunct therapeutics regimens e. Optimal treatment strategies for MDR- and XDRTB f. Safer and more effective highly active antiretroviral therapy (HAART)/anti-TB treatments g. Validated markers of TB disease activity
3. Immunopathogenesis, and vaccine studies
4. Improved programme performance and capacity building
Improving and evaluating existing diagnostic tools Developing and evaluating new diagnostic tools (e.g. an inexpensive, rapid, simple, accurate, practical point-of-care test useful in HIV-associated and drug-resistant TB) Developing tools/markers for monitoring disease activity, cure and relapse Developing tools that predict which subjects with latent infection will progress to active disease Strengthening research capacity and operational research Establishing and maintaining research resources for sustained activities in this field Facilitating new TB drug research and development Enhancing clinical trials site capacity for evaluating new drugs, diagnostics and vaccines Building evidence base for country adoption of new, more effective and shortened drug treatment regimens Optimizing existing treatment strategies for different categories of TB (special populations of TB patients: HIV-infected TB, M(X)DR-TB, paediatric, pregnancy) Optimizing timing of HAART therapy relative to anti-TB treatment or developing newer and safer treatment regimens for use with HAART Developing newer adjunct immunotherapies for improved outcomes for treatment failures, MDR-TB and XDR-TB Developing and validating surrogate endpoints and biomarkers to shorten clinical trials Evaluating the potential of simulation mathematical models for efficacy and costs of new interventions to better inform clinical trials of investigational new drugs Identifying immune correlates of protection to facilitate vaccine and immunotherapy studies Investigating and utilizing new information on the immunopathogenesis of Mycobacterium tuberculosis infection (latency, dormancy, reactivation) to inform new interventions for improved TB control Developing approaches to detect and manage immune reconstitution inflammatory syndrome (IRIS) and antiretroviral (ARV)/TB drug interactions Investigating and documenting geographic diversity of pre-existing immune status of the vaccine target population through target-country vaccine preparatory studies Improved delivery of care including DOTS Individual and institutional capacity building in the least developed countries including improving national TB programme (NTP) management Integration of TB and HIV/acquired immunodeficiency virus (AIDS) treatment strategies Linking research with national TB programmes and coordination of TB/HIV research Inclusion of basic social, economic and behavioural research in national programmes Development and evaluation of alternative TB care delivery strategies Improved case finding in vulnerable populations and access to care Focusing on partnership with local, regional and international organizations Identifying determinants and reduction of risk and vulnerability to TB (Continued)
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Table 73.1 Tuberculosis research priorities—(cont’d) Research priority area
Specific activities
5. Social, economic and behavioural research and the Global TB Agenda
Addressing impact of poverty on health-seeking behaviour Determining effects of gender inequality on disease severity and case detection Identifying impact of community factors on health services and DOTS programmes
6. Operational and implementation research
Developing practical solutions to common and critical issues in implementation of TB-related interventions by: Improving organization and management Building a close collaboration between researchers, national TB control and HIV/AIDS programmes, Ministry of Health and others. Engaging all healthcare providers Empowering patients and communities Generating political will and commitment Improving human resources Promoting (demand for) research Evaluating adherence support strategies Defining the macro- and micro-TB epidemiology
7. Epidemiological research in national TB programmes
Lower diagnostic priority
All forms of active TB disease Detection of multidrug-resistant TB Latent infection in high-risk groups Targeted at detecting and treating people with any form of tuberculosis (active or latent), with attention paid to: i) High-prevalence groups : socially marginalized/ people born in high-prevalence countries and ii) High-risk groups : HIV infected/close contacts of an active case/immunocompromised/ children under 5 years
Latent infection in lower risk groups Identification of individuals found to be infected, or likely to be infected, including recent tuberculin skin test converters and individuals with certain medical conditions (diabetes, kidney failure)
Developed country
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Developing country Low income High prevalence Goal: identify and treat cases Pulmonary tuberculosis highly contagious patients Target the reservoir of highly contagious patients to intercept transmission by early diagnosis and treatment
Pulmonary tuberculosis: less contagious patients (pulmonary smear negative) TB in other organs (extrapulmonary TB) Latent infection: surveillance purposes Multidrug-resistant TB: surveillance purposes
Developing country
Higher diagnostic priority
Higher diagnostic priority
Developed country High income Low prevalence Goal: elimination of TB
MDR- and XDR-TB (management and cost-effectiveness) Paediatric TB (new diagnostics, therapeutics and revised diagnostic algorithms) Regulatory issues (product registration) Biological banks (creation and monitoring) Ethics of research in developing countries
Lower diagnostic priority
8. Cross-cutting issues
Impact of early diagnosis on TB transmission Time to occurrence of TB disease after contracting HIV infection Development of systems to disaggregate NTP data for use in studying local and hard to reach populations Development of new diagnostic tools for identifying latent TB infection and conducting TB prevalence surveys Determinants of risk, poverty, gender and community factors
Fig. 73.2 Diagnostic priorities in high- and low-burden countries. Resource limitations in developing countries preclude the use of several diagnostic tests (liquid culture systems, nucleic acid amplification platforms, interferon (IFN)-g release assays, rapid tests for drug resistance, etc.). Here, the sputum smear is the backbone of TB diagnosis; fortunately, this century-old technique detects the most infectious patients, and, hence, those in most need of treatment. By contrast, in developed countries, where the goal is elimination of TB, identification and treatment of latent TB infection has assumed increasing importance.
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Types of testing Surveillance Reference methods Network supervision Resolution testing (current test: culture, drug susceptibility)
Health system levels
Fraction of patients seen at given level 5%
National reference laboratory Referral laboratory
Table 73.2 Priorities for tuberculosis diagnostics tool development Need for diagnostic tool
Type of TB disease to be detected
Case detection
10%
Drug susceptibility testing
Microscopy centre
Screening Primary care (current test: none)
Peripheral health clinic
25%
Latent TB infection
60%
Fig. 73.3 Tuberculosis diagnostic testing at different levels of the health system. In the public sector the laboratory capacity to perform different types of testing can usefully be divided into levels of the healthcare system. At the top of the pyramid is the national reference laboratory (sophisticated and limited in number but the percentage of TB cases diagnosed at this level is small), while the base comprises TB referral laboratories at district or regional level (provides resolution testing for patients not detected by screening methods at more peripheral clinics or laboratories; the latter are largest in number and diagnose the largest burden of disease).
centre levels as a means of overcoming infrastructural and manpower impediments to operating case detection services. Key factors to study include transportation, user fees, hunger, work and gender discrimination, and other barriers to accessing care. Better clinical diagnostic algorithms and case definitions are required for diagnosing TB in HIV-infected individuals and children. Thus, precisely in the areas of the world where TB microscopy has the poorest performance, the need for new early detection tests is the greatest. Current TB diagnostics research priorities include: 1. replacing or improving microscopy with a simpler technology for detecting smear-positive TB; 2. developing a faster alternative to culture for detecting smearnegative TB; 3. developing and evaluating tests for rapid antibiotic susceptibility testing; and 4. developing tests for detecting latent infection at risk for relapse. The priorities for developing more accurate and rapid tests for TB case detection, drug susceptibility testing and detection of latency are listed in the Table 73.2,4 in roughly rank order of importance to global TB control. To facilitate the relevant commercial activity, WHO, and later its Special Programme for Research and Training in Tropical Diseases (WHO-TDR), established an enabling infrastructure for industry that included banks of reference materials, diagnostic trial sites and market research. Subsequently, the Foundation for Innovative New Diagnostics (FIND), an independent non-profit foundation, was established to work in contractual partnership with industry and academic groups, acting as an engine to drive the development of new diagnostic technologies. Launched at the World Health Assembly in 2003 with initial funding from the Bill
and Melinda Gates Foundation, FIND works with WHO-TDR and other public sector agencies to fulfil its mission to accelerate the development, evaluation and appropriate use of high-quality yet affordable diagnostic tools for infectious diseases in developing countries. More detailed information about the emerging technologies is available on the FIND website (http://www.finddiagnostics. org). A major challenge in TB control is the diagnosis and treatment of latent TB infection. Until recently, there were no alternatives to the tuberculin skin test (TST) for diagnosing latent TB. However, an alternative has now emerged in the form of a new in vitro test: the interferon-g (IFN-g) assay.6–8 A systematic review for assessing the performance of IFN-g assays in the immunodiagnosis of TB was performed by Pai et al.8 Current evidence suggests that IFN-g assays based on cocktails of RD1 antigens have the potential to become useful diagnostic tools. Whether this potential can be realized in practice remains to be confirmed in well-designed, long-term studies. IFN-g release assay-specific research priorities,
Serology
Ease of use
Passive case finding (current test: microscopy) Detect and treat
Pulmonary TB with high bacterial load Pulmonary TB with low bacterial load Extrapulmonary and paediatric TB Paediatric TB MDR-TB for treatment MDR-TB for surveillance XDR-TB for treatment XDR-TB for surveillance Latent TB for treatment Latent TB for surveillance
Microscopy
Desired
X-ray Culture
NAAT
Performance 1. Performance is a compilation of sensitivity, specificity and speed. 2. Ease of use is a compilation of safety, number of steps, cost, robustness and training simplicity
Fig. 73.4 There are drawbacks and advantages of each existing diagnostic modality. Unfortunately, however, no test that can meet target specification (a simple easy-to-use test with high-performance outcome) is currently available. Several new tests in development, e.g. urine antigen detection or lateral flow immunoassays, have potential to meet these requirements.
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for improving the utility and interpretation of the assay, are outlined in a document summarizing the views of experts in the field.7 Good performance of diagnostic tests under trial conditions does not always translate into effectiveness after implementation. Demonstration projects are needed to evaluate the feasibility, impact and cost-effectiveness of new diagnostic interventions after scale-up in national control programmes. The outcome of these projects should provide evidence for policy, so that useful technologies can be rapidly adopted, and impractical or ineffective technologies improved or dropped. These tests that would have the greatest impact on TB control, point-of-care tests, are in early development. New diagnostics that increase the sensitivity or simplicity of diagnosing active disease are in later development. There are advantages and limitations of each diagnostic method and no test yet available meets the target specification (Fig. 73.4). Rapid implementation of proven new technologies will also be critical to meet the urgent public health need and TB control targets.
RESEARCH PRIORITIES FOR IMPROVED CLINICAL MANAGEMENT OF TUBERCULOSIS IN HIV-UNINFECTED AND -INFECTED INDIVIDUALS Table 73.3 depicts research topics of importance on improving clinical management of TB that require further study.
OPTIMIZING CURRENT TREATMENT OUTCOMES: IMPROVING CLINICAL MANAGEMENT OF TUBERCULOSIS IN HIV-INFECTED AND -UNINFECTED INDIVIDUALS The increasing numbers of new TB cases each year is attributable largely to HIV infection.9 Currently available short-course chemotherapy still requires 6 months of drug adherence with suboptimal toxicity profiles. Treatment failures do occur in drug-susceptible
Table 73.3 Research topics for improving clinical management of tuberculosis Item
Research topic
Treatment simplification and monitoring: more effective treatment with shorter duration therapy and more effective treatment for MDR/XDR-TB 1 a. Development and evaluation of efficacy of newer drugs for TB treatment b. Evaluation of newer drug regimens for shortening TB treatment from 6 to 4 months c. Evaluation of newer drug regimens for the treatment of MDR- and XDR-TB d. Development and evaluation of immunotherapies as adjunct treatment for MDR- and XDR-TB and TB treatment failures 2 Assessment of the efficacy and safety of fixed-dose versus ‘loose’ anti-TB medications in improving treatment compliance 3 Biomarkers/surrogate markers: a. Identification and evaluation of specific biomarkers and surrogate markers of disease activity in HIV-infected and -uninfected patients with active TB b. Evaluation of markers to monitor disease activity, cure, relapse and latency Treatment of TB/HIV coinfection 4 Evaluation of optimal treatment initiation (timing, dosing, specific drugs) of HAART, in randomized controlled trials, for TB/HIV coinfected patients 5 Evaluation of optimal duration of treatment using existing regimens for pulmonary and extrapulmonary TB in HIV-infected people 6 Pharmacokinetic and pharmacodynamic studies of treatment regimens in TB/HIV coinfected patients 7 Evaluation of optimal protocols for isoniazid preventive treatment, or alternative regimens, in HIV-infected people with latent TB infection 8 Evaluation of optimal protocols for cotrimoxazole treatment in TB/HIV coinfection 9 Development and validation of case definitions for immune reconstitution inflammatory syndrome (IRIS) in TB/HIV coinfected patients under ARV treatment 10 Epidemiological studies of IRIS in TB/HIV coinfected patients under ARV treatment 11 IRIS in TB/HIV coinfected patients under ARV treatment 12 Evaluation of clinical management strategies of IRIS in TB/HIV coinfected patients under ARV treatment Diagnosis of MDR- and XDR-TB 16 What is the optimal diagnostic algorithm for persons with suspected MDR- and XDR-TB? 17 Development and evaluation of rapid tests for drug resistance 18 What is the role of rapid rifampicin resistance tests in the management and control of MDR- and XDR-TB? Treatment of paediatric TB 19 Evaluation of safety and efficacy of current drug formulations in paediatric TB infection What is the optimal diagnostic algorithm for children with suspected TB? Can nucleic acid amplification tests (NAATs), IFN-g and urine DNA tests be utilized together to improve the diagnostic sensitivity for TB in children? All studies mentioned for adults apply to children as well Patient support strategies 20 Assessment of effectiveness of patient ‘treatment literacy’ programmes prior to treatment initiation 21 Evaluation of impact of DOTS and other adherence support strategies (including site-based vs community-based support, frequency and duration of support interventions) on treatment outcomes 22 Evaluation of impact of DOTS and other adherence support strategies on treatment outcomes in TB/HIV coinfection Implementation research: health systems and operations 23 How can the uptake of proven new diagnostic tests be accelerated in both public and private settings? 24 What measures will be helpful in shortening the duration of TB work-up (diagnostic pathway) and the number of consultation visits before a diagnosis is made? 25 How can laboratory workload be reduced, and communication of test results and quality improved in high-burden countries?
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TB due to poor patient compliance, drug availability and side effects among others. The need for shorter courses of anti-TB therapy is obvious. In HIV-infected individuals with active TB, drug interactions between anti-mycobacterial drugs and antiretroviral drugs for HIV treatment represent a major new challenge,10,11 and there is no proven, simple regimen for simultaneous treatment. How can current treatment outcomes be optimized to minimize morbidity and mortality rates from TB? Priorities for research to improve clinical management of TB include: a. new anti-TB drug research; b. new immunotherapeutics research leading to products that can be used as adjuncts to drug therapy; c. more effective shortened drug treatment regimens; d. more effective drugs with adjunct therapeutics regimens; e. optimal strategies for treatment failures and MDR- and XDR-TB with newer drug combinations or with drugs and adjunct immunotherapy; f. safer and more effective highly active antiretroviral therapy (HAART)/anti-TB treatments; and g. monitoring disease and relapse by developing accurate markers of TB disease activity.
RESEARCH AND DEVELOPMENT OF NEWER ANTITUBERCULOSIS DRUGS The current efforts at developing and evaluating new anti-TB drugs are discussed in Chapter 59. Waksman’s discovery of streptomycin in 1940 was the beginning of the modern era of anti-TB treatment. Following the successful application of multidrug therapy, the death rate from TB dropped rapidly in settings where diagnosis and treatment were available. Tuberculosis sanatoria closed. Research into developing new drugs, diagnostics and vaccines then stagnated. Despite early success, treatment costs, treatment duration and poor implementation prevented TB-infected people living in conditions of widespread poverty benefiting from multidrug treatment. No new classes of TB drugs were developed for 40 years. This complacency is now reflected by 1.8 million deaths from TB each year, evoking a renaissance of interest over the past decade, which is leading to several new compounds being made available for potential use in the treatment of TB and for shortening treatment regimens. The usefulness and effectiveness of new anti-TB drugs needs to be carefully reviewed – meta-analyses of prior trials and of new trials based on reasonable expectations of benefit and well-defined endpoints. The challenges of HIV coinfection, poor case detection, poor adherence and the reduced capacity of health systems to cope with the increasing burden of TB necessitate new drugs and adjunct immunotherapies with novel modes of action.12–15 The strategic treatment goals include shortening and simplification of TB treatment regimens, improved treatment outcome for MDR- and XDR-TB and management of TB/HIV coinfection with drugs which can be safely co-administered with antiretroviral drugs. For diagnostic, drug and vaccine development to succeed, a series of enabling factors must be in place. Studies must conform to international standards of quality. Pivotal trials will require a well-resourced infrastructure, including adequately trained staff; current clinical trial capabilities are insufficient to absorb all of the products in pre-clinical and clinical phases of development. This points to the need to strengthen research capacities in high-burden countries. Several efforts at capacity development in high-TB-burden countries are
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currently underway, funded by institutions supported by the European Commission, DFID, Gates Foundation and the National Institutes of Health (NIH).
TREATMENT SIMPLIFICATION EFFORTS Poor compliance, especially among HIV-infected TB cases, is primarily due to an increased rate of adverse drug events, length of treatment and pill burden for TB treatment.11,16–18 Two important research streams are exploring the feasibility of shortening TB treatment from 6 to 4 months through the use of gatifloxacin or moxifloxacin,13,14 as well as assessing the efficacy and safety of currently recommended fixed-dose combination therapy versus ‘loose’ anti-TB medications in improving treatment compliance among HIV-uninfected and -infected TB cases. In addition, the work builds institutional and research capacity within national control programmes for TB clinical trials in the conduct of such research.
DEVELOPMENT AND EVALUATION OF IMMUNOMODULATORS FOR ADJUNCT THERAPY OF TUBERCULOSIS Given the relative lack of new drugs for TB treatment and long (6 months) duration of current standard short-course chemotherapy, other investigators have pursued the development of other therapeutic vaccines or immunotherapeutic agents that could boost the host immune response, and enhance bacillary clearance leading to improved treatment outcomes and possibly the shortening of the required duration of treatment. There are several potential roles for immunotherapy in TB treatment in this context.
Containing bacillary replication and preventing emergence of resistance Therapeutic options for patients with MDR-TB are limited at present; adjunctive immunotherapy in combination with secondline drugs would be welcome in this setting. Ameliorating symptoms Tuberculosis is characterized by tissue necrosis and fibrocavitary disease with loss of functioning lung tissue. Adjunctive immunotherapy that could decrease host inflammation and decrease tissue necrosis and fibrosis, which lead to significant morbidity and mortality in patients with severe pulmonary TB, would be beneficial. Preventing deleterious immune activation in TB/HIV coinfection In HIV coinfection, an additional role of immunotherapy might be to modulate a host immune response that otherwise promotes T-cell activation and HIV expression. Eliminating persisters The development of new treatments capable of shortening TB treatment is a major objective of TB drug discovery.19–22 Immunotherapy that could enhance host responses against slowly replicating persistent tubercle bacilli, a subpopulation not effectively targeted by current therapy, could potentially shorten the required duration of TB treatment and decrease the risk of relapse. Alternatively, if host responses cannot effectively eradicate these persisting bacilli, but instead create the conditions leading to persistence, immunotherapy directed against the granulomatous host response might accelerate the response to treatment by increasing drug bioavailability and enhancing microbial susceptibility.
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Cytokine regulation of macrophage activation Tumour necrosis factor (TNF), IFN-g, interleukin (IL)-12, CD4 and CD8 cytokines act in an autocrine fashion to limit intracellular mycobacterial growth. Macrophage activation for killing intracellular M. tuberculosis is enhanced by interaction with antigen-specific T cells and local production of IFN-g. Nitric oxide (NO), the production of which is induced by IFN-g, is thought to be an important anti-mycobacterial effector mechanism of activated macrophages in both mice and humans. Other products of activated macrophages, including superoxide, IL-6 and calcitriol (1,25-dihydroxy-vitamin D3), also restrict intracellular mycobacterial growth. Administration of endogenous IFN-g or IL-2 and other agents have been investigated for their role in augmenting host cellmediated immune (CMI) responses in active TB, improving or accelerating clearance of tubercle bacilli and improving clinical outcomes. A substantial body of evidence indicates that the response to therapy in drug-sensitive disease may be accelerated, and treatment potentially shortened, by anti-granuloma strategies targeted at eliminating dormancy. Immunomodulators such as corticosteroids,23 HSP65DNA, transforming growth factor (TGF)-b inhibitors, HE2000, IL-4 inhibitors, intravenous immunoglobulin, rHuIFNg, and other drugs and biologicals have the potential to shorten TB treatment by modulating the host response, and helping the immune system eliminate persistent organisms. Immunotherapy is a novel approach to treatment shortening. Strategies studied to date in mouse models have been found to reduce the T-helper (Th)-2 inhibitory effect on the protective Th-1 response, either by inhibiting IL-4 production or by downregulating the Th-2 response.24,25 In animal models, impressive treatment shortening times have been observed, and further human testing under appropriate study designs is warranted.22 In addition to treatment shortening described above, treatment outcomes might be improved by using immunomodulators as adjunctive therapies to existing regimens in all groups of TB patients including those with MDR- and XDR-TB. The current understanding of severe TB is that the host inflammatory response induces pathology that contributes to mortality.25 The use of novel immunomodulators or adjunctive corticosteroids could downregulate this response. Adjunctive corticosteroids are widely used and have been shown to be beneficial in selected severe forms of TB. The level of evidence is incomplete in other forms of TB,23 and limited for HIV coinfected patients. Additional studies are warranted. Several claims have been made of immunomodulators which could shift Th-2 responses to Th-1. When subject to scrutiny through testing under randomized clinical trials, the mistletoe extract, South African potato and a single dose of a killed preparation of Mycobacterium vaccae did not do better than placebo. Newer immunomodulators, including multiple-dose M. vaccae and M.w, require evaluation through phase 1, 2 and 3 studies. The findings of the DAR study (published in extract form at the time of writing) are encouraging. RESEARCH ON DEVELOPMENT AND EVALUATION OF BIOMARKERS OF DISEASE Currently there are no practical accurate clinical, biochemical, immunological or molecular markers of TB disease activity, TB cure or TB relapse. The determination of a consistent global host immune response, or ‘immunological marker’, reflective of active TB has the potential to evolve into a useful tool for monitoring infection, disease activity, cure and relapse.
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The response to infection with M. tuberculosis in humans is multifactorial and includes pathogen factors, environmental factors, genetically determined host factors and immune host factors involved in innate and adaptive immune responses. These determine the change from latent to active or reactivated TB:
Microbial markers: key indicators of outcome: culture and early bactericidal activity, colony-forming units, mycobacterial acid-fast bacilli load; and ○ qualitative/quantitative assays for mycobacterial DNA (67bpDNA), RNA, peptides (Ag85), glycolipids (LAM). Host markers: chemotherapy results in downregulation of protective mechanisms: ○ inflammatory/activation biomarkers, chemokines (e.g. MIF), apoptosis mediators, serological markers; ○ cytokines associated with protection or pathogenesis (e.g. IL-12, IFN-g, TFN, IL-4 and IL-4d2); and ○ antibodies to microbial antigens. Early bactericidal activity in sputum by colony counts and mycobacterial DNA detection are two biomarkers currently being studied. A major challenge to drug, immunotherapeutic and vaccine development is the length of time for assessment of efficacy through dependence on long-term clinical outcomes. New biomarkers of treatment success or failure would provide useful surrogates in newer drug regimen trials, adjunct immunotherapy studies and vaccine studies, reducing costs, and decreasing the long development timeline.26–31 Particularly important will be surrogate biomarkers that can reduce the 2-year follow-up currently used to monitor relapse. ○
ANTIRETROVIRAL AND ANTITUBERCULOSIS THERAPY FOR PEOPLE LIVING WITH HIV/AIDS WHO HAVE TUBERCULOSIS Tuberculosis/HIV treatment is far from being a reality for people living with HIV/acquired immunodeficiency syndrome (AIDS) who have TB or develop TB while on antiretroviral therapy.10,11 Clear recommendations on the best-informed practice is needed. Given that limited data are available, there is a need to move from evidence-based individual clinical interventions to a public health approach that will be informed by emerging evidence. 1. Validating the optimal time to start antiretroviral therapy among people living with HIV/AIDS who have active TB (to improve efficacy and decrease toxicity). The frequent coexistence of TB and HIV, varying from about 35% to 70% in sub-Saharan Africa,32 implies the need to manage both diseases simultaneously. Managing TB alone in the absence of HIV treatment is associated with an increase in mortality during the treatment duration for TB. No prospective controlled study has examined the optimal timing of antiretroviral therapy after TB treatment is initiated. The decision about when to initiate antiretroviral therapy among people living with HIV/AIDS and TB must balance the risk of HIV disease progression, morbidity and mortality with the potential risk of drug toxicity and adverse events, including immune reconstitution inflammatory syndrome (IRIS) stratified by the stage of HIV disease. 2. Determining the best antiretroviral therapy regimens, with dose adjustment when required, to use with TB treatment regimens. Some evidence on the pharmacokinetics of efavirenz and nevirapine when co-administered with rifampicin-containing regimens is available. Additional studies to determine the
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clinical efficacy and safety profile of regimens containing efavirenz and nevirapine, to determine proper doses in the presence of rifampicin and to identify the best methods of monitoring them are needed. 3. Determining the efficacy and safety profile of alternative antiretroviral therapy regimens. Drug development should be an area of focus for research on effectively treating people living with HIV/AIDS who have TB in resource-constrained settings. In particular, the development of fixed-dose combinations of antiretroviral drugs (mainly efavirenz-containing fixed-dose combinations) for people with TB should also be pursued. Replacing rifampicin with rifabutin should also be considered. 4. Developing the best clinical definition for IRIS for use in resource-constrained settings (validation studies). Clinical data currently available are based on different definitions of IRIS. There is an urgent need to standardize the definition and to identify the risk factors and predictors for IRIS. Clear and standardized guidance on how to prevent and/or treat an episode of IRIS is essential. 5. Determining the cost-effectiveness of different regimens and strategies. 6. Determining the minimal requirements for clinical and laboratory monitoring for outcomes related to efficacy and safety. 7. Determining the best strategies (including DOTS) for measuring and enhancing adherence for people receiving TB therapy and antiretroviral therapy. For all these issues, consideration of special populations, including their co-morbidity and unique characteristics, is encouraged.
DIAGNOSIS AND TREATMENT OF PAEDIATRIC TUBERCULOSIS INFECTION Paediatric TB is a growing problem in developing countries.33 There is a clear gap in research for the paediatric population. All issues identified as priority research items for adults also remain a research element for children. Children rarely have sputum smearpositive TB, and diagnosing TB in children is difficult. Although a good TB control programme is the best way to prevent TB in children, studies are urgently needed to improve diagnosis of TB (both extrapulmonary and pulmonary) in children. The best way and models to integrate this revised algorithm into the WHO Practical Approach to Lung Health (PAL) and Integrated Management of Adult and Adolescent Illness (IMAI) strategies need to be explored. Many of the priorities for TB research in adult populations are applicable to children. There is a clear need for evidence of efficacy/safety of drug formulations in use, a need for information on paediatric pharmacokinetics in different epidemiological contexts and a need to focus on the special challenges of diagnosing TB in children:
treatment guidelines for MDR- and XDR-TB in children; the need for improved diagnostic methods for detecting active disease among infants and children; this requires investigating T-cell IFN-g assays and markers of disease activity in early detection of active disease; delineation and validation of clinical and laboratory diagnostic algorithms in children; the role of cotrimoxazole or other antibiotic treatment and prophylaxis in HIV-infected children with TB, including
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efficacy, incidence of side effects and how to manage complications in children; and establishment of clear guidelines for the use of anti-TB treatment with antiretrovirals in HIV-infected children with active TB.
IMMUNOPATHOGENESIS AND VACCINE STUDIES Mycobacterium tuberculosis is a successful pathogen that overcomes numerous challenges presented by the immune system of the host.19,20 This bacterium usually establishes a chronic infection in the host where it may silently persist until a failure in host defences leads to manifestation of the disease. None of the conventional anti-TB drugs are able to target these persisting bacilli. Development of drugs against such persisting bacilli is a constant challenge since the physiology of these dormant bacteria is still not understood at the molecular level.20 Some evidence suggests that the in vivo environment encountered by the persisting bacteria is anoxic and nutritionally starved. Based on these assumptions, anaerobic and starved cultures are used as models to study the molecular basis of dormancy. Research into the study of mycobacterial latency and dormancy is crucial for designing new drug treatment for latency and development of new TB vaccines.22–24 Now entering its ninth decade of use, Bacillus Calmette–Gue´rin (BCG) remains the only available vaccine against TB.25 The use of BCG to prevent TB, however, is limited to the prevention of severe paediatric disease; its efficacy against adult disease wanes in high-burden regions where TB protection is most needed. Nonetheless, with accelerating progress in deciphering the M. tuberculosis genome and proteome, and new insights into the immunopathogenesis of TB infection, significant progress has been made in TB vaccine development over the past 5 years. Several approaches to TB vaccine development have been made:24,25 1.‘Improved’ BCG: e.g. overexpression of protective antigens (AGs), or reconstitution of deleted genes. 2. Attenuated M. tuberculosis: targeted inactivation (‘knock-out’) of metabolic or virulence genes. 3. Adjuvanted protein subunit vaccines (also peptides or DNA vaccines): a. Hypothesis-driven selection: e.g. secreted AGs; and b. Empirical selection: e.g. T/B-cell recognition and/or major histocompatibility complex (MHC) binding, combination of AGs. 4. Other approaches: presentation of live-vectored AGs, e.g. vaccinia (MVP), adenovirus, Salmonella, or non-protein AGs, e.g. gd TCR or CD1-binding molecules; conjugates, etc. As of late 2005 at least five vaccine candidates are in phase I clinical trials (rBCG30; rBCG: D ureC-lloþ; MVA-85A; Ag85BESAT-6; Mtb72f);35 and several more candidates are in pre-clinical development. Many current vaccine candidates are based on modifications to BCG; yet our understanding of the immunobiology underlying BCG’s ineffectiveness remains incomplete.34 The understanding of the distinction between protective immune responses and immunopathology, though improving, remains blurred.35 In vaccine evaluation, study design is impeded by the lack of known immune correlates of protection against TB infection. Thus dependence on immunological endpoints for interpretation of vaccine efficacy is not reliable and difficult to interpret, whereas use of clinical endpoints delays assessment of vaccine efficacy – requiring several years and/or tens of thousands of
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subjects. Collectively, these gaps in knowledge make the design of vaccine assessment strategies difficult. The need for both pre-exposure vaccination (or ‘prime’ strategies) and post-exposure (or ‘boost’ strategies) is widely accepted, but the specific timing and vaccine component design remains to be established. Evaluation of vaccine candidates will require a transition through a series of clinical trials of increasing size, complexity and cost to progressively evaluate their safety, immunogenicity and eventual efficacy. Despite considerable progress, there is a need to expand discovery and translational research on vaccines. The early success of current clinical candidates does not signal an end of discovery research, but rather provides novel opportunities to link fundamental research to human studies.
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) INDUCED BY ANTIRETROVIRAL TREATMENT The clinical picture of HAART in HIV-infected patients restores protective immune responses against a wide variety of pathogens and dramatically decreases mortality.11,17 In a subset of patients receiving HAART, immune reconstitution is associated with a pathological inflammatory response leading to substantial shortterm morbidity and even mortality. Some patients with HIV/TB coinfection who are on anti-TB treatment and HAART will also develop an exacerbation of symptoms, signs or radiological manifestations of TB not due to relapse or recurrence of their TB, or another opportunistic infection. This subject needs to be defined and appropriate treatments and markers of disease activity determined.
WHO’s Interim Policy on Collaborative TB/HIV Activities11 suggests specific activities to address the dual epidemic including: 1. the establishment of mechanisms for collaboration; 2. the decrease of burden of TB among people living with HIV/ AIDS – through earlier detection of active TB through intensified case-finding, provision of isoniazid preventive therapy (IPT) for coinfected patients, and ensuring TB infection control in healthcare and congregate settings; 3. the decrease of burden of HIV among TB patients – through provision of voluntary counselling and testing for people at risk of HIV, introducing HIV prevention methods and cotrimoxazole preventive therapy, ensuring HIV/AIDS care and support and introducing antiretroviral therapy; and 4. the improvement of care for people infected with both TB and HIV – through cross-training and collaborative care initiatives.
PATIENT SUPPORT FOR STANDARDIZED TREATMENT Adherence to therapy remains a central issue in determining therapeutic effectiveness of TB treatment. There is a well-recognized need to evaluate ways for broadening DOTS to include more effective strategies for providing adherence support. Examples include evaluation of:
IMPROVING PROGRAMME PERFORMANCE AND CAPACITY BUILDING: COORDINATION OF TUBERCULOSIS AND HIV/AIDS PROGRAMMES The increasing number of new TB cases each year – especially those propelled by the 5–10% annual increase in TB incidence in sub-Saharan Africa – is attributable largely to HIV infection. Coinfection rates in TB-infected patients in some countries are as high as 70%.11 The HIV epidemic is not merely increasing TB but also driving a significant increase in the proportion of TB cases that are smear-negative pulmonary and extrapulmonary disease; these presentations of TB pose considerable challenges to currently available diagnostic methods and to clinical management. Even when diagnosed, HIV-infected, smear-negative pulmonary TB patients have inferior treatment outcomes, including excessive early mortality.16 It is now widely recognized that collaboration between TB and HIV/AIDS disease programmes to provide patient-centred, integrated care and services is essential to controlling the TB epidemic.11 Collaboration between TB and HIV programmes is, however, hindered by a history of independent structures and functions in established national TB programmes and newly established HIV programmes, by the differential funding and by the inadequacies of primary care and general health systems on which to build integrated care in many countries. In responding to the challenge of the synergistic HIV/TB pandemic, a key strategic objective of the Second Global Plan to Stop TB (2006–2015) is to scale up implementation of collaborative TB/HIV activities in all countries with a high burden of TB/HIV.
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patient ‘treatment literacy’ preparation before initiation of therapy; adherence support provision by healthcare workers and/or community or family members; the most effective frequency and intensity of adherence support; combinations of these interventions; and assessment of the most effective method of supporting adherence in HIV/TB patients receiving ARV therapy. For example, does the co-administration of TB and HIV therapies require different or expanded adherence support strategies compared with TB or HIV alone?
For these studies outcome measures should include both standardized and validated measures of adherence as well as biological and clinical measures for TB (sputum conversion, treatment completion, case-holding, relapse, resistance, etc.) and adherence and biological and clinical outcomes for HIV (adherence assessment through standardized measures, viral load, clinical disease progression, mortality).
PREVENTIVE THERAPY FOR TUBERCULOSIS The following research priorities, which distinguish between population and individual levels, were also suggested by the WHO February 2005 meeting.3 At population level 1. Identify macro-level barriers to implementing isoniazid preventive therapy and mechanisms to overcome these barriers. 2. Evaluate the outcomes of a national isoniazid preventive therapy programme in Botswana: lessons learned. 3. Establish the effectiveness in special populations and regions with elevated isoniazid resistance. 4. Determine the optimal duration of isoniazid chemoprophylaxis, the optimal regime (including rifampicinbased regimes) and incorporation of these strategies, where appropriate, into HIV care programmes.
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At individual level 5. Develop the optimum algorithm to exclude TB disease. 6. Determine the added benefit of isoniazid preventive therapy among people receiving antiretroviral therapy. 7. Determine whether there are subgroups of people who are likely to benefit. 8. Determine effectiveness among infants and children.
COTRIMOXAZOLE PROPHYLAXIS FOR OPPORTUNISTIC INFECTIONS The routine use of cotrimoxazole in developing countries, especially sub-Saharan Africa, has been minimal despite provisional recommendations from WHO and UNAIDS that cotrimoxazole be given to everyone in Africa with HIV/AIDS, including those who have TB. The Interim Policy on Collaborative TB/HIV Activities promotes cotrimoxazole use among people living with HIV/AIDS who have TB.11
SOCIAL SCIENCE AND IMPLEMENTATION RESEARCH TOPICS IN CLINICAL MANAGEMENT OF TUBERCULOSIS Social science research for TB control refers to the contributions of the basic and applied social sciences to addressing fundamental social, economic and behavioural questions related to TB (Table 73.4). Social science questions arise in nearly every area of TB research and have been covered by other chapters in this book. They include questions such as identifying the constraints on healthseeking behaviour (constraints in accessing diagnosis and care); gender differentials in the epidemiology of the disease, in case detection and treatment success; and adherence issues related to treatment response, including the impact of user fees and treatment adherence support strategies. The central focus of social science research is on identifying the barriers to timely case detection, diagnosis and treatment in the context of poverty and social inequality, and enabling interventions that would reduce these constraints. Four key domains within which social science research on TB operates are identified:36–39 1. determinants of risk and vulnerability to TB; 2. impact of poverty on TB;38–41
Table 73.4 Social science and implementation research topics in clinical management of tuberculosis Implementation research: health systems and operations 1 Studies to define effectiveness of HIV case-finding in TB programmes, including availability and uptake of HIV testing. 2 Operations research studies (including mathematical and simulation models) of resource needs, delivery sites, care models, costs and impacts of TB/HIV programme integration. 3 Assessment of training needs and training effectiveness for HIV and TB treatment providers. 4 Development and validation of systems to generate, process and use pharmacovigilance data, and impact on treatment outcomes.
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3. effects of gender inequality on disease risk, disease severity and case detection; and 4. impact of community factors on TB control efforts.
OPERATIONAL AND IMPLEMENTATION RESEARCH Operational (or operations) research involves the use of advanced analytical techniques to solve optimization problems under conditions of uncertainty and constraints. Classic operational research has only recently been applied to public health problems. Applied to TB control, the research questions can be condensed to: how can TB interventions – case-finding, diagnosis and treatment – be optimized, given resource constraints (Table 73.5)? Operations research for TB control can greatly assist efforts to bring effective interventions to a greater number of people. As new tools are developed, operational research methods can also be used to guide implementation of new drug regimens, clinical trial design and vaccine trial design. Thus, the overall objective of this research is to significantly improve access to efficacious interventions against tropical diseases by developing practical solutions to common, critical problems in the implementation of these interventions.
Table 73.5 Research topics on access to care and case-finding Item number
Research topic
Case-finding 1 Which factors lead to delays in establishing a diagnosis of TB? Where are the missing cases? 2 Which factors contribute to the low global case detection rate (‘diagnostic gap’)? 3 What is the role of active case-finding, especially in hardto-reach populations and areas of high HIV prevalence? User fees 4 How do user fees affect access to care, case detection, diagnosis and treatment? Community-based research 5 How can community-based social research enhance the identification of the most vulnerable subgroups and define strategies to enrol them in quality TB care? Transportation and other opportunity costs 6 How significant are the barriers created by indirect costs of care, such as transportation costs, and what are the most effective strategies to remove the barriers they create? Case-finding and access to care in the private sector 7 What are the most effective ways for leveraging private sector capacity to achieve TB control goals? Diagnostics in support of case-finding 8 What are the implications of changing current symptombased and laboratory-based diagnostic algorithms for case-finding? 9 What is the sensitivity and specificity of various thresholds for chronic cough (e.g. 2 vs 3 weeks) as screening tests for TB? 10 What is the role of culture-based detection methods in case-finding?
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EPIDEMIOLOGICAL RESEARCH IN NATIONAL TUBERCULOSIS PROGRAMMES MACRO-EPIDEMIOLOGY OF TUBERCULOSIS Global prevalence of latent TB infection is estimated at 32% of the world’s population, some 1.86 billion people. The total number of new cases is estimated at 8.8 million per year, including 3.9 million cases of infectious pulmonary disease; point-prevalence estimates indicate more than 16 million cases of active disease. Eighty per cent of all incident cases of TB are found in 22 countries and more than half of the cases occur in five populous south-east Asian countries. Ten of the 15 countries with the highest per capita rates of smear-positive disease are located in Africa. The prevalence of TB/HIV coinfection world-wide is estimated at 0.18%; some 656,000 new TB cases were coinfected with HIV in 2003. An estimated 1.7 million people die of TB each year. The global case-fatality rate is 23%, but exceeds 50% in some African countries with high HIV burden.32 A number of questions in relation to the timing of diagnosis and its potential impact on TB transmission remain. At present, it remains unclear how early TB diagnosis needs to occur in order to prevent transmission in different patient populations such as people living with HIV/AIDS, infants and pregnant women. For comprehensive TB and HIV prevention, care and support, there is a compelling need for research on specific elements of the interaction between HIV infection and TB, along with a better understanding of the epidemiology of coinfection, including a definition on the timing of development of TB after HIV infection, and the effect of comorbidity on TB susceptibility.
CHALLENGES AND OPPORTUNITIES Increasing the quality of surveillance data will provide a more accurate picture of the epidemic, and illuminate the global impact of TB control efforts. There is a clear need to improve case notification reliability; however, it is recognized that, given current diagnostic limitations, certain active cases, notably smear-negative disease, will remain difficult to identify even in ideal circumstances. Accurate estimates of the TB burden in selected countries can be obtained from special surveys of the prevalence of disease and infection. Unfortunately, good surveys are scarce and there are not enough resources to obtain survey information on a global scale. In addition, countries where the rates of HIV/TB coinfection are high or TB incidence rates are in decline make survey information hard to interpret. An additional and promising element in TB epidemiology would be the ability to disaggregate data from national TB programmes. The further implementation of computerized databases at the district level promises to provide TB notification data that allow a closer, more detailed look at relevant local and district-level micro-epidemiology – including data on poor, vulnerable and hard-to-reach populations.
nutrition, coinfections (such as HIV/AIDS) and migration from or to higher risk communities. In addition, patients suffering from TB are less able to work and to generate income for themselves and their dependants. These factors pose significant additional economic hardships on patients and households, with a disproportionate impact on the poor, further limiting their access to care.36–39 Research questions which arise include the following:
What kind of financing schemes, including partnerships between the private and public sectors, can enhance development of technology, and patients’ access to TB diagnosis and treatment (Fig. 73.5)? What type of social and economic incentives for patients and DOTS workers can improve case-finding and adherence to therapy? How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to case detection and access to care? How can health providers outside of the public health sector, including private practitioners and traditional healers, contribute to clinical management?
EFFECTS OF GENDER ON DISEASE RISK, DISEASE SEVERITY AND CASE DETECTION Both women and men face gender-specific barriers to TB diagnosis and care. These barriers, which vary in different settings, require thorough assessment and evaluation to identify interventions that can reduce these barriers. Poor women with TB also tend to suffer from fear of rejection by their families and their community. It has been shown that the stigma of TB is often more pronounced among women than men. While men usually worry more about loss of wages and capacity for work, women worry most about social rejection – from husbands, in-laws and the community in general – if they have TB. Women in many countries must overcome several barriers before they can access healthcare. Where they undertake multiple roles in reproduction, production and childcare, they may be left with less time to reach diagnostic and curative services than men. Women may be given less priority for health needs and generally have less decision-making power over
Public sector
Private sector
Needs-driven Altruism Partnership
Financing Market-driven Manufacture Product focus and distribution IP management Goal-directed R&D Rigid targets/ milestones Complex project Marketing
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1950
Publicprivate partnership Industry model Needs-driven Partnership
2000
Fig. 73.5 Evolution of technology development for diseases prevalent in
CROSS-CUTTING ISSUES IMPACT OF POVERTY ON TUBERCULOSIS While TB is not exclusively a disease of the poor, the association between poverty and TB is well established and widespread. Impoverished communities and social groups are at higher risk of infection with M. tuberculosis than are the general population because of overcrowded living or working conditions, poor
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developing countries. Poor understanding and perceived inaccessibility of TB-related treatment and diagnostics markets have limited private sector investment, and, thus, market forces have not delivered speedy development of new drugs or technologies. This shortcoming has inspired the growth of public–private partnerships, which are likely to change the way health products are developed and delivered to developing countries. Such partnerships, whilst driven by health needs in the global public interest, also benefit from a focused milestone-driven approach, intellectual property (IP) management and the manufacturing and distribution capacity of the commercial sector. R&D, research and development.
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the use of household resources. Research questions which arise include the following:
How do malnutrition and other comorbidities (such as malaria and HIV) relate to women’s and girls’ susceptibility to TB? In populations where women need to access healthcare accompanied by a man, what interventions would improve health-seeking for women? How can provider delays for women, men and children be reduced? What are the gender-specific barriers to TB diagnosis and care in different settings and how can they be translated into appropriate gender-sensitive interventions?
MULTIDRUG-RESISTANT TUBERCULOSIS MDR-TB is considered an important threat to TB control. Combating resistance is through application and strengthening of DOTS and appropriate treatment of resistant cases, DOTS-Plus. Globally, MDR-TB remains a locally severe problem. A three-pronged strategy for control of MDR-TB has been proposed by the Global Plan to STOP TB:1 1. widespread implementation of short-course chemotherapy; 2. improved resistance testing and surveillance; and 3. careful introduction of second-line drugs following proper evaluation, cost-effectiveness and feasibility. Research areas identified by the DOTS-Plus Working Group include: 1. ideal management of MDR-TB; 2. economic evaluation of DOTS-Plus; 3. transmissibility and fitness of MDR-TB strains; 4. effect of HIV epidemic on MDR-TB epidemic; 5. quality assurance of drug sensitivity testing on second-line agents; 6. resistance criteria for second-line drugs; 7. development of an early warning system for drug resistance; and 8. assessment of management strategies of MDR contacts and special populations, e.g. pregnant women, HIV-infected patients and children.
EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS On 1 September 2006 the WHO announced that a deadly new strain of extensively resistant M. tuberculosis had been detected in Tugela Ferry, a town in Kwazulu Natal, South Africa. It was resistant to rifampicin and isoniazid plus three other second-line agents. XDRTB is defined as MDR-TB (resistant to rifampicin and isoniazid) plus resistance to any fluoroquinolone, and to at least one of the following drugs: kanamycin, amikacin or capreomycin. XDR-TB is a serious threat to TB control, raising concerns of TB epidemics with severely restricted treatment options. Of 55 cases of XDR-TB 44 were tested for HIV and all of them were HIV-infected. The median survival time from sputum collection was 16 days! By December 2006, more than 500 cases were reported in South Africa.40 Treatment-related outcomes in high HIV prevalence settings such as South Africa may be poorer than in other settings.41 This now poses a very serious global threat and reflects a failure of the health system. Many research questions arise apart from those mentioned earlier under MDR-TB:
What is the extent of the problem? What factors fuelled the outbreak? Was the use of anti-TB drugs appropriate?
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Is DOTS applied effectively in the system? What is the micro- and macro-epidemiology of XDR-TB in South Africa, the region and the globe? What can be done to contain the spread of XDR-TB? How can the spread be monitored? What control measures can be instituted? What treatment regimens can be developed and used effectively? Should patients be forced to have supervised treatment?
ETHICAL ISSUES IN TUBERCULOSIS RESEARCH As the research community now moves away from ‘colonial parachute research’ and the concept of equal partnerships arises, focus is now on ethical issues governing these developed country partnerships. Performing the clinical trials of new drugs or interventions in Africa that if found effective, will not be affordable by countries in which research is performed highlights the ethical issues surrounding current clinical trials. A number of TB and TB/HIV research programme activities, especially in developing countries in the recent past, have fostered the discussion around research ethics and helped to establish bioethics as an integral part of health research in resource-limited settings. The WHO-TDR helped to set up a global Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), ensuring that appropriate and competent ethics committees are established in countries where research is carried out. Already under SIDCER, six regional forums and more than 15 national forums have been established. Guidelines for ethics committees that review biomedical research were developed by WHO-TDR (in 2000) and widely distributed. Guidelines were later established on surveying and evaluating ethical review practices. Guidelines on data and safety monitoring boards are now being finalized through coordination with local government to ensure political endorsement. Training of local ethics committee staff in developing countries has become a high priority and should be vigorously pursued. Audit and follow-up of ethics committee decisions and outcome of trials with subsequent actions on making the product available at affordable prices should be a priority.
CONCLUSIONS Remarkable progress has been made over the past decade in TB research, especially in the fields of drug/immunotherapy development, newer diagnostics and vaccine development. These achievements are a result of collaborative efforts between public and private organizations that have combined scientific and clinical knowledge with further developments in TB research. The battle is not won yet (as evidenced by high mortality rates from TB, the MDR-TB problem and recent reports of XDR-TB) and will require further close cooperation and investment by all concerned to develop, evaluate and introduce more effective interventions, which will lead to TB control world-wide.
ACKNOWLEDGEMENTS The authors thank the WHO/TDR Tuberculosis Diagnostics Economic Working Group (Jane Cunningham and Mark Perkins) and TDR (Nina Mattock) for permission to use figures displayed in this chapter (adapted from Diagnostics for Tuberculosis: Global Demand and Market Potential; Gevena: WHO and TDR).
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REFERENCES 1. Stop TB Partnership. Global Plan to Stop TB. STOP TB Partnership, 2005. [online]. Accessed 14 November 2005. Available from URL:http://www. stoptb.org/gpstb/assets/wgstrategicplans/ DEWGfull210905.pdf 2. WHO/TDR Report. Scientific Working Group on Tuberculosis. TDR/SWG/06. Geneva: World Health Organization, 2005. 3. World Health Organization. TB/HIV Research Priorities in Resource-Limited Settings. Report of an Expert Consultation, 14–15 February 2005, Geneva, Switzerland. WHO/HTM/TB/2005.355, WHO/HIV/2005.03. Geneva: World Health Organization, 2005. 4. Perkins M, Rosicgno G, Zumla A. Progress towards improved tuberculosis diagnostics in developing countries. Lancet 2006;367:942–943. 5. World Health Organization. Diagnostics for Tuberculosis. Global Demand and Market Potential. WHO/TDR/ FIND. Geneva: World Health Organization, 2006. 6. Dheda K, Udwadia ZF, Huggett JF, et al. Utility of the antigen specific interferon-gamma assay for the management of tuberculosis. Curr Opin Pulm Med 2005;11(3):195–202. 7. Pai M, Dheda K, Cunningham J, et al. T cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward. Lancet Infect Dis 2007;7(6):428–438. 8. Pai M, Riley LW, Colford JMJr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4(12):761–776. 9. Dye C, Watts C, Bleed D, et al. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence and deaths globally. JAMA 2005;293:2767–2775. 10. Harries A, Chimzizi R, Zachariah R. Safety, effectiveness and outcomes of concomitant usage of HAART or malaria therapy with anti-TB drugs in resource-poor settings. Lancet 2006;367:944–945. 11. World Health Organization. Interim Policy on Collaborative TB/HIV Activities. WHO/HTM/TB/ 2004.330 WHO/HTM/HIV/2004.1. Geneva: World Health Organization, 2004. 12. Andries K, Verhasselt P, Guillemont J, et al. A diarlyquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005;307(5707): 223–227.
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13. Ginsberg A. New Drug Development for TB: Opportunities and Challenges for Research. WHO Report TDR/SWG/06 92-97. 14. O’Brien, Spigelman M. New drugs for tuberculosis: current status and future prospects. Clin Chest Med 2005;26(2):327–340. 15. Wallis RS. Reconsidering adjuvant immunotherapy for tuberculosis. Clin Infect Dis 2005;41:201–208. 16. Maher D, Watt CJ, Williams BG, et al. Tuberculosis deaths in countries with high HIV prevalence: what is their use as an indicator in tuberculosis programme monitoring and epidemiological surveillance? Int J Tuberc Lung Dis 2005;2:123–127. 17. Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006;57: 167–170. 18. Dheda K, Lampe FC, Johnson MA, et al. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy (HAART). J Infect Dis 2004;190:1670–1676. 19. Zhang Y. Persistent and dormant tubercle bacilli and latent tuberculosis. Front Biosci 2004;1(9):1136–1156. 20. Stewart GR, Robertson BD, Young DB. Tuberculosis: a problem with persistence. Nat Rev Microbiol 2003;1:97–105. 21. Smith CV, Sharma V, Sacchettini JC. TB drug discovery: addressing issues of persistence and resistance. Tuberculosis 2004:84:45–55. 22. Zhang Y. The magic bullets and the tuberculosis drug targets. Annu Rev Pharmacol Toxicol 2005;45:529–562. 23. Dooley DP, Carpenter JL, Radhemacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25(4):872–887. 24. Doherty TM, Andersen P. Vaccines for tuberculosis: novel concepts and recent progress. Clin Microbiol Rev 2005;18(4):687–702. 25. Rook GAW, Dheda K, Zumla A. Immune responses to TB in developing countries: implications for new vaccines. Nat Rev Immmunol 2005;5:661–667. 26. Brindle R, Odhiambo J, Mitchison DA. Serial counts of Mycobacterium tuberculosis in sputum as surrogate markers of the sterilising activity of rifampicin and pyrazinamide in treating pulmonary tuberculosis. BMC Pulm Med 2001;1(1):2. 27. Mitchison DA. Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months [letter]. Am Rev Respir Dis 1993;147(4): 1062–1063.
28. Onyebujoh P, Rodriguez W, Mwaba P. Current priorities in tuberculosis research. Lancet 2006; 367:940–942. 29. Dheda K, Chang JS, Breen RA, et al. In vivo and in vitro studies of a novel cytokine, Interleukin-4d2, in pulmonary tuberculosis. Am J Resp Crit Care Med 2005;172(4):501–508. 30. Weiner M, Burman W, Vernon A, et al, TB Trials Consortium. Effect of HIV coinfection on two month sputum culture conversion and its associations with TB treatment outcomes. Proc Am Thorac Soc 2005;2:A20. 31. Joloba ML, Johnson JL, Namale A, et al. Quantitative sputum bacillary load during rifampin-containing short course chemotherapy in human immunodeficiency virus-infected and non-infected adults with pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4(6):528–536. 32. Dye C. The global epidemiology of tuberculosis. Lancet 2006;367:935–940. 33. Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis 2005;9:477–484. 34. Andersen P, Doherty TM. The success and failure of BCG - implications for a novel tuberculosis vaccine. Nat Rev Microbiol 2005;3:656–662. 35. Rook GAW, Doherty M. Towards developing new TB vaccines—progress and hindrances. Lancet 2006;367:947–949. 36. Nhlema B, et al. A Systematic Analysis of TB and Poverty. Geneva: Stop TB Partnership, World Health Organization, 2003. 37. Hanson CL. Tuberculosis, Poverty and Inequity: A Review of the Literature and Discussion of Issues. Geneva: Stop TB Partnership, World Health Organization, 2002. 38. Gwatkin D, Guillot M. The Burden of Disease among the Global Poor—Current Situation, Future Trends and Implications for Strategy. Global Forum for Health Research/World Bank, 2000. 39. World Health Organization. Addressing Poverty in TB Control. Options for National TB Control Programmes. WHO/HTM/TB/2005.352. Geneva: World Health Organizaation, 2005. 40. Singh J, Upshir R, Padayatchi N. XDR-TB in South Africa -no time for denial or complacency. PLoS Med 2007;4(1):1–7. 41. Dheda K, Shean K, Badri M. Extensively DrugResistant Tuberculosis. N Engl J Med 2008.
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BCG: History, evolution, efficacy, and implications in the HIV era Anneke C Hesseling and Marcel A Behr
INTRODUCTION Bacillus Calmette-Gue´rin (BCG) vaccines have been given to billions of people for nearly a century; yet BCG vaccination remains a controversial topic, even more so in the era of human immunodeficiency virus (HIV) infection.1 BCG usage worldwide has been estimated at over 100 million doses per year, resulting in BCG vaccination of 75% of 130 million children born in 2002.2 Despite this impressive coverage, the nature of BCG protection and the risks of BCG vaccination remain the subject of ongoing discussion. In this chapter, we briefly review the history of BCG vaccination, and then emphasize three areas for which there have been some developments in the past decade: 1. the genetics of BCG vaccines; 2. information on efficacy/effectiveness of BCG vaccination; and 3. data on BCG safety and efficacy in the context of the HIV epidemic. Readers are referred to excellent reviews on other aspects of BCG and TB vaccination that have been published previously.3–5
HISTORY OF BCG VACCINES The original BCG vaccine strain was derived by in vitro passage from an isolate of Mycobacterium bovis at the Institut Pasteur in Lille, France, in 1921. This work was conducted by Albert Calmette and Camille Gue´rin, after whom the vaccine is thus named. Previous attempts to develop a TB vaccine, for example by the boiling or treatment of tubercle bacilli, were unsuccessful, but the notion that small dosages of a live, attenuated form of the organism could be effective in protecting humans against disease eventually lead to the development of BCG. This notion was based on some experimental data from immunizing cattle with attenuated human strains of the tubercle bacillus, a process called bovo-vaccination, initiated by the Nobel Laureate Emil von Behring.6 The preparation of this first attenuated BCG strain was started in 1908 and involved multiple passages of a virulent M. bovis strain (isolated by Nocard in 1902), on bile, glycerine, and potato medium at 3-weekly intervals. The testing of this early vaccine was interrupted by the outbreak of the First World War in 1913. Subculture of this initial isolate was, however, continued throughout the duration of the war, with assistance from the German occupying force veterinary surgeons.7,8 In 1919, after
approximately 230 subcultures, this early vaccine demonstrated some protective effect against TB, measured as failure to produce progressive disease after Mycobacterium tuberculosis injection into several animals including cattle, horses, guinea pigs, and rabbits. This early vaccine was initially baptized as ‘Bacille Bilie´ CalmetteGue´rin’, which was later reduced to BCG. At this stage, Calmette and Gue´rin pronounced this vaccine strain a virus fixe.9 The term ‘fixe’ implied a state of permanence, indicating that they expected neither reversion of virulence nor further attenuation, a point that will be addressed later in the section on BCG genetics. The first administration of BCG as a vaccine occurred in 1921, when BCG was given orally to an infant born to a mother who had succumbed to TB 1 day after delivery. There were no adverse events, and the infant did not develop TB. The oral administration route was initially favoured as the gastrointestinal tract was regarded by some as the route of natural M. tuberculosis infection and avoided the observed severe local reactions following subcutaneous BCG administration. By 1924, 664 infants had been orally vaccinated.10 Mass production of BCG (named BCG Pasteur strain) was started at the Institut Pasteur in Lille, and, by 1928, in Paris. Between 1924 and 1928, 114,000 infants had been vaccinated without serious complications. In 1927, Wallgren had modified the subcutaneous administration method to intradermal vaccination in Sweden; this later became the most commonly used routine of administration.11 Early observational data produced by Calmette and Gue´rin following oral vaccination suggested drastically reduced mortality in BCG-vaccinated infants. With increasing use in Europe during the 1920s, consistent results were observed in nurses in Norway.12 However, considerable debate continued regarding the efficacy of BCG during this period, also regarding the statistical analysis of Calmette’s early data.13 Additionally, there remained a concern regarding the safety of injecting infants with live bacteria of undetermined virulence, especially as different forms of BCG bacteria had been described in the laboratory, associated with varying levels of virulence.14 In a tragic sequence of events, referred to as the ‘Lubeck disaster’, 251 infants in Lubeck, Germany, were inadvertently orally vaccinated with virulent M. tuberculosis strain instead of BCG Pasteur strain. Of these, 72 infant vaccinees died during the first year of follow-up; a further 135 showed evidence of TB but survived.15 Despite subsequent full exoneration of BCG, this tragedy resulted in considerable loss of public faith in BCG. As a result of the desire to obtain more data on the efficacy and safety of BCG, formal trials of BCG were organized; data are reviewed under the efficacy section.
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PREVENTION OF TUBERCULOSIS BCG family tree from archives with confirmed genomic deletions M. bovis 1908 1921 1927
It had long been recognized that some alteration occurred to a strain of virulent M. bovis around 1909 to produce the original Bacille Bilie´ de Calmette et Gue´rin.16 There were also a number of reports describing a further loss of virulence of BCG strains around 1928–1930, suggesting further alterations in the BCG stocks at the Institut Pasteur.17 Once BCG cultures had been distributed to different manufacturers for domestic vaccine propagation and production, it became apparent that there were now various BCG daughter strains, implying changes in the BCG stocks at different sites. Since lyophilization did not exist for BCG in the 1920s, there was no clear option but to continue passaging the bacteria every 2–3 weeks in the laboratory, a process that in retrospect was bound to result in further in vitro evolution. Until recently, this history did not lend itself to formal evaluation, because the tools to systematically compare the genome complement of different BCG substrains did not exist. As a result, although BCG vaccines were considered relatively safe, there was no information on the exact substrain characteristics and the degree of evolution that had occurred. Two sets of advances have permitted progress in the understanding of the genetics of BCG vaccines: 1. the determination of the M. tuberculosis H37Rv genome sequence, as a referent for BCG studies;18 and 2. the development of tools of comparative genomics, such as subtractive hybridization,19 DNA microarrays,20 and bacterial artificial chromosome libraries.21 Together, these new data sets and methodologies have provided a portrait of three steps in the evolution of BCG vaccines: 1. their derivation from M. bovis; 2. their ongoing evolution in France after their first introduction; and 3. the evolution of BCG daughter strains at other vaccine-manufacturing facilities. Because the original Nocard strain of M. bovis has been lost, and the slants of BCG at the Institut Pasteur are not subject to experimentation, current knowledge of BCG evolution results from inference and using related bacteria, such as clinical isolates of M. bovis and currently used daughter strains of BCG. Despite this limitation, the study of these organisms has provided an extremely detailed record of the evolution of BCG strains, and results to date have been completely reproducible, both across laboratories and when different lots of a BCG substrain are obtained from different sites.20–22 The general approach to studying BCG evolution has
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Pending information on efficacy from different studies, BCG vaccination was not widely implemented. However, in the aftermath of the Second World War, when TB emerged as a major public health concern, and massive TB epidemics swept through Europe and Asia, the use of BCG was encouraged based on several clinical trials and the observational data to date. An important advance in the 1950s was the mass production of freeze-dried vaccine and administration through percutaneous puncture, increasing availability, and standardization of inoculation. The use of BCG was particularly encouraged by UNICEF and by the Scandinavian Red Cross Societies, and then by the World Health Organization (WHO).
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Genomic deletion
Fig. 74.1 BCG genealogy, with genomic deletions indicative of in vitro genomic decay.85,86
been to use a combination of historical records of strain dissemination with genetic analysis of these various strains, together generating a family tree of BCG evolution with superimposed genetic alterations since the first passages in the early twentieth century (Fig. 74.1). The most evident form of variability has been the regions lost in all or some BCG strains, termed genomic deletions. These relatively large, polygenic elements represent unidirectional evolutionary events, as the re-acquisition of 10kb of DNA is prohibitively improbable during bacterial growth on potato-based media. These regions therefore provide an unambiguous record of genomic decay, and because they coincide with the record of strain distribution, indicate that genomic loss occurred in three settings: 1. during BCG derivation; 2. during BCG propagation; and 3. during BCG production in different laboratories. Moreover, the quantity and nature of genomic decay are informative in that they provide a list of genes dispensable for in vitro growth but potentially necessary for full virulence. During the years 1908–1961, from the first passages by Calmette to lyophilization, BCG Pasteur lost as much genomic material as is seen between strains of M. tuberculosis that have been circulating through their human hosts for millennia. This accelerated pace of genome decay affects decidedly different genes. Whereas M. tuberculosis deletions result in loss of insertion elements and phages,23 BCG deletions have resulted in the disproportionate loss of antigenic proteins and regulatory elements. Teleologically, these losses should result in a vaccine less immunogenic and less likely to produce a successful infection in the host, but experimental evidence for the role of most BCG deletions in virulence is still lacking. Notably, the original deletion that distinguishes M. bovis from BCG vaccines has been clearly demonstrated to disrupt an important antigen secretion system,24 and re-creation of this deletion has resulted in profound attenuation of virulence in experimental models.25 Therefore, the principle has been established that BCG evolution may affect natural virulence. However, further experimental data are now needed to demonstrate whether this is true, and if so, through what mechanisms. Beyond genomic deletions, comparison of BCG daughter strains has revealed duplications and single nucleotide polymorphisms.
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The demonstration that parts of the genome had been duplicated implies that not only was the in vitro passage associated with loss of unneeded elements, but that there might also be active selection for metabolic variants which had improved growth under laboratory conditions.26 Further evidence for the positive selection of BCG mutations comes from a study of pyruvate production. Whereas M. tuberculosis and BCG vaccines can be grown in vitro without the addition of pyruvate, it has long been known that the addition of pyruvate can facilitate the growth of M. bovis. Recently, Keating and colleagues showed that M. bovis is a natural pyruvate kinase mutant, but that this mutation was reversed early in the derivation of BCG vaccines.27 Other single nucleotide polymorphisms have been shown to affect mycolic acid production,28 the cyclic AMP receptor protein,29 and a regulatory gene, sigK, responsible for production of the antigenic proteins MPB70 and MPB83.30 As is the case for the genomic deletions, the impact of these genetic events on the safety and efficacy of BCG vaccination remains to be clarified. However, using the record of strain dissemination, one can separate BCG vaccines into two groups: (1) those obtained in the 1920s, and (2) those obtained after 1930. Of note, none of the vaccines obtained in the 1920s have been subject to a randomized clinical trial. In contrast, the vaccines obtained after 1930 have been used in clinical trials, with varying degrees of success. All of these ‘late’ BCG strains are lacking the genomic region RD2 (encoding the antigenic proteins MPB64 and CFP21), and have mutations in mmaA3, Rv3676, and sigK. Whether further mutations in these strains may account for their variable efficacy in clinical trials remains to be determined. The availability of the complete genome sequence for BCG Pasteur 1173 will serve as an important resource for such studies.31
EFFICACY OF BCG VACCINES The clinical efficacy of a vaccine is measured in terms of the percentage reduction in disease among vaccinated individuals that is attributable to vaccination. This efficacy represents a composite outcome of three events: 1. the proportion of vaccine ‘take’; 2. the degree of vaccine protection; and 3. the duration of protective immunity. Protective efficacy is best measured in human randomized clinical trials, but unfortunately, the field trials of BCG vaccines have provided considerable variability in estimated protection. This has stimulated further ongoing research to better understand the nature of BCG-induced immunity. As a result, much of what is known about BCG vaccines in humans comes from observational data (cohort studies and case-control studies) and most of what is understood about mechanism of action comes from experimental models in small mammals. Because of these considerations, we will try to note, where applicable, the nature of the data cited, and provide ranges of protection rather than precise numbers. Unlike most vaccines, for which there is a validated surrogate of clinical protection, in the case of BCG immunization there is no simple laboratory or clinical test that can demonstrate that someone has been effectively immunized. In the early twentieth century, the use of Mantoux skin testing was advanced as a marker of vaccination, based on epidemiological reasoning: nurses who were Mantouxnegative upon entering a high-risk environment had elevated rates of
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TB compared to Mantoux-positive nurses. Hence, the goal of BCG vaccination was to convert their Mantoux test to positive.32 However, in an analysis of clinical trial data, Comstock was unable to reveal an association between the proportion of subjects with a positive purified protein derivative (PPD) weeks after vaccination and the ultimate efficacy over 10- to 20-year clinical trials.33 To address this deficiency, researchers have attempted two broad approaches: 1. to describe the nature of immunity observed during contained infection, such as after BCG vaccination or in persons with latent M. tuberculosis infection; or 2. to describe the immune defects in humans that clearly render them susceptible to mycobacterial disease. Ironically, some of the most compelling data on immune defects are derived from infants who received BCG vaccines, as their inability to contain attenuated vaccine has helped uncover a number of critical steps in anti-mycobacterial immunity.34 From these children with primary immune deficiencies, along with observations of elevated rates of TB in individuals with HIV/acquired immunodeficiency syndrome (AIDS) and those receiving tumour necrosis factor (TNF)-a inhibitors, one can now safely state that TNF-a, CD4 T cells, and elements of the interleukin (IL)-12interferon (IFN)-g axis are critical in the containment of mycobacterial infection. However, while the absence of such immune responses is clearly associated with an elevated risk of mycobacterial disease, it has not been shown that vaccine-induced increases in IFN-g, IL-12, TNF-a, or CD4 T cells provide clinical protection. This is why one of the major aims of a large ongoing clinical trial in South African infants is to look for novel immune markers that distinguish vaccinated children who have an elevated or reduced rate of developing subsequent TB (Aeras Foundation, SATVI, Hussey GD, Hanekom WA, personal communication). In the absence of a surrogate that can be measured after immunization, the most solid data on BCG protection comes from large, randomized clinical trials. Despite the definitive architecture of these studies, the results have been strikingly variable, with efficacy against adult pulmonary disease ranging from no protection to 80% reduction in disease. Large trials were set up by the British Medical Research Council (BMRC) and by the US Public Health Service (USPHS) in the early 1950s.35,36 It became evident that the strategy employed by the BMRC (Danish strain BCG, administered to tuberculin-negative 13 year olds) provided high efficacy against adult pulmonary TB. In contrast, the strain used by the USPHS (Park or Tice strains given to tuberculin-negatives of various ages) provided very little protection.37 In some of the early trials demonstrating protective effect, the strongest effects were observed in populations with exceptionally high annual risk (ARI) of M. tuberculosis infection. These results were, however, not replicated in large Indian trials, where no protective effect due to BCG was observed in a setting with a high ARI.38 These variable data have stimulated a number of hypotheses to explain the observed results. However, the number of proposed explanatory variables exceeds the number of studies, so metaregression is unlikely to resolve this controversy. In addition, biological material was not banked in these earlier studies, such that formal comparison of retained seed lots of vaccines used in different studies cannot be undertaken. Instead, the broadest approach to understanding the data and forming a semi-coherent picture that may explain results in field trials is to incorporate data from case-control studies and animal experiments into a working model of BCG immunization.
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One important feature of BCG vaccination is that, where data are available, there appears to be a trend that the greatest protection is observed in the youngest subjects, and against extrapulmonary disease. In one meta-analysis of BCG studies, the average efficacy of BCG vaccination was estimated at 0.50, but in children, the overall protective effect of BCG against all TB was 0.74.39 An independent group has also meta-analysed randomized controlled trials and observational studies. They found that the protective effect of BCG against tuberculous meningitis and miliary TB was 0.86 in clinical trials and 0.75 in case-control studies. In contrast, the protective effect against pulmonary disease was found to be lower and more heterogeneous.40 The most recent meta-analysis confirmed these findings, with a summary estimate of a BCGinduced protective effect of 73% (67–79%) against tuberculous meningitis and 77% (58–87%) against miliary disease in children.41 In a recent before-and-after South African study assessing BCG efficacy following a switch in local vaccination policy from percutaneously administered BCG Tokyo strain (PC) to intradermally administered Danish strain BCG (ID), the total incidence of TB in children did not decline (incidence rate 866/100,000 in the PC group (95% CI 821–914) compared to 858/100,000 in the ID group (95% CI: 814–914); however, the rate of extrapulmonary disease was significantly lower in children in the ID group than in the PC group (4.7 vs 8.6%).42 These data from clinical studies are consistent with a working model where BCG prevents dissemination of M. tuberculosis, and therefore has a role not in preventing M. tuberculosis infection, but rather, in preventing progression and dissemination of the infection. Assuming that this is the only role of BCG, one can extract two messages about BCG, depending on one’s perspective. If one considers TB a contagious disease, the paucity of evidence that BCG interrupts transmission of infection by adults with pulmonary TB would argue for a relatively ineffective vaccine. On the other hand, given the high morbidity and mortality of invasive forms of TB in young children, the use of BCG in newborns still represents a cost-effective intervention, with recent estimates of one case of TB meningitis being prevented for every 3,435 vaccinations (range: 2,771–4,177) and one case of miliary TB being prevented for every 9,314 vaccinations (range: 6,172–13,729). Based on these analyses, at US$2–3 per dose, BCG vaccination costs just US$206 ($150–272) per year of healthy life gained.41 BCG revaccination has not been associated with increased protective effect.43 The most commonly cited reason for the variable efficacy of BCG vaccination stems from the observed negative association between responsiveness to non-tuberculous mycobacterium (NTM) and protection afforded by BCG in observational studies. Of note, the measurement of mycobacterial experience remains an inexact science, since: 1. the different modalities generate different results, as seen when comparing traditional skin-testing and blood-based IFN-g release assays;44 and 2. the molecular constitution of most mycobacterial preparations used as sensitins is unknown.45 Moreover, NTM PPD does not specifically indicate exposure to that mycobacterium, as considerable cross-reactivity occurs. Therefore, it appears safest to refer to individuals as mycobacterialexperienced, rather than exposed to NTM, and to then analyze data from the vantage of whether individuals had evident immune responses to mycobacterial antigens prior to vaccination. In a study contrasting subjects in Malawi and the UK, individuals with
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evidence of prior exposure to mycobacterial antigens had blunted immune responses to BCG.46 These findings are supported by animal models which show that prior sensitization with M. avium can prevent replication of the BCG vaccine, and thereby prevent the generation of BCG-induced protection.47 While these data provide a compelling explanation for how pre-sensitization can affect BCG vaccination; it is noteworthy that the majority of BCG vaccination is done within the first days after birth in most countries, so that the degree of such exposure is expected to be small. Recently, a distinct experimental model for the converse scenario was developed. Flaherty and colleagues were able to show that M. avium exposure by the oral route altered the efficacy of prior BCG vaccination when measured by protection against an aerosol challenge of M tuberculosis studies.48 Together with the results of the field trials in Malawi and other sites, these findings show that immunological effects of different mycobacterial exposures require further investigation, both in terms of their capacity to provide protection against natural mycobacterial disease and based on their modulation of vaccine-induced immunity. On the basis of the demonstrated differences in protective efficacy in field trials in different settings, respective public health agencies have established their own distinct protocols for vaccination. In the UK, routine BCG vaccination is recommended for tuberculin-negative adolescents, whereas BCG has never been recommended for routine use in the USA, but was restricted to certain high-risk populations only.2 BCG vaccination policies currently differ greatly between countries, including: 1. BCG only at birth or at first contact with health services, the current recommendation of the WHO Expanded Programme on Immunization (EPI) and the policy currently most widely used in developing countries; 2. BCG given once in childhood, e.g. in school-aged children, as in the UK, where BCG was until recently given routinely to tuberculin-negative adolescents;49 3. repeated or booster BCG; and 4. no routine BCG use, as in the USA and the Netherlands. Current International Union against Tuberculosis and Lung Disease (IUATLD) guidelines suggest criteria under which it may be reasonable for a country to shift from routine BCG vaccination to selective vaccination of high-risk groups only: 1. if an efficient notification system is in place and either: a. the average annual notification rate of smear-positive pulmonary TB is less than 5 per 100,000; or b. the average annual notification rate of tuberculous meningitis in children under 5 years of age is less than 1 per 10 million population during the previous 5 years; or 2. if the ARI is less than 0.1%.50
BCG VACCINES IN THE CONTEXT OF THE HIV EPIDEMIC RISK OF TUBERCULOSIS IN HIV-INFECTED INDIVIDUALS Over the past two decades, the TB pandemic has been exacerbated by the HIV pandemic, particularly in developing countries. UNAIDS estimates that every year, between 570,000 and 740,000 children are newly infected with HIV (the vast majority by mother-to-child transmission).51 More than 90% of these
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BCG: History, evolution, efficacy, and implications in the HIV era
infections occur in sub-Saharan Africa. HIV-infected adults are at increased risk of TB, particularly in highly endemic settings. This risk persists even in the presence of antiretroviral therapy, likely due to only partial restoration of cellular immunity to mycobacterial antigens.52 The risk of progression to TB following M. tuberculosis infection in HIV-infected children is at least six- to eightfold higher than that in uninfected children,53 with an incidence of TB of 9.2% (95% CI: 0.14–0.97) recently recorded in South African HIV-infected children in the absence of isoniazid preventative therapy.54 Reports of neonatal TB in BCGvaccinated infants born to HIV-infected women have further raised concerns regarding the risk of TB very early in life in HIV-exposed infants.55 Of key importance is the observation that in non-HIV-infected adults, not even natural infection and disease with M. tuberculosis affords protection against future TB episodes, as has been demonstrated in settings with high TB incidence. Verver et al. have shown that non-HIV-infected adults with a previously documented TB episode in South Africa, a setting highly endemic for TB, were at higher risk of future TB episodes.56 As both multiple TB episodes with different strains (exogenous reinfection and reactivation disease) and simultaneous disease with multiple strains of M. tuberculosis have been demonstrated in settings with high rates of M. tuberculosis transmission,57 it is therefore not surprising that BCG vaccination during infancy may not afford adequate protection against adult pulmonary disease. However, the use of alternative preventative strategies for TB in HIV-infected individuals such as isoniazid preventative therapy has been associated with reduced TB incidence in HIV-infected adults and children.54,58 The long-term efficacy and feasibility of such strategies in highburden settings are currently unknown.
UNCERTAIN EFFICACY OF BCG IN THE PRESENCE OF HIV As most large BCG trials were conducted in the pre-HIV era or in settings where HIV prevalence was very low, epidemiological evidence of the protection of BCG in HIV-infected individuals is extremely limited.2 It is plausible that when a specific T-cell mediated response is required for control of haematogenous spread of M. tuberculosis, the suppression of T-cell immunity as a result of HIV may render this defence inadequate. In HIV-infected adults, one case-control study demonstrated a modest BCG protective effect in 88 HIV-infected adults with TB and 88 matched non-diseased controls. The level of protection was 22% (OR 0.78; 95% CI 0.48–1.26) and the protective effect was significantly stronger against extrapulmonary than pulmonary disease.59 Similarly, in HIV-infected children, extremely limited data exist on BCG protective efficacy. No protective effect due to BCG vaccination was found in HIV-infected children in a Zambian retrospective case-control study of 116 TB cases and 154 non-diseased controls (OR 1.0, 95% CI 0.2–4.6), but BCG was associated with a 59% protective effect (OR 0.41, 95% CI 0.18–0.92) in non-HIV-infected children.60 Similar to these findings, Fallo et al., in a retrospective study including a 12-year follow-up period, of 374 HIV-infected children in Argentina found no significant difference in the incidence of TB in children who routinely had BCG versus those who were not vaccinated (14 vs 11%).61 Limitations of such retrospective studies on BCG efficacy in HIV-infected children include the use of BCG scarring as a surrogate of BCG-induced protection against TB, and
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potential bias due to selective non-vaccination. Ota et al. have demonstrated a tendency for reduced BCG scarring in HIVinfected compared to non-HIV-infected Gambian children;62 this may lead to an underestimate of the true protective effect of BCG in HIV-infected children in epidemiological studies, or may reflect a true tendency for reduced BCG-induced immune responses in HIV-infected children. Very limited data exist on longitudinal clinical and immunological profiles in HIV-exposed or -infected infants vaccinated with BCG. A study of 6-week-old infants born to HIV-infected mothers who escaped HIV infection found that IFN-g responses to BCG and M. tuberculosis PPD were of a lower magnitude than responses observed in HIV-unexposed infants.63 These findings suggest that even HIV exposure may alter the host mycobacterial immune response. The long-term clinical significance of these findings and its relation to BCG efficacy in infants in high-burden HIV settings are not yet known. There is an urgent need to assess the protective effect of BCG vaccination in HIV-exposed and -infected children. In the light of its widely accepted efficacy against disseminated childhood TB in non-HIV-infected children, the implementation of placebo-controlled trials to assess BCG efficacy in HIV-infected children is difficult, and is further complicated by the fact that the HIV status of vertically infected infants is not known at birth, when BCG vaccination is usually given in developing countries.
BCG SAFETY IN THE CONTEXT OF HIV INFECTION: BCG ADVERSE EVENTS In the pre-HIV era, BCG was regarded as a reactogenic but safe vaccine, and the most severe BCG vaccine adverse event, disseminated BCG disease (BCG-osis), was very rarely seen, with a reported frequency of less than 5 per 1 million vaccinees.2 Where an underlying diagnosis was secured, these cases often involved children with congenital cellular immune deficiency, such as severe combined immunodeficiency (SCID), chronic granulomatous disease, diGeorge syndrome, IFN-g receptor deficiency, and IL-12 deficiency.64,65 A case of reactivation disseminated BCG disease was reported in a 30-year-old HIV-infected male who was vaccinated with BCG during infancy.66 In a subsequent multicentre study, the risk of disseminated BCG disease in adults with severe HIV-related immune suppression and who were vaccinated with BCG in infancy was shown to be very low.67 However, the major public health concern regarding BCG and HIV safety results from its potential risk in HIV-infected children, and mainly in developing countries. WHO currently recommends that BCG be given to all asymptomatic infants born to HIV-infected mothers in settings with high TB incidence. This policy has practical limitations, as most HIV-exposed infants, if HIV-infected, are infected perinatally, and are therefore asymptomatic at birth. Reliable infant HIV infection status is usually only determined from 3 weeks postnatally onwards. In the past decade, several reports from developing countries including Argentina and South Africa have emerged, suggesting that BCG may pose a serious risk of local and disseminated disease to HIV-infected infants, especially in those infants with rapid HIV disease progression early in life.61,68 In the light of such reports and growing concern, WHO has recently qualified its recommendations for BCG vaccination in HIV-exposed infants to also include prospective follow-up of HIV-exposed infants vaccinated with BCG at birth to assess for
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BCG adverse events,69 and has further stated that the risk of BCG may outweigh the benefits in HIV-infected children.70 Although universal follow-up of HIV-exposed infants for BCG adverse events in settings with limited resources and other major paediatric health burdens is not always feasible, improved surveillance data on BCG adverse events, especially in HIV-infected children, is essential. Potential future policy considerations include delaying BCG vaccination in infants born to HIV-infected mothers until the infants’ HIV status is known. The feasibility, safety, and implementation of such policies are currently unknown.
DIAGNOSIS AND MANAGEMENT OF BCG ADVERSE EVENTS WHAT IS A NORMAL REACTION TO BCG VACCINATION? The normal evolution following intradermal BCG vaccination in infants is a small area of redness at approximately 3 weeks, followed by a raised papule with slight redness at 6-10 weeks, followed by a shallow ulceration with crusting at 14 weeks (Fig. 74.2).
WHAT ARE BCG ADVERSE EVENTS? BCG adverse events range from localized and less serious complications, to systemic or disseminated BCG disease. The risk of BCG adverse events varies with strain type, physical-chemical properties, route of administration, vaccine bacillary load, and the underlying immune condition of the patient.2 For the diagnosis and classification of BCG adverse events, see Fig. 74.3.
GENERAL PRINCIPLES FOR THE DIAGNOSIS AND MANAGEMENT OF BCG ADVERSE EVENTS Diagnostic investigation of suspected BCG adverse events should be guided by the level of resources available. In general, the management of BCG adverse events should be guided by the underlying immunological condition of the patient; more aggressive
investigation and management of adverse events is warranted in patients with underlying immune deficiency. In the presence of immune suppression, it is important to maintain an index of suspicion for systemic BCG adverse events, especially where local or regional BCG manifestations are present. The most specific diagnostic result is a positive culture, so where possible, samples (sputum, biopsies, blood, as clinically indicated) should be obtained for mycobacterial culture. A clinical isolate can then be used to speciate the cause of disease (BCG vs virulent member of the M. tuberculosis complex) and to obtain antibiotic susceptibility results. Even where routine mycobacterial culture is available, accurate differentiation of M. tuberculosis complex isolates is difficult, and identification of BCG is best done based on polymerase chain reaction (PCR) for the RD1 region lost during the original attenuation of BCG.71 BCG strains, as M. bovis strains, are inherently resistant to pyrazinamide and some strains (e.g. Danish strain 1331, Statens Serum Institute) have demonstrated low or intermediate grade resistance to isoniazid.72 Antituberculous monotherapy for serious BCG adverse events is not recommended, and since speciation of the isolate can take time, one can consider most serious cases to be possible M. tuberculosis until proven otherwise. Therefore, management typically involves multidrug regimens, as is the case for standard TB treatment, along with monitoring for drug toxicity, and the precise combination of drugs to use is tailored as susceptibility data are provided. As cases of both M. bovis BCG and M. tuberculosis (e.g. concurrent BCG adenitis and pulmonary TB) have been reported, the presence of BCG does not eliminate the possibility of active TB. Algorithms to classify, diagnose, and manage different BCG adverse events in children are outlined in Figs 74.3 and 74.4.70 Similar broad management principles may also be applied to adults with serious BCG adverse events. Routine reporting of serious BCG adverse events to regional, national, and international EPI or other public surveillance teams is of paramount importance. Notification should also include information on the immune status of the patient. It is important to adhere to standard case definitions to classify local, regional, and systemic BCG adverse events, to enhance surveillance and improve case management.
CLASSIFICATION OF BCG ADVERSE EVENTS LOCAL BCG REACTIONS
Fig. 74.2 The normal evolution of BCG ulceration at 14 weeks following intradermal vaccination with Danish strain (1331) at birth in the right deltoid region.
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Case definition: a local process at the site of vaccination. This includes a BCG injection abscess (at least 10 10 mm2 diameter) and severe or persistent BCG scar ulceration beyond 20 weeks following vaccination.72 The proportion of individuals vaccinated who develop local BCG reactions is not well quantified. Almost all correctly administered intradermal BCG vaccinations will lead to a minor local reaction (erythema, induration, and tenderness). Non-infected or ‘cold’ injection abscesses may be associated with programmatic errors such as inadequately reconstituted BCG vaccine, or error in administration, or may constitute a true biological reaction. Infected lesions can occur from non-sterile technique or secondary bacterial infection. Management: It is rare for localized reactions to require investigation or therapy. In general, local reactions should be left untreated and are expected to resolve spontaneously. Reassurance
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Local BCG disease A local process at the site of vaccination. This includes any of the following: BCG injection site abcess conforming to EPI definitions: ³10 mm ¥ 10 mm or Severe BCG scar ulceration beyond 14 weeks
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Dual disease with tuberculosis and BCG Dual disease with M. tuberculosis and M. bovis BCG may occur, e.g. BCG regional disease and pulmonary M. tuberculosis
Regional BCG disease Involvement of any regional lymph nodes or other regional lesions beyond the vaccination site: ipsilateral axillary, supraclavicular, cervical and upper arm glands. Lymph node involvement must conform to EPI definitions of 15 mm ¥ 15 mm and may include enlargement, suppuration and fistula formation. Background: Ipsilateral axillary lymph nodes are unlikely to be due to another cause in children < 1 year of age. Supraclavicular and cervical lymph nodes require exclusion of other causes such as tuberculosis or malignancy.
Rights were not granted to include this content in Distant BCG disease BCG IRIS book. electronic Involvement of any site beyond a local ormedia. regional Please refer to the printed ipsilateral process. This includes any of the following: Immune reconstitution inflammatory syndrome BCG confirmed from at least one distant site beyond the (IRIS) is defined as BCG disease that presents vaccination site, e.g. pulmonary secretions (gastric in an HIV-infected child within 3 months after aspirate, tracheal aspirate), cerebrospinal fluid, urine the initiation of highly active antiretroviral osteitis and distant skin lesions. therapy (HAART), with/without immunological or viral proof of immune reconstitution Background: The presence of clinically relevant systemic symptoms, e.g. fever, may be helpful. The prescence of Identical criteria apply for local, regional, distant symptoms in HIV-infected or other immune compromised or disseminated disease, e.g. Regional disease children may be non-specific; a high index of suspicion is IRIS. therefore required.
Fig. 74.3 Revised classification of complications following BCG vaccination in children.68
Disseminated disease BCG confirmed from > 1 remote site, as described under distant disease, and/or from at least one blood or bone marrow culture. Background: The presence of clinically relevant systemic symptoms, e.g. fever, may be helpful. The presence of symptoms in HIV-infected or other immune compromised children may be non-specific; a high index of suspicion is therefore required.
and follow-up should be provided. Ulcers or abscesses that enlarge or are clinically infected (increasing erythema, induration, tenderness) or are associated with systemic symptoms and signs should be investigated. A fine needle aspiration (FNA) of a local abscess may be diagnostic and therapeutic. All specimens from complicated local lesions should be sent for appropriate testing. The evidence for oral medications is very limited. Most experts do not recommend any drugs to treat local lesions. If the clinical suspicion is high for an infected abscess and bacterial superinfection is suspected or confirmed, appropriate antibiotic therapy should be considered. Local complications in immune compromised infants warrant further investigation.
REGIONAL BCG DISEASE (BCG ADENITIS) Case definition: Involvement of any regional lymph nodes or other regional lesions beyond the vaccination site. If BCG vaccine is administered intradermally or percutaneously in the recommended site over the insertion of the lower deltoid insertion, the ipsilateral axillary nodes are most commonly involved. Other lymph node involvement may include supraclavicular, cervical, and upper arm glands. Small regional lymph nodes (15 15 mm2) are commonly palpable following BCG vaccination. BCG lymph node involvement must conform to EPI case definitions
Other BCG syndromes Rare syndromes following vaccination in which bacteria are identified (e.g. keloid formation and uveitis); these syndromes may have an immune basis.
(at least 15 15 mm2 in diameter) and may include enlargement, suppuration, and fistula formation. Most enlarged regional lymph nodes will present within 6 months following vaccination. However, delayed presentations may occur, particularly in immune-deficient individuals. Lymph nodes can remain enlarged for up to 10 months. BCG adenitis has been reported in both immune-deficient and immune-competent individuals. FNA is a useful procedure for the diagnostic confirmation of BCG adenitis and exclusion of other causes of lymphadenitis. Complications such as fistulation and tract formation are extremely rare.72 FNA or pus swabs with smear microscopy, culture, and sensitivity testing should be performed. Definitive molecular confirmation of BCG is recommended where available (see General Principles). The estimated percentage of infants with BCG adenitis is 0–17%.2 Suppurative lymphadenitis has been associated with outbreaks following vaccination policy changes, e.g. in the UK, where recent policy changes resulted in suppurative adenitis being observed in 310 per 100,000 vaccinated infants.73 In the case of suppurative lymphadenitis, the affected nodes soften. A fluid collection may be palpable, the overlying skin becomes adherent, and the lesion increases in size. Lymphadenitis that presents early and with suppurative changes within 2 months post-vaccination may be more likely to develop these complications.
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Management: In immunocompromised patients, there is a risk of BCG dissemination beyond the regional lymph node. Classification of BCG lymphadenitis as non-suppurative or suppurative can help direct the course of management. Non-suppurative lymphadenitis, where the nodes remain small and firm, should be left untreated and reassurance and follow-up provided to the patient. Untreated suppurative lymphadenitis will heal spontaneously in the majority of patients. The aim of any therapy should be to reduce the risk of complications and shorten the duration to healing. Therapeutic repeated FNA may be beneficial in the treatment of suppurative lymphadenitis,74 but the evidence is limited. Oral antituberculous therapy is not recommended in immunocompetent
individuals. In immunocompromised individuals, medical and/or other therapy may be necessary, due to the potential risk of dissemination beyond the regional lymph node. A combination of four drugs is indicated in such patients (see treatment algorithm, Fig. 74.4). Intralesional instillation of drugs such as isoniazid has been described, but this should not be encouraged, as evidence in support of this practice is very limited. Surgical excision is rarely necessary and should be reserved for extreme cases when aspiration is inadequate, e.g. matted, recurrent, large suppurative or multiloculated nodes. Surgical excision in such cases may lead to earlier resolution.75 The risks of surgery and anaesthesia should be considered in systemically ill and immunosuppressed patients.
A. All children Full history and clinical assessment, including documentation of size and location of local and regional BCG lesions. Note the presence or absence of a BCG scar and whether BCG was given. Fine needle aspirate for mycobacterial culture HIV testing B. All HIV-infected children or other suspected/proven immune deficiency Chest radiography (antero-posterior and lateral) Minimum two gastric washings for mycobacterial culture Mycobacterial blood culture if febrile (TB Bactec) CD4+ T lymphocyte count and viral load, if applicable and not done in prior 2 months Full blood and differential count Baseline liver function tests for monitoring of toxicity Refer to infectious diseases service C. Additional investigations for HIV-related and other immune deficiencies with suspected distant or disseminated BCG diseases As in A and B and: Bone marrow aspirate/biopsy for mycobacterial culture Mycobacterial blood culture (even if afebrile) Abdominal ultrasound for intra-abdominal lymphadenopathy Radiography if osteitis is suspected Other systemic investigations as clinically indicated BCG confirmation: M. bovis BCG should be confirmed by culture and PCR or by culture and biochemical methods.
Antimycobacterial drugs: Isoniazid (INH) 15 20 mg/kg/day Rifampicin (RMP) 20 mg/kg/day Pyrazinamide (PZA) 2025 mg/kg/day (2 months, or until tuberculosis excluded, as TB often co-exist; BCG is PZA-resistant) Ethambutol (EMB) 20 25 mg/kg/day Ofloxacin (OFL) 15 mg/kg/day or Ciprofloxacin 30 mg/kg/day Local or regional BCG disease Treat medically: Consider using the above five drugs until disseminated disease excluded (if suspected) For local/regional disease INH, RMP, EMB (and PZA) until TB excluded Consider therapeutic aspiration if node fluctuant 2 4 weekly follow-up; if no improvement, or deterioration of adenitis after 6 weeks antituberculous therapy, consider excision biopsy If on HAART, ensure HAART is antituberculous-drug compatible Refer to infectious disease service Monitor for drug toxicity Notify as vaccine adverse event to the Provincial Expanded Programme on Immunization (EPI) if fulfilling case definition B. Suspected or confirmed distant or disseminated BCG disease Treat medically as above use five drugs including PZA until TB excluded Expedited initiation of HAART Monitor for drug toxicity Report as vaccine-related adverse event to EPI C. Local or regional disease not conforming to EPI criteria, local or regional BCG IRIS with no suspected dissemination Observe, follow closely for progression Report as vaccine-related adverse event to EPI
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Fig. 74.4 Suggested diagnostic work-up and management of BCG adverse events in children.
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SYSTEMIC BCG DISEASE Systemic BCG disease represents the most serious BCG vaccine adverse event and has mostly been reported in patients with underlying immune deficiency. BCG osteitis, an adverse event resulting from spread of the organism distant to the vaccination site, and therefore a form of systemic disease, has, however, been documented in both immunocompromised and immunocompetent patients. Although a distinction has been made between ‘distant’ and ‘disseminated’ BCG disease in immunocompromised children in the recent literature based on the level of diagnostic certainty achieved,65 the pathogenesis is identical, i.e. haematogenous dissemination of BCG beyond the vaccination site. The medical management of distant and disseminated BCG disease is therefore also identical. For surveillance purposes, it is, however, helpful to classify these disease entities separately.
Distant BCG disease Case definition: Involvement of any site beyond a local or regional ipsilateral process. BCG is confirmed from at least one distant site beyond the vaccination area, e.g. pulmonary sections, bone and distant skin lesions. This most commonly includes disease entities such as BCG osteitis and pulmonary BCG disease. The presence of systemic systems are helpful, e.g. pyrexia of unknown origin. The presence of non-specific systems is helpful, but the presentation may be non-specific. Any diagnosis of distant BCG infection should signal a search for an underlying immune deficiency and should include HIV testing. Definitive molecular confirmation is recommended where available (see General principles). BCG-osteitis Case definition: BCG-osteitis is a well-documented BCG adverse event that has been reported in both immunodeficient and immunocompetent patients. Immunodeficient individuals may be at higher risk of multiple bony infections or recurrences after therapy. The clinical presentation may be delayed (> 12 months) following vaccination. BCG-osteitis can affect many different bony sites and is diagnosed with appropriate investigations including imaging and biopsy. Estimated incidence: In immune competent vaccinees, Lotte et al. described the global incidence of BCG-osteitis of all age groups as 0.57 per million in European countries.76 The highest incidence occurred in Sweden and Finland, which reported osteitis outbreaks between 1971 and 1978, associated with a change of manufacturer of the BCG Gothenburg strain.77,78 This was the main reason for Sweden’s discontinuation of the routine BCG vaccination program in 1975. BCG osteitis has been rarely reported in HIV-infected children. Management: The recommended management of isolated BCG-osteitis is a four-drug oral antituberculous regimen at adequate dosages (see Fig. 74.4). Some cases may require additional surgical management. The majority of 6- to 9-month treatment regimens in immunocompetent individuals report good outcomes.79 The risk of bony deformities or growth disturbances is low. Treatment of the underlying immunological condition, where present, is essential. Pulmonary BCG disease Case definition: Pulmonary BCG disease has only been reported in immunocompromised patients and is one of the more commonly reported forms of distant BCG disease, especially in HIVinfected infants. The diagnosis is usually made through repeated culture of pulmonary secretions, such as gastric aspirates or tracheal
Fig. 74.5 Chest radiograph demonstrating mediastinal adenopathy in a 6-month old HIV-infected infant with pulmonary (distant) BCG disease. The initial clinical diagnosis was that of pulmonary TB and multidrug therapy was initiated. Mycobacterium bovis BCG was subsequently confirmed through PCR testing of M. tuberculosis complex cultures from gastric aspirates.
aspirates. The radiological appearance is very similar to that of pulmonary TB, with mediastinal adenopathy and parenchymal lesions in the majority (see Fig. 74.5).68 Further systemic investigations should be done as clinically indicated (see Disseminated BCG disease); the management is identical to that of disseminated BCG disease.
Disseminated BCG disease (BCG-osis) Case definition: Mycobacterium bovis BCG is confirmed from more than one remote site, as described under distant disease, and from at least one blood culture, cerebrospinal fluid, or bone marrow specimen. Definitive molecular confirmation is recommended where available (see General principles). Disseminated BCG disease will usually cause severe systemic illness, which may mimic septicaemia or severe end-organ disease. The presence of systemic symptoms is helpful, but the presentation may be non-specific. Estimated incidence of distant and disseminated BCG disease in HIV-infected children: Recent preliminary estimates indicate a high risk of distant or disseminated BCG disease in South African HIV-infected infants of 110–417/100,000 vaccinees.80 This is several-hundredfold higher than the reported incidence in the preHIV era; further prospective surveillance is likely to yield more accurate data. Management of distant and disseminated BCG disease: The reported case fatality of distant or disseminated BCG disease in immunocompromised individuals ranges up to 80%. In a recent case series of 25 South African children with BCG disease including eight with distant or disseminated disease, the median age at BCG diagnosis in HIV-infected children was 8.47 months (range 3–21 months) and mortality was 75% in those children with distant or disseminated disease. Antiretroviral therapy (ART) was significantly associated with survival in HIV-infected children.68 Rapid and full investigation must therefore be undertaken when distant or disseminated BCG infection is suspected. In infants or children, this includes, in addition to FNA of local or regional lesions,
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a minimum of two gastric washings or sputa for mycobacterial culture; mycobacterial urine, blood, or bone marrow culture; chest radiography; and baseline complete blood count. Further investigation should be guided by the clinical presentation and available resources. It is important to remember that, in settings where the risk of TB is high, BCG complications may occur simultaneously with TB, e.g. BCG adenitis with concurrent pulmonary TB. Initial antituberculous regimens should be rapid and aggressive. Initial management should therefore also include pyrazinamide until such time TB is excluded (usually approximately 2 months). Any diagnosis of disseminated BCG disease should signal a search for an underlying immune deficiency including HIV infection, if not already known. A four-drug regimen should be used including isoniazid, rifampicin, ethambutol, and ofloxacin or an alternative drug, and at adequate dosages. Treatment should be continued for at least 9 months. Patients should be monitored for drug interactions and drug toxicity. All cases require specialist management. Specific treatment of the underlying condition, e.g. ART in the presence of HIV-related immune compromise, is essential. Pulmonary BCG disease and osteitis in immunocompromised children should be managed as aggressively as confirmed disseminated BCG disease, as it represents distant spread beyond the local lesion or regional lymph node in the presence of immune compromise (see Fig. 74.4).
BCG IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME Case definition: BCG immune reconstitution inflammatory syndrome (BCG IRIS) is defined as BCG disease that presents in an HIV-infected individual within 3 months following initiation of ART, with/without immunological or viral proof of immune reconstitution.81 Identical diagnostic criteria apply as for local, regional, distant, or disseminated BCG adverse events. The mechanism of BCG IRIS is unclear but may be a deregulated, vigorous immune response to the latent organism soon after ART is initiated and not necessarily indicate a true reactivation of infection. BCG IRIS usually presents with a vaccine-related local abscess and/or suppurative lymphadenitis following ART (see Fig. 74.3). To date, reports of BCG IRIS indicate that the risk of disseminated BCG disease or fatality is low in HIV-infected children with immune recovery. More accurate surveillance of this condition, which is likely to become more common as ART becomes more available in HIV-endemic settings, will contribute to more complete data on the incidence, management, and outcome. It is important to note that IRIS due to BCG is described only in HIV-infected individuals recently started on ART. The term BCG IRIS and its usual benign course should not be applied to non-HIV, immune-deficient conditions where immune reconstitution is achieved, for example in a patient with SCID who receives a bone marrow transplant. Experience is currently limited on immune reconstitution with BCG complications under nonHIV immune-deficient conditions (Dr. Tippi Mak, personal communication). Management: As BCG IRIS reports to date have been limited to local or regional disease only and outcomes have been favourable, BCG IRIS in HIV-infected children on ART may not always require antituberculous treatment if there is no evidence or suspicion of systemic spread. However, management should always be guided by the degree of immune suppression and clinical
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features and should be aggressive if clinically or immunologically indicated. Local or regional lesions should be carefully observed for progression, e.g. enlargement or suppuration. BCG IRIS patients should be closely monitored for the level of immune restoration and any systemic symptoms and signs of possible BCG disseminated disease.
OTHER BCG ADVERSE EVENTS Cutaneous lesions such as lupus vulgaris have been infrequently reported. Disseminated cutaneous lesions have been reported in immune-deficient individuals as part of distant or disseminated BCG disease and should be a signal to screen for an underlying immune-deficient condition. Other rare events associated with BCG vaccine include ocular lesions (conjunctivitis, choroiditis, optic neuritis), erythema nodosum, and large keloids. These rare associated events may reflect a hypersensitivity-type reaction and should be managed by specialist referral.
BCG ADVERSE EVENTS FROM USE AS A CHEMOTHERAPEUTIC AGENT BCG strains are used for immune chemotherapy of some adult cancers, in particular bladder carcinoma. Adverse events from intravesical BCG instillation including disseminated infections have been documented in these patients.82 Case reports of nosocomial infections from BCG chemotherapy strains have also occurred in patients whose therapies were cross-contaminated with BCG chemotherapy. These nosocomial cases were initially and erroneously attributed to BCG vaccine strains from the common history of vaccination.83 The misattribution was only confirmed by DNA techniques,84 again highlighting the improved diagnosis of BCG complications using molecular methods.
SUMMARY BCG remains a controversial topic, with a rich history, illustrating not only the development of global public health interventions, but also the evolution of both the organism itself and our understanding of the organism. Many uncertainties regarding the efficacy and mechanisms of action of BCG vaccines remain. Although the protective effect of BCG against disseminated TB in young children is reasonably well established, BCG vaccination in adults has demonstrated variable efficacy in clinical trials, and there is no convincing evidence for its protective effect in HIVinfected individuals, a population at high risk of TB disease progression following infection. The risk/benefit ratio of BCG in HIV-infected infants is unknown, but recent data indicate that the risk of serious BCG complications in HIV-infected infants in developing countries is exceptionally high. Improved access to HAART may modulate the risk of the most serious form of BCG adverse event, disseminated BCG disease. However, other entities such as BCG IRIS following initiation of HAART are likely to become more common. Despite being one of the oldest vaccines in use, the area of BCG vaccination will remain a key topic, both as a public health measure and as a comparator, as new TB vaccine candidates are brought forward towards clinical trials.
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REFERENCES 1. Girard MP, Fruth U, Kieny M. A review of vaccine research and development: tuberculosis. Vaccine 2005;23:5725–5731. 2. Fine PEM, Carneiro IAM, Milstien JB, Clements C. Issues relating to the use of BCG in immunization Programmes: A discussion document (WHO/V&B/ 99.23). Geneva: World Health Organization, 1999. 3. Comstock GW. Identification of an effective vaccine against tuberculosis. Rev Respir Dis 1988;138(2):479–480. 4. Fine PEM. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995;346(8986):1339–1345. 5. Doherty TM, Andersen P. Vaccines for tuberculosis: novel concepts and recent progress. Clin Microbiol Rev 2005;18(4):687–702. 6. von Behring E. Serum therapy in therapeutics and medical science. Nobel Lecture, 12 December 1901, Nobel Prize in Physiology or Medicine 1901. [online]. Accessed 7 March 2007. Available at URL: http://nobelprize.org/nobel_prizes/medicine/ laureates/1901/behring-lecture.html 7. Sakula A. BCG: who were Calmette and Guerin? Thorax 1983;38(11):806–812. 8. Comstock G. Prevention of tuberculosis. Bull Int Union Tuberc Lung Dis 1990–1991; 66(Suppl):9–11. 9. Calmette A, Boquet A, Negre L. Les variations naturelles de virulence du bacille tuberculeux. In: Masson et Cie (ed.) L’infection bacillaire et la tuberculose. Paris: Libraires de l’Acade´mie de Medecine, 1936: 735–738. 10. Calmette A. Preventive vaccination against tuberculosis with BCG. Proc R Soc Med 1931; 24:85–94. 11. Wallgren A. Intradermal vaccinations with BCG virus. JAMA 1928;91:1876–1881. 12. Heimbeck. Tuberculosis in hospital nurses. Tubercle 1936;18:97–99. 13. Greenwood M. Professor Calmette’s statistical study of BCG vaccination. Br Med J 1928;1:793–795. 14. Petroff SA. A new analysis of the value and safety of protective immunization with BCG (Bacillus Calmette-Guerin). Am Rev Tuberc 1929;20:275–296. 15. Wilson GS. Faulty production: use of wrong culture. In: Wilson, GS (ed.) The Hazards of Immunization. London: Athlone Press, 1967: 66–74. 16. Calmette A, Guerin C. Recherches experimentales sur la defense de l’organisme contre l’infection tuberculeuse. Ann Inst Pasteur 1911;25:625–641. 17. Zeyland J, Piasecka-Zeyland E. Sur la Vitalite du BCG dans l’Organisme Vaccine. Ann Inst Pasteur 1936;56:46–51. 18. Cole ST, Brosch R, Parkhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 1998;393:537–544. 19. Mahairas GG, Sabo PJ, Hickey MJ, et al. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J Bacteriol 1996; 178:1274–1282. 20. Behr MA, Wilson MA, Gill WP, et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 1999;284:1520–1523. 21. Gordon SV, Brosch R, Billault A, et al. Identification of variable regions in the genomes of tubercle bacilli using bacterial artificial chromosome arrays. Mol Microbiol 1999;32:643–655. 22. Behr MA, Small PM. A historical and molecular phylogeny of BCG strains. Vaccine 1999;17:915–922. 23. Tsolaki AG, Hirsh AE, DeRiemer K, et al. 2004. Functional and evolutionary genomics of Mycobacterium tuberculosis: insights from genomic deletions in 100 strains. Proc Natl Acad Sci USA 2004;101:4865–4870. 24. Pym AS, Brodin P, Majlessi L, et al. Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 2003;9:533–539. 25. Lewis KN, Liao RL, Guinn KM, et al. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille
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Calmette-Guerin attenuation. J Infect Dis 2003;187:117–123. Brosch R, Gordon SV, Buchrieser C, et al. Comparative genomics uncovers large tandem chromosomal duplications in Mycobacterium bovis BCG Pasteur. Yeast 2000;17:111–123. Keating LA, Wheeler PR, Mansoor H, et al. The pyruvate requirement of some members of the Mycobacterium tuberculosis complex is due to an inactive pyruvate kinase: implications for in vivo growth. Mol Microbiol 2005;56:163–174. Belley A, Alexander D, Di Pietrantonio T, et al. Impact of methoxymycolic acid production by Mycobacterium bovis BCG vaccines. Infect Immun 2004;72:2803–2809. Spreadbury CL, Pallen MJ, Overton T, et al. Point mutations in the DNA- and cNMP-binding domains of the homologue of the cAMP receptor protein (CRP) in Mycobacterium bovis BCG: implications for the inactivation of a global regulator and strain attenuation. Microbiology 2005;151:547–556. Charlet D, Mostowy S, Alexander D, et al. Reduced expression of antigenic proteins MPB70 and MPB83 in Mycobacterium bovis BCG strains due to a start codon mutation in sigK. Mol Microbiol 2005;56:1302–1313. Brosch R, Gordon SV, Garnier T, et al. Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci USA 2007;104(13):5596–5601. Epub 2007 Mar 19. Heimbeck J. Tuberculosis in hospital nurses. Tubercle 1936;18:97–99. Comstock GW. Prevention of tuberculosis among tuberculin reactors: maximizing benefits, minimizing risks. JAMA 1986;256(19):2729–2730. Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 2002;20:581–620. Hart PD, Sutherland I. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. Final report to the Medical Research Council. Br Med J 1977;2:293–295. Comstock GW. Field trials of tuberculosis vaccines: how could we have done them better? Control Clin Trials 1994;15:247–276. Comstock GW, Palmer CE. Long-term results of BCG vaccination in the southern United States. Am Rev Respir Dis 1966;93:171–183. Baily GV. Tuberculosis prevention trial, Madras. Trial of BCG vaccines in South India for tuberculosis prevention. Indian J Med Res 1980;72(Suppl):1–74. Colditz GA, Berkley CS, Mosteller F, et al. The efficacy of Bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analysis of the published literature. Pediatrics 1995;96:29–35. Rodrigues LC, Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol 1993;22:1154–1158. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 2006; 367:1173–1180. Mahomed H, Kibel M, Hawkridge T, et al. The impact of a change in bacille Calmette-Guerin vaccine policy on tuberculosis incidence in children in Cape Town, South Africa. Pediatr Infect Dis J 2006;25(12):1167–1172. Rodrigues LC, Pereira SM, Cunha SS, et al. Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet 2005;366(9493): 1290–1295. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4(12):761–776. Semret M, Bakker D, Smart N, et al. Genetic analysis of Mycobacterium avium complex strains used for producing purified protein derivatives. Clin Vaccine Immunol 2006;13:991–996.
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46. Black GF, Dockrell HM, Crampin AC, et al. Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi. J Infect Dis 2001;184(3):322–329. 47. Brandt L, Cunha JF, Olsen AW, et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun 2002;70:672–678. 48. Flaherty DK, Vesosky B, Beamer GL, et al. Exposure to Mycobacterium avium can modulate established immunity against Mycobacterium tuberculosis infection generated by Mycobacterium bovis BCG vaccination. J Leukoc Biol 2006;80(6):1262–1271. 49. Fine PEM. Stopping routine vaccination for tuberculosis in schools. Br Med J 2005;331(7518): 647–648. 50. International Union against Tuberculosis and Lung Disease. Criteria for discontinuation of vaccination programmes using Bacillus Calmette Guerin (BCG) in countries with a low prevalence of tuberculosis. Tuber Lung Dis1994;75:179–181. 51. Walker N, Grassly NC, Garnett GP, et al. Estimating the global burden of HIV/AIDS: what do we really know about the HIV pandemic? Lancet 2004; 363(9427):2180–2185. 52. Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS 2005;19(18):2109–2116. 53. Mukadi YD, Wiktor SZ, Coulibaly IM, et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cote d’Ivoire. AIDS 1997;11:1151–1158. 54. Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. Br Med J 2007;334(7585):136. 55. Pillay T, Sturm AW, Khan M, et al. Vertical transmission of Mycobacterium tuberculosis in KwaZulu Natal: impact of HIV-1 co-infection. Int J Tuberc Lung Dis 2004;8(1):59–69. 56. Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005;171(12):1430–1435. 57. Warren RM, Victor TC, Streicher EM, et al. Patients with active tuberculosis often have different strains in the same sputum specimen. Am J Respir Crit Care Med 2004;169(5):610–614. 58. Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004;(1):CD000171. 59. Arbelaez MP, Nelson KE, Munoz A. BCG vaccine effectiveness in preventing tuberculosis and its interaction with human immunodeficiency virus infection. Int J Epidemiol 2000;6:1085–1091. 60. Bhat GJ, Diwan VK, Chintu C, et al. HIV, BCG and TB in children: a case control study in Lusaka, Zambia. J Trop Pediatr 1993;39(4):219–223. 61. Fallo A, Torrado L, Sanchez A, et al. Delayed complications of bacillus Calmette-Guerin vaccination in HIV-infected children. [Abstract] Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. WeOa0104. 62. Ota MO, O’Donovan D, Marchant A, et al. HIV-negative infants born to HIV-1 but not HIV-2-positive mothers fail to develop a Bacillus Calmette-Guerin scar. AIDS 1999;13(8):996–998. 63. Van Rie A, Madhi SA, Heera JR, et al. Gamma interferon production in response to Mycobacterium bovis BCG and Mycobacterium tuberculosis antigens in infants born to human immunodeficiency virusinfected mothers. Clin Vaccine Immunol 2006; 13(2):246–252. 64. Casanova JL, Jouanguy E, Lamhamedi S, et al. Immunological conditions of children with BCG disseminated infection. Lancet 1995;346:581.
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65. Talbot EA, Perkins MD, Silva SF, et al. Disseminated bacille Calmette-Guerin disease after vaccination: case report and review. Clin Infect Dis 1997;24:1139–1146. 66. Armbruster C, Junker W, Vetter N, et al. Disseminated bacille Calmette-Guerin infection in an AIDS patient 30 years after BCG vaccination. J Infect Dis 1990;162(5):1216. 67. Marsh BJ, von Reyn CF, Edwards J, et al. The risks and benefits of childhood bacille Calmette-Guerin immunization among adults with AIDS. International MAC study groups. AIDS 1997;11(5):669–672. 68. Hesseling AC, Rabie H, Marais BJ, et al. Bacillus Calmette-Guerin vaccine-induced disease in HIVinfected and HIV-uninfected children. Clin Infect Dis 2006;42:548–558. 69. World Health Organization. BCG vaccine. WHO position paper. Wkly Epidemiol Rec 2004;79:27–38. [online]. Accessed 5 March 2007. Available at URL: http://www.who.int/wer/2004/wer7904/en/index. html 70. World Health Organization. Wkly Epidemiol Rec 2007;82(3):18–24. Global Advisory Committee on Vaccine Safety, 29–30 November 2006. 71. Talbot EA, Williams DL, Frothingham R. PCR identification of Mycobacterium bovis BCG. J Clin Microbiol 1997;35:566–569. 72. Hesseling AC, Schaaf HS, Victor T, et al. Resistant Mycobacterium bovis Bacillus Calmette-Guerin
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disease: implications for management of Bacillus Calmette-Guerin Disease in human immunodeficiency virus-infected children. Pediatr Infect Dis J 2004;23(5):476–479. Teo SS, Smeulders N, Shingadia DV. BCG vaccineassociated suppurative lymphadenitis. Vaccine 2005; 23(20):2676–2679. Banani SA, Alborzi A. Needle aspiration for suppurative post-BCG adenitis. Arch Dis Child 1994;71(5):446–447. Hengster P, Solder B, Fille M, et al. Surgical treatment of bacillus Calmette Guerin lymphadenitis. World J Surg 1997;21(5):520–523. Lotte A, Wasz-Hockert O, Poisson N, et al. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bull Int Union Tuberc Lung Dis 1988;63(2):47–59. Kroger L, Brander E, Korppi M, et al. Osteitis after newborn vaccination with three different Bacillus Calmette-Guerin vaccines: twenty-nine years of experience. Pediatr Infect Dis J 1994;13(2):113–116. Bottiger M, Romanus V, de Verdier C, et al. Osteitis and other complications caused by generalized BCGitis. Experiences in Sweden. Acta Paediatr Scand 1982;71(3):471–478. Sasaki Y, Nomura A, Kusuhara K, et al. Genetic basis of patients with Bacillus Calmette-Gue´rin osteomyelitis in Japan: Identification of dominant
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partial interferon-gamma receptor 1 deficiency as a predominant type. J Infect Dis 2002;185(5):706–709. Hesseling AC, Marais BJ, Gie RP, et al. The risk of disseminated Bacillus Calmette-Guerin (BCG) disease in HIV-infected children. Vaccine 2007; 25(1):14–18. Puthanakit T, Oberdorfer P, Punjaisee S, et al. Immune reconstitution syndrome due to bacillus Calmette-Guerin after initiation of antiretroviral therapy in children with HIV infection. Clin Infect Dis 2005;41(7):1049–1052. Lamm DL. Efficacy and safety of bacille CalmetteGuerin immunotherapy in superficial bladder cancer. Clin Infect Dis 2000;31(Suppl 3):S86–90. Vos MC, de Haas PE, Verbrugh HA, et al. Nosocomial Mycobacterium bovis-bacille CalmetteGuerin infections due to contamination of chemotherapeutics: case finding and route of transmission. J Infect Dis 2003;188(9):1332–1335. Van Deutekom H, Smulders YM, Roozendaal KJ, et al. Bacillus Calmette-Guerin (BCG) meningitis in an AIDS patient 12 years after vaccination with BCG. Clin Infect Dis 1996;22(5):870–871. Behr MA. BCG—different strains, different vaccines? Lancet Infect Dis 2002;2(2):86–92. Mostowy S, Tsolaki AG, Small PM, et al. The in vitro evolution of BCG vaccines. Vaccine 2003; 21(27-30):4270–4274.
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Contact tracing and follow-up Christian Lienhardt
INTRODUCTION Persons who are in contact with patients who have active pulmonary TB are at risk of Mycobacterium tuberculosis infection and disease. Therefore, together with activities related to case-finding and treatment, contact tracing is an important procedure aiming at reducing transmission of TB disease within the context of TB control programmes. The main goal of contact tracing is to identify, amongst contacts of infectious TB cases, secondary cases of active TB who would deserve treatment and individuals with latent TB infection (LTBI) who could benefit from preventive therapy. Appropriate follow-up of contacts identified either as TB cases or persons with LTBI is requested to ensure completion of curative or preventive therapy. The risk of transmission to contacts is dictated by epidemiological features pertaining to the characteristics of the index case (see Box 75.1), the organism, the susceptible host, the nature of the contact and the environment shared.1 Systematic assessment of the risk factors for disease transmission is therefore an integral part of contact investigation. Although based on a core of basic principles,2,3 contact tracing procedures must adapt to changing epidemiology features, both in low- and high-prevalence countries (such as the effect of the human immunodeficiency (HIV) epidemics), and integrate new cultural, linguistic and socioeconomic factors to address specific situations related to specific risk groups such as migrants, substance abusers or homeless persons. In the USA, Canada and Europe, contact investigation is recommended for all patients with suspected or confirmed TB, and procedures are well delineated.4,5 The situation seems to differ, however, in low-income countries, where recommendations vary widely and contact tracing is often not considered a priority in TB control programmes with limited resources. In this chapter, we will discuss: 1. the epidemiological background for contact investigation; 2. the objective and purposes of contact tracing; 3. the recommended step-by-step methodology for contact investigation; 4. the specific aspects of contact tracing in low- and highprevalence countries; and 5. the technologies used. We will then evaluate the potential obstacles to efficient contact tracing and will review the pertinent research questions to be addressed with the aim of improving the effectiveness of this procedure.
BACKGROUND EPIDEMIOLOGY The development of TB in man is a two-stage process in which a susceptible person exposed to an infectious TB case first becomes infected and may later develop the disease, depending upon various factors (Fig. 75.1). The endpoint of the chain (TB disease) depends on the succession of various factors influencing respectively the risk of exposure, the risk of infection and the risk of development of disease. Among persons exposed to an infectious TB case, the risk of becoming infected is primarily determined by the combined action of the infectivity of the source case, the degree and intensity of exposure to the case and the degree of susceptibility of the host.1 The infectivity of the case is a function of the frequency of cough, the density of bacilli in the sputum and the microbial ‘virulence’.6–9 The degree of exposure is determined by the proximity of contact between a susceptible person and the infectious TB case. Household studies conducted more than 30 or 40 years ago in both industrialized and non-industrialized countries showed that the risk of becoming infected increased with intimacy of contact with a TB case.10–12 Data from nosocomial outbreaks of TB in HIV-infected subjects suggest that susceptibility to infection is dependent on the health status of the individual,9 and studies have suggested that susceptibility to mycobacterial infection might be genetically modulated.13,14 It is generally estimated that about 10 persons are infected, on average, with tubercle bacilli during 1 year by one smear-positive case of pulmonary TB, but this depends on the prevalence of sources of infection in the population.15 In patients infected with M. tuberculosis, TB can develop at a variable time through reactivation of a previously acquired (latent) infection or through exogenous reinfection, and the time from infection to disease may range from a few weeks to a lifetime.16,17 Any condition modifying the balance established in the body between the tubercle bacilli and the host’s immune defence can have an impact on the risk of developing the disease: hence the effect of HIV infection, immunosuppressive treatment, diabetes, malnutrition and alcoholism. In addition, environmental factors that have an effect on the risk of infection and on the risk of disease (such as volume of shared air space, ventilation, crowding) may affect transmission of TB in a given population and thus ought to be considered within the process of contact investigation.18 The risk of developing disease after infection is much greater in the 5 years following infection and declines as the time interval since infection increases. In children under 5 years of age, the risk
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Box 75.1 Definitions used in contact screening Source (index) case Secondary case Contact investigation
TB contacts
A case of pulmonary TB (usually sputum smearpositive) believed to have transmitted infection to other persons. TB disease in a contact as a result of transmission from an identified index case. Process of conducting an epidemiological investigation in order to identify contacts of a (usually infectious) TB case, screen them for infection or TB disease and give treatment as appropriate. Persons who may have a risk of acquiring TB because they have shared air with the index case.
Natural history of TB Environmental mycobacteria Non-exposed
Tuberculin skin test Immunological markers
Exposure
Prevention ±BCG Post-exposure vaccine
Infection Preventive therapy BCG
Diagnosis Phenotyping Disease
Open PTB
Treatment
Fig. 75.1 Natural history of TB.
of progressive TB disease after primary infection has been shown to be high, reflecting probably high-dose challenge within the home environment. Then, the risk was shown to decrease up to 12 years old and to rise again in young adults. Once infected, the cumulative lifetime risk of developing disease was classically estimated to be approximately 10%.16 In HIV-infected persons, the risk of progression from LTBI to active TB is estimated at 10% per year.19–21
casual based on risk assessments (Fig. 75.2).4 In order to address issues related to the assignment of priorities to contact investigation, the National TB Controllers Association (NTCA) and the Centers for Disease Control and Prevention (CDC) issued recently a joint statement intending to provide guidelines concerning investigation of TB exposure and transmission and prevention of future TB cases through contact investigation.
DECISION TO INITIATE A CONTACT INVESTIGATION The decision to seek and evaluate contacts is usually recommended for forms of TB that are contagious, i.e. smear-positive pulmonary or laryngeal TB. Contact investigations of persons with smear- or culture-positive sputum and cavitary TB are assigned the highest priority. If time and resources permit, other pulmonary TB cases may be investigated if chest radiograph is consistent with pulmonary TB.
COLLECTION OF INFORMATION ON THE INDEX CASE Background information The initial assessment of the index case aims at collecting all relevant information in a systematic way. Information should be obtained, usually from the medical record or the treating physician, on the patient and disease characteristics: time of onset of symptoms, medical history (past personal or family episode of TB, earlier tuberculin skin test (TST) results), present clinical signs and symptoms, current medical factors (whether treatment started, presence of other medical condition such as diabetes, renal insufficiency, or treatment with immunosuppressing drugs, etc.), acid-fast bacilli (AFB) test results, chest radiograph results (extent of disease, cavity), other results of Household /residence environment
OBJECTIVES OF CONTACT TRACING In the frame of the newly launched Stop TB strategy to meet the Millennium Development Goals objectives, TB programmes have placed renewed emphasis on contact investigation to prevent emergence of further cases and curtail transmission of TB. In this context, the objectives of contact tracing are the following: 1. to identify persons exposed to a TB case who are at a greater risk of LTBI or of developing overt TB disease; 2. through appropriate screening, to identify contacts who are infected with M. tuberculosis (LTBI) and would benefit from preventive therapy; 3. through appropriate screening, to identify additional TB cases and ensure their access to full treatment; and 4. to identify the source of TB transmission for cases under investigation (especially in children), and initiate TB outbreak investigation if appropriate.
CONTACT TRACING IN LOW-PREVALENCE COUNTRIES The traditional approach to contact investigation is based on the ‘concentric circle method’, defining contacts as either close or
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Index patient
Leisure environment
Work/school environment
Close contacts (high priority) Other-than-close contacts (medium priority) Other-than-close contacts (low priority)
Fig. 75.2 The concentric circle approach for contact investigation. From Etkind and Veen (2000).4 Scientific Foundations of Urology Vol 1, Chapter 30 (eds. D. Innes Williams and G.D.Chisholm), pp 211–217. London, Heinemann. Figure 16.
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diagnostic tests (computed tomography scan, histology specimen) and demographic information. These elements will permit an evaluation of the infectivity of the index case and determine the infectious period that allows focusing the investigation on those contacts more likely to be at risk for infection. This period of infectiousness can be determined from the date of onset of symptoms. When a case is unable to remember when the symptoms started, it is usually recommended to define the period of infectiousness as beginning at least 3 months before treatment of the case started. This period ends when the index case has been receiving adequate treatment for at least 2 weeks, symptoms have improved and there are at least two consecutive negative sputum smears.
Patient’s interview Once the information above is collected, the patient can be interviewed, with the objective of assessing the TB transmission risk and determining likely contacts at risk of infection. The interview must take place as soon as possible after diagnosis of TB has been done, but should also leave time for the patient to adjust to the disruption caused by the illness. Establishing trust is fundamental to obtain relevant information, and good interview skills are necessary to collect information that might not be forthcoming spontaneously. Interview must be conducted in a professional way, respecting patient’s privacy, and in the language most suitable for good understanding. The interview should first confirm some of the points identified in the pre-interview period (see above), and complete information as needed. Then, information is collected regarding the transmission settings that the patient attended during the infectious period in order to list all possible contacts and assign priorities for investigation, according to the type, duration and frequency of exposure. All possible sites of transmission should be listed, and priorities are defined on the basis of the time spent by the index case in these sites. For each of them, the interview tries to gather the names of contacts, and collect information on the type, frequencies and duration of exposure. Usually, transmission is more likely to have occurred at home, but other types of transmission settings can be identified, such as institutions,23,24 aeroplanes,25 housing facilities for HIV-infected persons,26 homeless shelters,24 drug rehabilitation centres,27 navy ships,28 renal transplant units,29 or prisons.30 In addition, it is important to collect information on environmental factors that might affect exposure: volume of ventilation, UV light, volume of air space, crowding, etc.
on the environment, collect diagnostic sputum specimens, schedule clinic visits and provide education on TB. This visit should be conducted as soon as possible after the interview of the index case, preferably within 7 days, and the medical evaluation of high-risk contacts should be completed within a month. Follow-up visits and interviews might have to be set, in order to get complementary information or check results. The information collected with the interview of the index case and at the transmission settings are used to design an investigation plan that includes a registry of all identified contacts with their assigned priorities. It is important to set limits and establish priorities for the contact investigation, in order to focus on those contacts most at risk. The index patient should be re-interviewed after some time (1–2 weeks) for potential clarification or additional information. Drug-susceptibility results of the case’s sputum culture should be checked, in order to evaluate the presence of potential drug resistance, and decide whether systematic drug-susceptibility testing of secondary TB cases detected amongst contacts should be performed.
ASSIGNING PRIORITIES TO CONTACTS The priority ranking of contacts for investigation is set on the basis of the characteristics of the index patient, the characteristics of the contacts (vulnerability or susceptibility to disease progression from M. tuberculosis infection) and the features of exposure (duration and circumstances of exposure to the case). Factors to consider for assigning priorities are:
FIELD INVESTIGATION (BOX 75.2) Once interview is over, all potential settings for transmission should be visited in order to interview and test contacts, get more information Box 75.2 Content of the field visit
Interview identified contacts. Perform a TST on each of them. Inquire for any signs and symptoms of TB. Collect sputum samples from symptomatic contacts. Identify additional potential contacts. Educate patients and contacts on TB pathogenesis, transmission and treatment. Identify potential environmental factors that may impact transmission (crowding, ventilation, size of the settings). Evaluate potential compliance of contacts with treatment (curative or preventive). Reinforce confidentiality.
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The characteristics of the index patient: the most significant factors determining the infectivity of the index case are the disease site and the sputum smear-positivity, since more infectious patients are more likely to spread infection, and their contacts are more likely to have recent infection or TB disease. Presence of a cavity on the chest radiograph or haemoptysis among the clinical signs is in favour of a high risk of transmission, and urge for rapid contact tracing. The characteristics of the contact: the susceptibility of the host will also affect the likelihood of TB transmission. ○ Children < 5 years of age have high priority for investigation, as they are the more likely to develop disease soon after infection,1 and primary prophylaxis should be initiated rapidly.22,31 ○ Immune status: ▪ HIV-infected persons are at much greater risk of developing TB soon after recent infection, particularly disseminated or extrapulmonary disease,32,33 and are therefore a high priority for contact investigation. They deserve particular vigilance as per the development of TB. ▪ Contacts receiving immunosuppressive agents (prednisone, anti-cancer chemotherapy, etc.) are also assigned high priority. ○ Other medical conditions, such as diabetes mellitus and silicosis. The features of exposure: the likelihood of transmission depends upon the intensity, frequency and duration of exposure. The exposure period for individual contacts is determined through the time spent with the infectious case during the infectious period. The degree and duration of proximity and the characteristics of the place where transmission occurred can therefore influence transmission of infection: lengthy exposure in
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infection or are most vulnerable patients. In the NTCA/CDC guidelines, an algorithm describes the prioritization of contacts exposed to persons with AFB sputum smear-positive or cavitary pulmonary TB into high, medium or low rankings according to the transmission settings, the age and the presence of medical factors (Fig. 75.3). Similar algorithms have been drawn for assigning priority to contacts of sputum smear-negative TB, or suspect TB cases with abnormal chest radiograph findings not consistent with TB disease.22 In the ‘concentric circle approach’,4 contacts are prioritized for investigation based on their amount of exposure to the index case.
a closed or small environment is more likely to expose to transmission of infection than a brief exposure in a large and ventilated area. Various scoring systems have been proposed to assess the proximity or intensity of exposure,34–36 but the classic distinction between ‘close’ versus ‘casual’ contact has, however, not been defined uniformly,36 and cannot reliably be used to discriminate the intensity of exposure to the index case. All the above make it possible to form a priority ranking of contact for investigation. In short, the higher priority contacts are those who have secondary case of TB disease, have a recent M. tuberculosis Patient has pulmonary/laryngeal/pleural TB with cavitary lesion on chest radiograph or is AFB sputum smear-positive
High-priority contact
Yes
Household contact No
High-priority contact
Yes
Contact aged < 5 years No
High-priority contact
Yes
Contact with medical risk factor* No
High-priority contact
Yes
Contact with exposure during medical procedure No
High-priority contact
Yes
Contact with exposure in congregate setting
Medium-priority contact Yes
No
High-priority contact
Yes
Exceeds duration environment limits§
Medium-priority contact
No
Aged 5 15 years
Yes
No
Exceeds duration environment limits¶
No
Low-priority contact
*Human immunodeficiency virus or other medical risk factor. Bronchoscopy, sputum induction, or autopsy. § Exposure exceeds duration/environment limits per unit time established by the health department for high-priority contacts. ¶ Exposure exceeds duration/environment limits per unit time established by the health department for medium-priority contacts.
Fig. 75.3 Priority ranking of contacts exposed to sputum smear-positive or cavitary TB cases. From Centers for Disease Control and Prevention (2005).22 Guidelines for the investigation of contacts of persons with infectious tuberculosis; recommendations from the National Tuberculosis Controllers Association and CDC. MMWR 2005;54(No RR-15):1–37.
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With this method, patients judged to have had the most contact with the case are evaluated first, and the investigation is then expanded to the next ‘circle’ to include contacts with less exposure if infection rates in the highest priority group are greater than the expected background rate in the community (Fig. 75.2).
FIELD VISITS TO CONTACTS Visits to contacts must be done within 3 days of the history being taken for investigation. A face-to-face assessment should be done for each contact in order to assign priority, and a TST can be administered at that time. It is important to inform contacts about the purpose of the investigation. Information is collected from each contact on the following items:
being infected, but to discourage testing in low-risk individuals. Once TB has been formally ruled out, those who tested positive should benefit from prophylactic TB therapy. Because children aged < 5 years are more susceptible to TB disease, they are assigned a high priority as contacts and should receive a full diagnostic medical evaluation, including chest radiograph regardless of whether the TST is positive or not (Fig. 75.4). Similarly,
Evaluate with medical history, physical examination, chest radiograph and TST*
Does the contact have symptoms consistent with TB disease?
medical history (including previous M. tuberculosis infection or disease, and potential treatment); previous TST; current symptoms of TB disease; other medical condition that could favour development of TB (e.g. HIV infection, IV drug use, diabetes); type, duration and intensity of exposure; and sociodemographic factors (age, ethnicity, residence, country of birth).
All contacts classified as having high or medium priority and who do not have a documented previous positive TST result or previous TB disease should receive a new TST. A transverse induration diameter of 5 mm is considered positive. A negative test obtained < 8 weeks after exposure is considered unreliable for excluding infection and a follow-up test at the end of the window period (8–10 weeks after exposure) is recommended. Skin test conversion from negative to positive result is considered as reflecting recent infection. Contacts who do not know their HIV status should be offered HIV counselling and testing. It has been suggested that contacts of HIV-infected TB patients are more likely to be HIV-infected than contacts of HIV-uninfected patients.37 Therefore, voluntary HIV counselling, testing and referral for contacts are key steps in providing optimal care to HIV-infected patients, as they will inform on the need to prevent or treat TB and on the need to associate antiretroviral therapy, as well as directing potential measures for the prevention of opportunistic infections.38,39 After initial information has been collected from each contact, priority assignments should be re-assessed and a medical plan for diagnostic tests can be formulated for high- and medium-priority contacts. Field visits should also be the occasion of delivering appropriate health education on TB pathogenesis and transmission. It should also allow the investigator to assess environmental factors of importance for transmission (e.g. crowding, ventilation), as well as assessing the contacts’ psychosocial needs and risk factors that may influence compliance with medical recommendations.
Yes
Fully evaluate for TB disease
No
Is the chest radiograph abnormal?
Yes
No
Complete full treatment course for LTBI
No
Yes
No Begin treatment for LTBI; repeat TST 8 10 weeks post exposure
MEDICAL EVALUATION OF CONTACTS The purpose of this evaluation is to confirm or rule out TB, in order to decide on appropriate therapeutic strategy (treatment of TB disease or treatment of LTBI). All contacts who report any symptom consistent with TB disease or who have a positive induration to the TST ( 5 mm) must undergo further examination and investigation, particularly a chest radiograph. Mycobacteriological testing is not advised for healthy contacts with normal chest radiograph. The usual policy is to screen those individuals at increased risk of
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*Tuberculin skin test. Latent TB infection.
Stop: no further evaluation or treatment required No
Yes Complete full treatment course for LTBI
Fig. 75.4 Evaluation, treatment and follow-up of TB contacts aged < 5 years. From Centers for Disease Control and Prevention (2005).22 Guidelines for the investigation of contacts of persons with infectious tuberculosis; recommendations from the National Tuberculosis Controllers Association and CDC. MMWR 2005;54(No RR-15):1–37.
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contacts classified as high priority due to special vulnerability to TB (e.g. HIV infection) should undergo further examination regardless of whether the TST is positive or not. Contact investigation poses specific challenges in some special groups or populations, such as the homeless or incarcerated persons, due to the special social aspects and the temporary nature of the housing that complicates contact investigation.40 In migrants from high-endemic countries, identifying and screening contacts might be complicated by cultural and linguistic aspects that need to be addressed carefully.
TREATMENT OF CONTACTS WITH LATENT TUBERCULOSIS INFECTION The direct benefit of contact investigation is to treat secondary TB cases that may occur amongst contacts of infectious TB cases and to give preventive treatment to contacts with M. tuberculosis infection who are at risk of developing TB disease.31 It is usually estimated that antituberculous prophylaxis in patients with LTBI reduces the probability of progression to active disease by up to 80%.31 Treatment of LTBI should be offered to all contacts who have a positive TST result, after active TB has been excluded. High- and medium-priority contacts with positive TST who come from countries with prevalent TB should be treated, regardless of whether they have had routine Bacillus Calmette-Gue´rin (BCG) vaccination. It is recommended to focus first on high-priority contacts, then on medium-priority contacts, for the allocation of resources for treatment. For healthy contacts aged under 5 years, the recommended treatment is isoniazid 5 mg/kg daily for 6 months. Once therapeutic measures are taken, it is essential to guarantee complete intake of treatment, and directly observed therapy (DOT) is highly recommended. If not possible, self-supervised treatment with monthly checks (home visits, pill counts, clinic appointments) should be proposed. In all cases, close follow-up is needed, in order to make sure that treatment course is fully completed. As a means to increase adherence to treatment, health education regarding TB and its treatment is to be stressed.
CONTACT TRACING IN HIGH-PREVALENCE COUNTRIES Reports and guidelines recommending methods for contact tracing in high-TB-prevalence countries are scarce, and the emphasis is usually more on the capacity to treating cases fully rather than on identifying secondary cases amongst contacts or even preventing development of TB in infected persons. The IUATLD’s Tuberculosis Guide for High Prevalence Countries simply specifies that: the most important group that can be identified as needing preventive therapy are children < 5 years who are living in the same household as a newly discovered smear-positive TB case. New smear-positive patients must be questioned carefully to determine if there are children in their household. These children must be examined and treated as appropriate.41
Several studies have shown that the risk of TB infection in highly prevalent areas was higher in contacts of TB cases than in the general population and increased with the intimacy of contact with the case.12,42,43 In a study in Botswana, contact with a TB case came out as the strongest risk factor for TB infection.44 A study carried out amongst 2,870 contacts of 315 sputum smear-positive TB cases in The Gambia showed a clear relation
776
Table 75.1 Association of the response to tuberculin skin test with a gradient of exposure to the case amongst adults and children contacts of smear-positive tuberculosis cases in The Gambia a
Contacts
Gradient of exposure at night time within the household
OR
95% CI
Adults (TST > 10 mm)
Same Same Same Same
compound house room bed
1 1.42 1.36 2.12
1.05–1.92 0.85–2.17 1.45–3.10
Children (TST > 5 mm)
Same Same Same Same
compound house room bed
1 2.20 2.61 3.61
1.01–4.77 0.88–7.73 0.88–7.73
p value
0.001 (test for trend: p< 0.001) 0.04 (test for trend: p¼ 0.009)
a
Adjusted on age, sex, household size and chest radiograph extent of disease. From Lienhardt (2003).45,46
between the risk of a positive response to TST amongst adults and child contacts and their intensity of exposure to the case within the household.45,46 The degree of TST positivity in contacts was also associated with markers of infectivity of the source case (presence of a cavity and number of pulmonary zones affected in the chest radiograph) (Table 75.1). Children in contact with infectious TB cases are at high risk of developing TB.47 A positive TST in a child who has close contact with an adult with infectious TB is usually considered as representing infection with M. tuberculosis, even in the presence of former vaccination with BCG, and treatment of this latent infection is recommended, especially if the child is under 5 years of age.48 Tracing children in contact with infectious TB cases has been relatively neglected within TB control programmes in developing countries, mainly due to managerial difficulties and unavailability of drugs. In order to improve casefinding and cure, contact tracing activities aimed at assessing the level of TB infection in children living in the household of infectious TB cases should clearly become a significant part of TB control activities, particularly in areas with high BCG coverage.46 In the guidelines for management of TB in children recently published by WHO, a whole section is devoted to the screening and management of children living in contact of TB cases.49 In particular, indication is given on an approach for contact management in settings where TST and chest radiographs are not readily available.
NEW TECHNOLOGIES The TST has long been the only method for assessing the presence of M. tuberculosis infection in individuals.50 An alternative method, based on the principle that T cells of individuals sensitized with TB antigens produce interferon (IFN)-g when they re-encounter mycobacterial antigens, has been developed recently.51,52 A high level of IFN-g production is presumed to be indicative of TB infection. These IFN-g release assays (IGRA) use antigens specific to M. tuberculosis, such as the ESAT-6 or CFP10, which are not shared with any BCG substrain or with the majority of environmental mycobacteria.53 It is generally
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Contact tracing and follow-up
reported that these IGRAs have a lower sensitivity than the TST, but this is balanced by a higher specificity.53 At present, two types of IGRAs, the QuantiFERON-TB Gold assay (Cellestis Ltd, Carnegie, Victoria, Australia) and the T.SPOT-TB assay (Oxford Immunotec, Oxford, UK), have been developed commercially. Both tests measure the IFN-g released from T cells in response to M. tuberculosis-specific antigens, through either an ELISA or an ELISPOT assay method. A large number of studies using either of the commercial assays or in-house ELISPOT tests have been conducted in people at risk of having LTBI, usually contacts of active TB cases or healthcare workers. In a high school contact investigation in Denmark, amongst 85 contacts of a TB case who had not received BCG vaccination, excellent agreement was found between TST and QFT-G (94%).54 In BCG-vaccinated subjects with various levels of exposure to active TB cases in Korea, IGRAs were showing higher performance than the TST for detecting LTBI.55 Similarly, studies conducted among household contacts of TB cases in India or amongst secondary school children with possible long-term exposure to a pulmonary TB case in UK showed a highly significant association between positive ELISPOT responses and degree of exposure to active TB cases, independent of BCG vaccination status.56,57 In terms of contact investigation, one of the most important questions is whether these assays can be used to identify latently infected individuals who are more likely to progress to active disease, and hence may benefit from preventive therapy. Data are limited at present but cohort studies are being conducted to address this.58 Guidelines on the use of QFT-G assay, in which it is stipulated that QFT-G may be used in all circumstances in which TST is usually recommended, including contact investigation, have been published recently.59 These guidelines suggest that QFT-G be used in place of the TST. The UK National Institute for Health and Clinical Excellence (NICE) produced TB guidelines in March 2006 recommending a hybrid two-step approach: initial screen with TST, and in those who are positive, IGRA testing to confirm positive TST results.60 These guidelines are, however, due to be revised rapidly as new evidence accumulates. Detection and treatment of LTBI is an important component of TB control efforts in low-income settings. IGRAs are currently seen as promising in individuals with HIV infection, contacts, children and healthcare workers,53,58 but this requires further confirmation in larger studies. At present, the role of IGRAs in low-income, high-burden settings appears very limited. The need for developed laboratory infrastructure and trained personnel, as well as their cost, are limiting factors in the widespread use of IGRAs in high-burden countries. Simplification of the test format and reduction of costs might enhance applicability in such settings, particularly in selected subgroups, such as HIV-infected individuals or children. Until such times, the TST will continue to be a useful, simple, low-cost tool in developing countries where BCG vaccination is given in infancy, and thus has limited impact on TST results.46
PRESENT OBSTACLES AND CHALLENGES FOR OPTIMAL CONTACT TRACING EVALUATION OF CONTACT TRACING ACTIVITIES The number of persons potentially exposed to a patient with TB varies considerably from patient to patient and is highly dependant on the individual’s social life and environment. There is no
75
standard definition for the type, duration, closeness and time period of exposure to an active TB case, and the procedures followed for contact investigation vary considerably between health programmes. In a retrospective evaluation of records of contacts of 349 culture-positive pulmonary TB cases reported from five study areas in the USA, a total of 3,824 contacts were identified, but no contact was identified for 45 (13%) TB cases.61 Only 50% of patients who resided in homeless shelters had contacts identified. Of all contacts identified, 2,095 (55%) completed screening, and more than half of the contacts with LTBI did not complete a full course of treatment. Close contacts younger than 15 years or exposed to a TB patient with positive smear were more likely to be fully screened. Lastly, factors associated with TB patients’ infectiousness, contact susceptibility to infection, type and amount of contact exposure to the case, risk of contact to progress to active TB disease (including HIV status) and contact history of prior TB infection were not routinely recorded. This underscores the importance of written documentation of key patient and contact characteristics, particularly those useful for establishing priority in contact investigation. The authors stressed the need for a standard approach to TB contact investigation that has the potential to improve outcome—and the guidelines established by the NTCA and CDC go in that direction.
STANDARD APPROACH TO TUBERCULOSIS CONTACT INVESTIGATION TO IMPROVE OUTCOME The difficulty of defining ‘close’ or ‘casual’ contact is recognized by several authors.36,37 No study of TB transmission has simultaneously evaluated information on case, contact and environmental exposure factors. In an attempt to improve contact investigation, Bailey et al. designed a model for predicting a positive TST result during contact investigation.36 They identified seven variables capable of predicting significantly a positive TST among contacts of active TB case, relating to the index case (positive smear status and cavitation on chest radiograph), contact (race, sex, age) and environment (total hours exposed each month) characteristics. The CDC guidelines recognize the difficulty in establishing standards for comparison and recommend an alternative way of assessing the extent of contact, through various algorithms intending at helping decision-making on priority assignment to contacts.22
THE IMPORTANCE OF ENSURING CURATIVE AND PREVENTIVE TREATMENT COMPLETION IN CONTACTS Finding ways to improve treatment completion rates for persons found with LTBI among contacts is an important aspect of the contact investigation procedure. Among 6,225 close contacts being reported from the investigation of 1,080 pulmonary smear-positive TB patients reported to CDC in 1996–1997, 1,259 contacts started treatment for LTBI, but only 707 (56%) completed it.62 Among them, those on DOT were more likely to complete LTBI treatment. All efforts should be made to ensure complete treatment of LTBI among the contacts of TB cases, especially for those at higher risk of developing disease (HIV-infected persons, children). Ensuring complete LTBI treatment should therefore be viewed as an integral part of the contact investigation process, in order to maximize public health prevention efforts aimed at eliminating TB.37 Lastly, an important unresolved issue is whether IGRAs have the ability to identify latently infected individuals who are most likely to progress to active disease, and therefore, most likely to benefit
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8
PREVENTION OF TUBERCULOSIS
from preventive therapy. The association between IGRA positivity and progression to active TB disease remains largely unknown, and long-term cohort studies are required to address this, in order to assess the respective roles of TST and newly developed IGRAs in the contact investigation procedures.
CONCLUSION Contact investigations focus on the very important aspect of transmission of TB in the community, by targeting people recently in contact with infectious TB cases. Properly conducted
REFERENCES 1. Comstock GW, Cauthen GM. Epidemiology of tuberculosis. In: Reichman LB, Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. New York: Marcel Dekker, 1993. 2. Hsu KHK. Contact investigation: a practical approach to tuberculosis eradication. Am J Pub Health 1963;53:1761–1769. 3. Etkind S. Contact tracing. TB: a comprehensive international approach. In: Reichman L, Hershfield E, eds. Lung Biology in Health and Disease. New York: Marcel Dekker, 1993: 275–289. 4. Etkind SC, Veen J. Contact follow-up in high- and low-prevalence countries. Reichman LB, Hershfield ES, eds. Tuberculosis: A Comprehensive International Approach. New York: Marcel Dekker, 2000: 377–399. 5. Broekmans JF, Migliori GB, Rieder HL, et al. European framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Royal Netherlands Tuberculosis Association (KNCV) Working Group. Eur Respir J 2002;19:765–775. 6. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954;69:724–732. 7. Loudon RG, Spohn SK. Cough frequency and infectivity in patients with pulmonary tuberculosis. Am Rev Respir Dis 1969;99:109–111. 8. North RJ, Izzo AA. Mycobacterial virulence. Virulent strains of Mycobacteria tuberculosis have faster in vivo doubling times and are better equipped to resist growth-inhibiting functions of macrophages in the presence and absence of specific immunity. J Exp Med 1993;177:1723–1733. 9. Valway SE, Sanchez MPC, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998;338:633–639. 10. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975;50:90–106. 11. Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: the effects of chemotherapy. Tubercle 1976;57:275–299. 12. Andersen S, Geser A. The distribution of tuberculous infection among households in African communities. Bull World Health Organ 1960;22:39–60. 13. Newport MJ, Huxley CMP, Huston S, et al. A mutation in the interferon-g -receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996;26:1941–1949. 14. Bellamy R, Ruwende C, Corrah T, et al. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998; 338:640–644. 15. Styblo K. State of the art: epidemiology of tuberculosis. Bull Int Union Tuberc 1978;53: 141–152.
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contact investigations help increase case-finding by increasing detection of secondary TB cases but also help prevent the development of TB in infected persons, particularly children and HIVinfected individuals. Particularly in countries hit hard by the HIV epidemics, contact investigation can also help directing measures for detection and prevention of HIV. Intensified case-finding will be required to meet the newly set goals of the Stop TB Strategy Plan. Within this renewed effort for addressing a better control of TB worldwide, with a focus on high-TB-prevalent countries, contact investigation is an important part of the public health procedures for the control of TB and can usefully contribute to boosting TB case detection.
16. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99:131–138. 17. Styblo K. Epidemiology of tuberculosis. In: Selected papers, vol 24. The Hague: KNCV, 1991. 18. Lienhardt C. From exposure to disease: the role of environmental factors in susceptibility to TB. Epidemiol Rev 2001;23:288–301. 19. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320:545–550. 20. Narain JP, Raviglione MC, Kochi A. HIV associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuber Lung Dis 1992;73:311–321. 21. Girardi E, Raviglione MC, Antonucci G, et al. Impact of the HIV epidemic on the spread of other diseases: the case of tuberculosis. AIDS 2000;14(Suppl 3):S47–S56. 22. Centers for Disease Control and Prevention. Guidelines for the investigation of contacts of persons with infectious tuberculosis; recommendations from the National Tuberculosis Controllers Association and CDC. MMWR 2005;54(RR-15):1–37. 23. Centers for Disease Control and Prevention. Multidrug-resistant tuberculosis—North Carolina. MMWR 1987;35(51–52):785–787. 24. Centers for Disease Control and Prevention. Tuberculosis among residents of shelters for the homeless—Ohio, 1990. MMWR 1991;40:869–871, 877. 25. Kenyon TA, Valway SE, Ihle WW, et al. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 1996;334:933–938. 26. Daley CL, Small PM, Schecter GK, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus: an analysis using restrictionfragment-length polymorphisms. N Engl J Med 1992;326:231–235. 27. Centers for Disease Control and Prevention. Tuberculosis in a drug rehabilitation center— Colorado. MMWR 1980;29(45):543–544. 28. DiStasio AJ, Trump DH. The investigation of a tuberculosis outbreak in the closed environment of a US navy ship, 1987. Mil Med 1990;155:347–351. 29. Jereb JA, Burwen DR, Dooley SW, et al. Nosocomial outbreak of tuberculosis in a renal transplant unit: application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates. J Infect Dis 1993;168:1219–1224. 30. Jones TF, Craig AS, Valway SE, et al. Transmission of tuberculosis in a jail. Ann Intern Med 1999;131:557–563. 31. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49(RR-6):1–51. 32. De Cock KM. Impact of interaction with HIV. In: Porter JMH, McAdam KPWJ, eds. Tuberculosis: Back to the Future. London: Wiley, 1994.
33. Antonucci G, Girardi E, Raviglione MC, et al. Risk factors for tuberculosis in HIV-infected persons: a prospective cohort study. JAMA 1995;274:143–148. 34. Rose CE, Zerbe GO, Lantz SO, et al. Establishing priority during investigation of tuberculosis contacts. Am Rev Respir Dis 1979;119:603–609. 35. Gerald LB, Tang S, Bruce F, et al. A decision tree for tuberculosis contact investigation. Am J Respir Crit Care Med 2002;166:1122–1127. 36. Bailey WC, Gerald LB, Kimerling ME, et al. Predictive model to identify positive tuberculosis skin test results during contact investigations. JAMA 2002;287:996–1002. 37. Reichler MR, Bur S, Reves R, et al. Results of testing for human immunodeficiency virus infection among recent contacts of infectious tuberculosis cases in the United States. Int J Tuberc Lung Dis 2003;7:S471–478. 38. Centers for Disease Control and Prevention. Revised guidelines for HIV counselling, testing, and referral. MMWR 2001;50(RR-19):1–58. 39. Godfrey-Faussett P, Maher D, Mukadi YD, et al. How human immunodeficiency virus voluntary testing can contribute to tuberculosis control. Bull World Health Organ 2002;80:939–945. 40. Yun LW, Reves RR, Reichler MR, et al. Outcomes of contact investigation among homeless persons with infectious tuberculosis. Int J Tuberc Lung Dis 2003;7: S405–411. 41. International Union against Tuberculosis and Lung Diseases. Tuberculosis Guide for High Prevalence Countries, 5th edn. Paris: IUATLD, 2000. 42. Roelsgaard E, Iversen E, Blocher C. Tuberculosis in tropical Africa. Bull World Health Organ 1964;30: 459–518. 43. Narain R, Nair SS, Rao GR, et al. Distribution of tuberculous infection and disease among households in a rural community. Bull World Health Organ 1966;34:639–654. 44. Lockman S, Tappero JW, Kenyon TA, et al. Tuberculin reactivity in a paediatric population with high BCG vaccination coverage. Int J Tuberc Lung Dis 1999;3:23–30. 45. Lienhardt C, Fielding K, Sillah J, et al. Risk Factors for tuberculosis infection in sub-Saharan Africa: a contact study in The Gambia. Am J Respir Crit Care Med 2003;168:448–455. 46. Lienhardt C, Sillah J, Fielding K, et al. Risk factors for tuberculosis infection in children in contact with infectious tuberculosis cases in The Gambia, West Africa. Pediatrics 2003;111:e608–614. 47. Beyers N, Gie RP, Schaaf HS, et al. A prospective evaluation of children under the age of 5 years living in the same household as adults with recently diagnosed pulmonary tuberculosis. Int J Tuberc Lung Dis 1997;1:38–43. 48. Arbela´ez MP, Nelson KE, Mun˜oz A. BCG vaccine effectiveness in preventing tuberculosis and its interaction with human immunodeficiency virus infection. Int J Epidemiol 2000;29:1085–1091. 49. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. WHO/HTM/TB/2006.371. Geneva: WHO, 2006.
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Contact tracing and follow-up 50. Huebner RE, Schein MF, Bass JB. The tuberculin skin test. Clin Infect Dis 1993;17:968–975. 51. Andersen P, Munk ME, Pollock JM, et al. Specific immune-based diagnosis of tuberculosis. Lancet 2000;356:1099–1104. 52. Barnes PF. Diagnosing latent tuberculosis infection: turning glitter to gold. (Editorial) Am J Respir Crit Care Med 2004;170:5–6. 53. Pai M, Riley LW, Colford JM. Interferon-g-assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761–776. 54. Brock I, Weldingh K, Lillebaek T, et al. Comparison of tuberculin skin test and new specific blood test in tuberculosis contacts. Am J Respir Crit Care Med 2004;170:65–69. 55. Kang YA, Lee HW, Yoon HI, et al. Discrepancy between the tuberculin skin test and the whole-blood
interferon-g assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA 2005;293:2756– 2761. 56. Lalvani A, Pathan AA, Durkan H, et al. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enumeration of antigenspecific T-cells. Lancet 2001;357:2017–2021. 57. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003;361:1168–1173. 58. Pai M, Kalantri S, Deeda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part 1. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413–422.
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59. Mazurek GH, Jereb J. Lobue P, et al. Guidelines for using the QuantiFERON-TB GOLD test for detecting Mycobacterium tuberculosis infection, United States. MMWR 2005;54(RR-15):49–55. 60. National Institute for Health and Clinical Excellence. Tuberculosis: Clinical Diagnosis and Management of Tuberculosis, and Measures for Its Prevention and Control. Clinical Guideline 33. London: NICE, 2006. Available at URL:http://www.nice.org.uk/page.aspx? o=CG033NICEguideline 61. Reichler MR, Reves R, Bur S, et al. Evaluation of investigations conducted to detect and prevent transmission of tuberculosis. JAMA 2002;287:991–995. 62. Marks SM, Taylor Z, Qualls NL, et al. Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med 2000;162:2033–2038.
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Prophylaxis with antituberculous drugs in special situations Ludwig Apers, Colebunders Robert, and Jean B Nachega
HISTORY OF TUBERCULOSIS PREVENTIVE TREATMENT Preventive therapy (treatment of infected persons to prevent the progression of latent infection to clinical disease) is based on the widely accepted theory that primary infection with Mycobacterium tuberculosis (MTB) is followed by a latent phase in the majority of patients, with tubercle bacilli surviving for a long time in a dormant condition.1 TB disease results from reactivation of these dormant bacilli when triggered by certain conditions.2 As will be explained later, it is the identification of these ‘conditions’ that will be decisive in selecting the target groups for screening for latent TB infection (LTBI) and eventual prophylactic treatment. Prevention of TB with isoniazid (INH) was first documented in children in the mid-1950s. Thereafter a number of controlled clinical trials of INH chemoprophylaxis was undertaken, and its efficacy established. A meta-analysis of 11 placebo-controlled trials of INH, involving more than 70,000 persons, found that TB preventive therapy reduced TB incidence by 63%. Among patients who adhered to more than 80% of the INH regimen, protection was 81%.3 These studies also showed that INH chemoprophylaxis reduced TB deaths by 72%.3 The efficacy of INH therapy in preventing TB in high-risk persons is overwhelming. In addition, the use of highly active antiretroviral therapy (HAART) has been shown to reduce the incidence of TB among HIV-infected individuals in developed and developing countries.4,5 Although the mechanism of preventive therapy is not known, it is assumed that administration of INH results in sterilization of infection and elimination of organisms from infected persons.6 Follow-up studies have shown that the duration of protection in areas where the rate of new infection is low is at least 19 years.7 The picture is totally different in areas with high (re)infection rates where INH alone as preventive treatment has an efficacy of only 18 months, whereas 3-month regimens with rifampicin (RIF) and pyrazinamide or RIF and INH are efficacious for 3 years.8 Enthusiasm for INH chemoprophylaxis was considerably dampened in the late 1960s and early 1970s when drug-related hepatotoxicity, including deaths, were observed. A number of studies based on decision analysis or modelling suggested that the risks of chemoprophylaxis might outweigh the benefits, and use of preventive therapy was curtailed or ignored in many settings. Because the risk of INH-related toxicity increases with age, use of chemoprophylaxis in people over 35 years old was particularly discouraged. However, the resurgence of TB in the developed world,
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particularly human immunodeficiency virus (HIV)-related TB, and the uncontrolled global epidemic have renewed interest in the use of preventive therapy targeted to high-risk individuals.
TARGET GROUPS FOR TUBERCULOSIS PREVENTIVE TREATMENT The use of preventive therapy for TB now focuses on high-risk groups of individuals who are either known or strongly suspected to be latently infected with MTB. The term ‘treatment of LTBI’ is now preferred, emphasizing that preventive treatment is really targeted to an established infection. The American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) published guidelines in 2000 on screening for latent TB that stress the importance of targeting efforts on populations and patients who would benefit from treatment to prevent active disease.9 In the past, screening for TB infection has been unfocused and often directed at patients who, if found to be infected, would have little risk of progressing to active disease. The new guidelines propose that only people with a risk of disease or high prior probability of latent TB be tested, and that treatment be offered to infected individuals regardless of age. Individuals who should be targeted for tuberculin testing are those listed in the first and second columns of Table 76.1, that is, those in whom a positive test is considered as 5- or 10-mm or more induration. For people without risk factors for TB testing is not recommended, but if done (e.g. at entry into a work site where risk for exposure to TB is anticipated and a longitudinal tuberculin testing programme is in place) the cut-off point is set at 15 mm or more. Detection of latent TB in persons with HIV infection can be challenging. Indeed, the sensitivity of tuberculin skin testing may be depressed in patients with advanced immunosuppression as reflected by low CD4 cell counts. In addition, the reactivity to tuberculin, as well as mumps and candida antigens, can fluctuate in HIV-infected individuals. For these reasons, anergy testing is no longer recommended for the diagnosis of latent TB.10 Testing with tuberculin purified protein derivative (PPD) is dependent on the presence of an intact cell-mediated immune response. False-negative skin tests are particularly common in HIV-infected people, reflecting the stage of immunocompression. New diagnostics, including cytokine detection assays, are under development. A commercially available interferon-g release assay (Quantiferon TB Gold) is an immunodiagnostic assay detecting interferon-g response to TB-specific antigen in blood.11,12 This
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76
Table 76.1 Criteria for tuberculin positivity by risk group Reaction > 5 mm of induration
Reaction 10 mm of induration
Reaction 15 mm of induration
HIV-infected persons
Recent immigrants (i.e. within the past 5 years) from high-prevalence countries or regions Injection drug users Residents and employees of the following high-risk settings: prisons and jails, nursing homes and other long-term facilities for the elderly, hospitals and other healthcare facilities for patients with AIDS, and homeless shelters Mycobacteriology laboratory personnel Persons with the following clinical conditions that place them at high risk: silicosis, diabetes mellitus, chronic renal failure, some haematological disorders (e.g. carcinoma of head or neck and lung), weight loss of 10% of ideal body weight, gastrectomy, and jejunoileal bypass Children younger than 4 years of age, or infants, children, and adolescents exposed to adults at high risk
Persons with no risk for TB
Recent contacts of patients with infectious TB Persons with fibrotic changes on chest radiograph consistent with prior TB Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of 15 mg/day of prednisone for 1 month or more)
Centers for Disease Control and Prevention. Update: Adverse Event Data and Revised American Thoracic Society/CDC Recommendations against the Use of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis Infection – United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52(31):735–739.
test has recently been recommended by the CDC to be utilized in all circumstances in which the TST is currently used.1 A second enzyme-linked immunospot (ELISPOT) assay (T-SPOT TB) proved to be significantly more sensitive than the TST in a prospective study in children in South Africa and was not affected by the HIV serostatus of the child.2 This was also observed in a study in the UK, in 144 patients with HIV-1 infection: ELISPOT was found to be a useful test for screening for TB infection even in HIV-1 patients with low CD4 T-cell counts.13 Both the Quantiferon and the T-SPOT TB test seem to be able to distinguish TB infection from BCG and other non-tuberculous mycobacteria. The advantages of these blood-based tests are that the need for a return visit to the health services after 48–72 hours is avoided and the interpretation is less subjective than tuberculin skin testing. Another advantage of these tests is the ability to perform serial testing without inducing the boosting phenomenon. These tests, however, still need validation in long-term follow-up studies. In their recent review article, Nahid and Daley conclude that additional studies will be needed with both the QuantiferonTB Gold and the ELISPOT tests before they can be used widely in HIV-infected populations.14
TUBERCULOSIS PREVENTIVE TREATMENT IN SPECIAL GROUPS Target groups for treatment of latent TB are listed in Table 76.1. In low-incidence countries two categories of the following high-risk groups can be identified (ATS guidelines9): persons or groups with presumed recent MTB infection and persons who suffer from clinical conditions associated with progression to active TB. To the first group belong close contacts of persons with infectious pulmonary TB, especially children younger than 5 years of age, homeless persons, those with HIV infection, injection drug users, and (health) professionals who work in institutional settings with persons at risk for TB. Persons who suffer from clinical conditions associated with progression to active TB are people infected with HIV, injection drug users, persons with pulmonary fibrotic lesions, underweight persons, persons with silicosis, chronic renal failure, or diabetes mellitus. Other clinical conditions that have been associated with active TB include
gastrectomy, jejunoileal bypass, renal and cardiac transplantation, and certain neoplasms. Persons receiving therapy with corticosteroids (a dose 15 mg of prednisone) may be at risk for reactivation of TB. Alcohol abuse has been associated with a higher risk for TB. but it is difficult to disentangle this as an independent risk factor as it may be compounded by other factors common in this category of patients. Other immunosuppressive agents that may increase the risk have been described, but the exact risk is unknown. The most recent immunosuppressive drug that has been added to the list is antitumour necrosis factor (TNF)-a, a drug used for treatment of rheumatoid arthritis and Crohn’s disease.6 Post-marketing surveillance in the USA has identified cases of TB with a median of 12 weeks from commencing treatment, and most in extrapulmonary sites. Calculations have suggested that TB rates in patients treated in the USA with anti-TNF-a are six times that of untreated patients. The British Thoracic Society recommends that, prior to starting, these patients should have a clinical examination, a chest X-ray, and if appropriate a tuberculin test.7 Within these target groups, tuberculin skin testing remains the best documented test for identifying the persons at high risk for TB who would benefit by treatment of LTBI. As discussed earlier, it could be replaced by the newer serological tests that recently have been developed, as the interpretation of the skin test needs experience, and should be a function of the risk group to whom the patient belongs (Table 76.1). Criteria for treatment include a positive tuberculin test according to the categories in Table 76.1, elevated risk for developing active TB if untreated, and exclusion of active TB by clinical evaluation and chest radiography. In addition, HIV-infected and other severely immunocompromised persons who are contacts of a patient with infectious TB should be treated for latent TB regardless of tuberculin skin test results.
TUBERCULOSIS PREVENTIVE TREATMENT REGIMENS Treatment regimens for latent TB are listed in Table 76.2, along with the rating given to the regimen by the ATS and CDC. INH remains a favoured drug for TB preventive therapy because
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Table 76.2 Treatment regimens for latent tuberculosis Drug regimen
Isoniazid Isoniazid Isoniazid Isoniazid Rifampicin and pyrazinamide Rifampicin and pyrazinamide Rifampicin
Duration (months)
Interval
9 9 6 6 2
Rating HIV –ve
HIV +ve
Daily Twice weekly Daily Twice weekly Daily
A II B II BI B II B II
A II B II CI CI AI
2-3
Twice weekly
C II
CI
4
Daily
B II
B III
Ratings: A, strongly recommended; B, recommended; C, optional; I, randomized trials; II, data from other scientific studies; III, expert opinion.
of its well-documented efficacy, low cost, and relatively low toxicity. The optimal duration of INH therapy for latent TB has been a subject of extensive debate in the past 20 years. The International Union against TB and Lung Disease conducted a landmark trial in Eastern Europe in the 1970s and 1980s that compared no treatment with 3, 6, or 12 months of INH in adults with fibrotic changes on radiography.8 The results showed that, compared with placebo, 12 months of INH reduced the incidence of TB by 75%, compared with 66% for 6 months and 20% for 3 months. In addition, patients who completed the 12 months of therapy and were judged to be compliant experienced a 92% reduction in TB risk, compared with a 69% decrease for compliant patients completing a 6-month regimen. A meta-analysis by the Cochrane Collaborative found that 12 months of INH was more effective than 6 months for prevention of TB. A recent analysis of varying durations of INH therapy in Alaskan natives revealed that the effectiveness of INH therapy was optimal after 9 months, and that further treatment conferred no additional benefit.15 The ATS/CDC statement, therefore, recommends 9 months of INH as the preferred regimen.9 Although INH is a well-tolerated drug, serious hepatotoxicity can occur in a small proportion of patients. INH may result in asymptomatic elevations in hepatic transaminase levels, but this does not always signal impending clinical toxicity. Hepatotoxicty is of concern when symptoms of hepatitis, including pain, nausea, vomiting, and jaundice, develop. Continuing INH in the presence of symptoms may lead to death from fulminant hepatic necrosis and liver failure, with a case-fatality rate of 10–15%. Studies in the 1960s and 1970s found evidence of hepatotoxicity in 1–5% of INH recipients, with higher rates among older patients. More recent experience with INH therapy that is closely monitored shows a risk of hepatotoxicity in the range of 0.1–0.3%. Thus, appropriate patient screening and follow-up makes the use of INH for treating latent infection markedly safer. Several studies have evaluated alternative regimens for the treatment of latent TB with the aim to shorten the duration of treatment. Rifamycin antibiotics have greater potency against the dormant and semidormant organisms that characterize LTBI than INH alone.16 Based on studies in animal models of latent TB, both RIF alone given for 3–4 months and rifampin and pyrazinamide given for 2–3 months were felt to be potentially active regimens and were tested in clinical trials.10,17–20 A 3-month regimen of RIF alone was found to reduce the incidence of TB by about
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65% in men with silicosis, and was more effective than 6 months of INH.10 Three studies of RIF and pyrazinamide for treatment of latent TB in HIV-infected, tuberculin-positive patients have been carried out.18–20 In each of these studies, the combination of RIF and pyrazinamide was as effective as 6 or 12 months of INH. RIF with pyrazinamide was generally well tolerated in the above studies, but can be associated with serious hepatotoxicity. Indeed, the use of this combination in non-HIV-infected patients has been associated with a concerning rate of hepatotoxicity. Twenty-one patients with liver injury resulting from the use of rifampin/pyrazinamide preventive therapy have been reported to CDC; five of these patients died. Based on these findings, CDC and ATS have revised their 2000 recommendations.9 The 2003 CDC/ATS revisions now recommend that rifampicin/pyrazinamide should generally not be offered for the treatment of latent TB infection.21 The use of RIF does pose the risk of important drug interactions. For example, reduction in methadone concentrations caused by RIF can precipitate narcotic withdrawal. Moreover, RIF can lower levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors used to treat HIV infection. Substitution of rifabutin for RIF in patients receiving HIV drug is based on the observation that rifabutin is equally as efficacious as RIF in the treatment of active TB. Rifapentine is a long-acting rifamycin with a comparable activity to RIF but with a prolonged half-life that permits weekly dosing. Schechter et al. reasoned that a once-weekly regimen of rifapentine and INH for 12 weeks would be efficacious for the treatment of latent TB in high-risk individuals.22 They compared a weekly rifapentine/INH regimen with a daily RIF/pyrazinamide regimen in tuberculin skin test-positive household contacts in Brazil, of which only one was HIV-infected.22 They concluded that the weekly regimen for 12 weeks was better tolerated than RIF/pyrazinamide and was associated with good protection against TB. In the latter arm 10% of the patients experienced hepatotoxicity. If multidrug-resistant (MDR) TB is suspected, the recommended preventive therapy is pyrazinamide and ethambutol or pyrazinamide and a fluoroquinolone (i.e. levofloxacin or ofloxacin) for 6–12 months. Treatment for suspected exposure to MDR-TB should be routinely extended to 12 months in HIV-infected individuals.
MONITORING TUBERCULOSIS PROPHYLACTIC TREATMENT Patients receiving treatment for latent TB should be monitored for drug toxicity, as well as to promote adherence to therapy. As in treatment of active TB, patients receiving INH should be warned about signs and symptoms of hepatotoxicity and advised to discontinue therapy and seek care if any of these occur. Patients with or at risk of chronic liver disease should have baseline liver enzymes obtained, with monthly monitoring if the results are abnormal. All patients should be clinically evaluated at least monthly. Preventive therapy should be terminated for asymptomatic transaminase elevation. Treatment of patients on other preventive regimen (i.e. INH) and with mild transaminase elevations (three times upper limits of normal or less) can proceed with regular clinical and laboratory monitoring. Higher elevations of transaminases, or the development of symptoms or signs of hepatitis, should be managed with discontinuation of therapy at least temporarily. Patients who complete therapy for latent TB do need periodic monitoring for TB subsequently.23
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Prophylaxis with antituberculous drugs in special situations
TUBERCULOSIS PREVENTIVE TREATMENT IN LOW-INCOME COUNTRIES TUBERCULOSIS PREVENTIVE TREATMENT IN THE PRESENCE OF HIV INFECTION Studies that showed the benefit of TB preventive therapy on TB disease incidence in HIV-infected individuals were carried out in Haiti, Mexico, Zambia, Kenya, Uganda, and Thailand. Several meta-analyses were subsequently performed.16,24 The most recent and extensive analysis was done by Woldehanna and Volmink, and was based on 8130 randomized participants.25 They came to the following conclusions: preventive therapy (any antituberculous drug) versus placebo is associated with a lower incidence of active TB (RR 0.64 (0.51–0.83)). This benefit was more pronounced in individuals with a positive tuberculin skin test (RR 0.38 (0.25–0.57)) than in those who had a negative test (RR 0.83 (0.58–1.18)). Overall there was no evidence that preventive therapy reduces all-cause mortality (RR 0.95 (0.85–1.06)) although a favourable trend was found in people with a positive tuberculin skin test (RR 0.80 (0.63–1.02)). In a very recent study in South Africa in HIV-infected children, INH prophylaxis, either three times a week, or daily, was shown to be associated with a reduced incidence of TB and an early survival benefit.26
TARGET GROUPS FOR TUBERCULOSIS PREVENTIVE TREATMENT In countries with limited resources, people living with HIV/ acquired immunodeficiency syndrome (AIDS) (PLHA) are the most important target group for treatment of LTBI.24 Indeed in these countries, people with HIV infection with a positive tuberculin skin test have a 30% or more lifetime risk of developing active TB,3,27 and TB is the most common HIV-related disease.4 Before considering TB prophylactic treatment, however, active TB should be excluded. The latter may be a problem in countries with high HIV/TB prevalence and limited resources. According to the World Health Organization (WHO) guidelines, it is recommended to do a chest radiograph in any patient who is to be started on INH. Recurrent TB is more common among HIV-infected patients.28 Therefore, secondary prophylaxis should also be considered. In Haiti post-treatment INH prophylaxis for 1 year reduced the incidence of recurrent TB by 80%, but post-treatment INH prophylaxis did not prolong survival.12 In a cohort of South African gold miners, secondary prevention using INH 300 mg daily for an indefinite period reduced the incidence of TB by 55%. This difference was especially tangible in the group of patients with advanced disease and low CD4+ lymphocyte counts.20 The most complicated group of patients are those exposed to MDR-TB. A recent systematic review identified only two comparative studies of people treated and not treated for LTBI following exposure to MDR-TB. One study found individualized treatment to be effective for preventing active TB in children, while a retrospective cohort study found INH not to be effective.29 With the increasing global spread of MDR- and extensively drugresistant (XDR-) TB and the difficulties in treating there is an urgent need for clinical trials and cohort studies to identify effective preventive measures.
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TUBERCULOSIS PREVENTIVE TREATMENT REGIMENS The WHO/UNAIDS still recommends INH as a daily, self-administered therapy for 6 months in people living with HIV.5 Especially for dually infected patients where there is a possibility of having to combine INH with antiretroviral drugs, INH remains a favoured drug for TB preventive therapy because of its relatively low toxicity. Studies that documented reinfection as the major cause of TB recurrence in HIV-infected people living in high-TB-prevalence areas provide further support to the suggestion that the efficacy of preventive therapy may not be long term in these regions.15 In this case it would be logical to suppose that prophylaxis is necessary as long as the risk factor is present. The current recommendations for persons with HIV infection in high-TB-prevalence regions have been formulated before the antiretroviral era. We do not know how long TB prophylaxis should be continued in patients on HAART and whether prophylaxis should be stopped based on CD4 count results. These research questions are currently under study and will hopefully lead to evidence-based recommendations.
MONITORING TUBERCULOSIS PREVENTIVE TREATMENT REGIMENS Crucial aspects include monitoring of adherence, side effects, and development of active TB disease. With the exception of adherence, all these aspects will be easier to monitor in high-income countries as they may require laboratory investigations and chest radiography. In low-income countries it will be pivotal to educate and instruct patients on the occurrence of signs and symptoms of active TB and of side effects, especially hepatitis. This counselling should be part of every patient contact. Liver enzyme monitoring as recommended in high-income settings will not always be possible, although the roll-out of antiretroviral (ARV) programmes may be accompanied by an increasing accessibility to these laboratory tests.23 Also for this aspect operational research should try to assess the feasibility of integrating a TB preventive programme in an ARV roll-out programme.
TUBERCULOSIS PREVENTIVE TREATMENT: PROGRAMME ASPECTS Historically, treatment of LTBI has since long been considered a public health intervention that could prevent latent TB from progressing to TB disease in the infected individual and at the same time an intervention that could have an impact on TB transmission by reducing the progression to infectious cases. However, there has never been an internationally accepted consensus among experts for introducing preventive programmes on a wide scale.21 Some industrialized countries have introduced this intervention on a public health scale;22 others have limited its application to strictly defined individual cases. To introduce this preventive therapy on a wide scale, INH preventive programmes must be designed and implemented, ideally based on the guidelines stipulated by the WHO.5 If followed rigorously, such programmes require human resources and infrastructure that may be major constraints for a successful implementation. Well aware of the possible risks of further compromising the already overstretched TB programmes, WHO and UNAIDS set
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out a series of conditions that needed to be fulfilled before TB preventive therapy could be recommended in high-HIV-prevalent communities.5 These conditions defined requirements for identifying HIV-infected subjects, for screening them to exclude active TB, for targeting those most likely to be infected with TB (either by PPD skin test or by identifying high-risk groups), for providing them with drugs, and for monitoring and following them up to guarantee compliance. These conditions were further inspired by the ever-looming risk of inducing resistance against one of the most cost-effective bactericidal antituberculous drugs at the TB programme manager’s disposal. The pro-test initiative was one example of how to operationally combine TB/HIV reduction activities.30 The promotion of voluntary counselling and testing (VCT) was seen as an entry point for access to the core interventions of intensified TB case-finding and INH preventive treatment. The benefits of VCT for HIV to TB patients include referral for appropriate clinical care and support for those found to be HIV-infected. Likewise, people attending a VCT centre can benefit from TB screening: those found to be both HIV-infected and with active TB need referral for TB treatment and cotrimoxazole prophylaxis; those without active TB should be offered TB preventive treatment with INH. It can hardly be said that INH preventive programmes became a success story everywhere: the few feasibility studies done in operational circumstances that were published showed limited results in terms of numbers treated and adherence.31 Constraints included limited motivation and knowledge by counsellors to discuss TB issues during HIV pre- and post-test counselling, insufficient availability for TB screening, insufficient sites to distribute pills, and high prevalence of tuberculin anergy. Early, passive case-finding and treatment of infectious, sputumpositive cases remains the prime strategy for reducing the infection rate of pulmonary TB.25,26 Using this strategy pulmonary TB incidence rates dropped dramatically in industrialized countries and in a substantial number of developing countries, at least, before the rise of the HIV epidemic. TB transmission occurs, however, before cases are detected, and is reduced to undetectable levels soon after the patient is put on treatment. In theory, preventive therapy should have a more direct impact on transmission, as cases are treated before they ever become infectious. Moreover, detection rates could be pushed up by actively screening for active TB as part of the procedure for eligibility for INH preventive therapy. For preventive therapy to have any impact, however, the scale of preventive therapy services should be expanded greatly.30 Some authors tried to answer the question to what level they should be expanded, by entering different scenarios in computer models. Corbett et al. came to the conclusion that combined approaches that tackle both latent TB and ongoing TB transmission are likely to be most successful, particularly when not exclusively targeted to those of known HIV status.32 Caution needs to be exerted, however, as some assumptions and estimations in these models are based on observational TB studies carried out before the HIV era.
TUBERCULOSIS PREVENTION IN THE ERA OF HIGHLY ACTIVE ANTIRETROVIRAL TREATMENT It has been demonstrated in South Africa that a substantial impact on TB disease incidence can be expected from ART: HAART
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reduced the incidence of HIV-1-associated TB by more than 80% in an area endemic with TB and HIV-1.33 The greatest number of TB cases averted by HAART was in the subset of patients with baseline WHO stage 3 or 4 or CD4 counts below 200. In patients with a CD4 count of more than 350 cells/mL there was no difference in TB incidence. The authors concluded that TB preventive therapy might be a more attractive alternative for reducing the risk of TB in patients with CD4 counts between 200 and 350 cells/mL. In this group of patients it is likely to be more feasible to exclude active TB than in patients who have advanced HIV disease. So far, all TB prophylaxis trials have been performed in persons who were not receiving ART. These trials have often been performed in VCT sites including persons who were asymptomatic or pauci-symptomatic and without severe immune deficiency. Today we need to determine when and which TB prophylaxis regimens could be used in symptomatic patients and/or patients with severe immune deficiency who meet the criteria for starting ART. Tuberculosis prophylaxis regimens in the era of HAART offer quite some opportunities (Box 76.1): 1. Taking INH everyday can give an idea of the adherence potential of the patient, invaluable information in view of its importance once the patient eventually needs ART. 2. Tuberculosis prophylaxis regimens could reduce the risk of the immune reactivation inflammatory syndrome (IRIS) once ART is started.34–36 As mentioned earlier, challenges remain: first there is the obvious risk of combining potentially toxic and interacting drugs (see above). Second, in countries with limited resources HAART is started in patients in WHO stage 3 or 4 or with CD4 counts below 200 cells/mL. Before considering TB prophylaxis in these patients the presence of active TB should be excluded. There is a high probability that patients, categorized as WHO stage 3 or 4, do have either latent or even clinical TB, which cannot be diagnosed because of the characteristics of the currently available diagnostic tests in resource-poor settings.37
Box 76.1 Key learning points 1. INH effectively reduces the risk of reactivation TB. 2. Short RIF-based regimens improve patient adherence but need to be used with caution in view of toxicity and interactions with ARV drugs. 3. TB preventive treatment should be targeted to well-defined risk groups. 4. Risk groups are different in high- and low-income countries. 5. Identification of candidates for preventive treatment depends on tuberculin testing; if resources permit, the new interferon-g tests may be more appropriate. 6. Implementing TB preventive treatment on a large scale in high-HIV/ TB-prevalent countries with limited resources is complicated. One of the main obstacles is how to exclude active TB in a symptomatic person with HIV infection. 7. TB preventive treatment remains useful in the era of HAART but strategies need to be reassessed.
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Prophylaxis with antituberculous drugs in special situations
REFERENCES 1. Centers for Disease Control and Prevention. Guidelines for using QuantiFERON-TB Gold Test for detecting Mycobacterium tuberculosis infection, United States. MMWR Morb Mortal Wkly Rep 2005;54(RR15):49–55. 2. Liebeschuetz S, Bamber S, Ewer K, et al. Diagnosis of tuberculosis in South African children with a T-cellbased assay: a prospective cohort study. Lancet 2004;364(9452):2196–2203. 3. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc 1970; 26:28–106. 4. Jones JL, Hanson DL, Dworkin MS, et al. HIVassociated tuberculosis in the era of highly active antiretroviral therapy. The Adult/Adolescent Spectrum of HIV Disease Group. Int J Tuberc Lung Dis 2000;4(11):1026–1031. 5. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002;359(9323):2059–2064. 6. Ormerod LP. Tuberculosis and anti-TNF-alpha treatment. Thorax 2004;59(11):921. 7. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005;60(10):800–805. 8. International Union against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Organ 1982;60(4):555–564. 9. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Pt 2):S221–S247. 10. Chaisson RE. New developments in the treatment of latent tuberculosis. Int J Tuberc Lung Dis 2000; 4(12 Suppl 2):S176–S181. 11. Streeton JA, Desem N, Jones SL. Sensitivity and specificity of a gamma interferon blood test for tuberculosis infection. Int J Tuberc Lung Dis 1998;2(6):443–450. 12. Kimura M, Converse PJ, Astemborski J, et al. Comparison between a whole blood interferongamma release assay and tuberculin skin testing for the detection of tuberculosis infection among patients at risk for tuberculosis exposure. J Infect Dis 1999;179(5):1297–1300.
13. Clark SA, Martin SL, Pozniak A, et al. Tuberculosis antigen specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV-1) patients with advanced disease. Clin Exp Immunol 2007;150(2):238–244. 14. Nahid P, Daley CL. Prevention of tuberculosis in HIV-infected patients. Curr Opin Infect Dis 2006;19(2):189–193. 15. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 1999;3(10):847–850. 16. Ji B, Truffot-Pernot C, Lacroix C, et al. Effectiveness of rifampin, rifabutin, and rifapentine for preventive therapy of tuberculosis in mice. Am Rev Respir Dis 1993;148(6 Pt 1):1541–1546. 17. Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. Uganda-Case Western Reserve University Research Collaboration [see comments]. N Engl J Med 1997;337(12):801–808. 18. Halsey NA, Coberly JS, Desormeaux J, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998;351(9105):786–792. 19. Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice weekly tuberculosis preventive therapy in HIV infection in Zambia. AIDS 1998;12(18):2447–2457. 20. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS Clinical Trials Group, the Pan American Health Organization, and the Centers for Disease Control and Prevention Study Group. JAMA 2000;283(11):1445–1450. 21. Centers for Disease Control and Prevention. Update: Adverse Event Data and Revised American Thoracic Society/CDC Recommendations against the Use of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis Infection – United States, 2003. MMWR Morb Mortal Wkly Rep 2003;52(31):735–739. 22. Schechter M, Zajdenverg R, Falco G, et al. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. Am J Respir Crit Care Med 2006;173(8):922–926. 23. Centers for Disease Control and Prevention. Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC
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recommendations – United States, 2001. MMWR Morb Mortal Wkly Rep 2001;50(34):733–735. Davies PDO. Chapter 8: Histopathology. In: Clinical Tuberculosis. London: Chapman & Hall, 1998. Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004;(1):CD000171. Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ 2007;334(7585):136. Lucas SB. Mycobacteria and the tissues of man. In: The Biology of the Mycobacteria. London: Academic Press, 1988: 107–176. Lambert ML, Hasker E, Van Deun A, et al. Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 2003;3(5):282–287. Fraser A, Paul M, Attamna A, et al. Treatment of latent tuberculosis in persons at risk for multidrugresistant tuberculosis: systematic review. Int J Tuberc Lung Dis 2006;10(1):19–23. Wilkinson D, Squire SB, Garner P. Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials. BMJ 1998;317(7159):625–629. Bucher HC, Griffith LE, Guyatt GH, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: a metaanalysis of randomized controlled trials. AIDS 1999;13(4):501–507. Corbett EL, Marston B, Churchyard GJ, et al. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet 2006;367(9514):926–937. Guelar A, Gatell JM, Verdejo J, et al. A prospective study of the risk of tuberculosis among HIV-infected patients. AIDS 1993;7(10):1345–1349. Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158(1):157–161. Navas E, Martin-Davila P, Moreno L, et al. Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 2002;162(1):97–99. Wendel KA, Alwood KS, Gachuhi R, et al. Paradoxical worsening of tuberculosis in HIVinfected persons. Chest 2001;120(1):193–197. WHO Global Tuberculosis Programme, UNAIDS. Policy statement on preventive therapy against tuberculosis in people living with HIV. WHO, 1998.
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Issues in global tuberculosis control Donald A Enarson, Asma I ElSony, Chiang Chen-Yuan, and I D Rusen
Tuberculosis remains an important challenge to global public health, despite more than a century of efforts to control it, the relative lack of success being noted during that time. King Edward VII famously remarked, ‘If preventable—why not prevented?’1 More recently, Gro Harlem Brundtland, Director General of the World Health Organization, remarked, ‘An ancient disease is killing more people today than ever before. Tuberculosis—which many of us believed would disappear in our lifetime—has staged a frightening comeback.’ These remarks are as relevant today as they were when they were made. This chapter will examine various issues in global TB control. The term ‘control’ as used in respect to communicable diseases is defined by Last as ‘ongoing operations or programs aimed at reducing the incidence and/or prevalence, or eliminating such conditions.’2 Concerted efforts have been directed to control TB for a very long time. At the first international conference on internal medicine in Paris in 1867, even before the etiological agent had been identified, physicians noted that TB was one of the most frequent and difficult conditions with which they had to deal. They concluded that there was a need for periodical meetings of interested parties to share progress and insights in the control of TB and, since that time, periodical international conferences have been held. This led in 1901 to the creation of a ‘Bureau’ in Berlin for organizing these conferences and to a permanent office in Paris, called the International Union against Tuberculosis (now termed The Union) in 1920. Thus, The Union is the oldest international non-governmental organization in the world dealing with health. A significant amount of groundwork to address other communicable diseases prior to the organized efforts to address TB had been undertaken. While critical thinking was developing in regard to other communicable diseases, the line of development for action against TB, in many ways, paralleled, rather than coordinated with, it. Accordingly, it is useful and important to revisit progress in other domains to understand the general outline of thinking and approach to the control of communicable diseases, to abstract lessons learnt, and to evaluate the progress in the control of TB from this perspective. In order to develop a framework for considering approaches to communicable disease control in general, we have drawn on several sources.3–5 From these, we have prepared a framework for evaluating the present state of global TB control and to critically evaluate it in light of work on other communicable diseases.
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FRAMEWORK FOR CONTROL OF COMMUNICABLE DISEASES AND ITS RELATIONSHIP TO TUBERCULOSIS CONTROL THEORY OF COMMUNICABLE DISEASE AND ITS RELATION TO TUBERCULOSIS The earliest expositions on communicable disease theory, including that of ‘phthisis’ (TB) in western Europe, were published by Girolamo Fracastoro (1478–1553).6 In his treatise he hypothesized the origin of TB from both agents outside the body and those that arose from within and advised their control through ‘sterilization’. The general concept of the contagious nature of TB was maintained throughout much of southern Europe over the following 150 years, with isolation, sterilization, and mandatory reporting of cases as measures for controlling it. Criteria for establishing aetiology in relation to communicable diseases were developed in the 1840s by Henle. The theoretical work of Henle was followed a decade later by that of Snow.7 This theoretical framework was developed at least a year prior to the observations concerning the role of the Broad Street pump in the cholera epidemic in the city of London. Thus the theory informed the observation so that it is not surprising that the removal of the handle from the pump was later seen to be incidental to the control of the epidemic. Addressing the theory of communicable disease in relation to cholera, Snow noted that:
For each communicable disease there is a distinct and specific cause; The causal agent is a living organism which is stable over many generations of propagation; Infection is necessary for communication to occur; and The quantity of infectious material transmitted is increased by multiplication after infection to produce disease manifestations.
Henle’s work was later refined by Koch. By 1882, these had been formulated into Henle–Koch postulates which specified the criteria for a causative agent (Table 77.1).2 Villemin’s experiments, even prior to the definition of the Henle– Koch postulates, demonstrated that inoculation of material from patients with TB into animals created the disease in the inoculated animals.8 These experiments were further expanded by Koch who demonstrated all the criteria of his famous postulates for TB, reported in 1882.9 Thus, TB was at centre stage in the development of communicable disease theory during these formative years.
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Issues in global tuberculosis control
Table 77.1 Henle-Koch postulates for essential criteria 2 for a causative agent Criterion
Specification
1. 2. 3.
Shown to be present by pure culture in every case Not found in cases of other diseases Capable of reproducing the disease in experimental animals Recoverable from the experimental disease
4.
AGENT, HOST, ENVIRONMENT, AND TRANSMISSION Given the background of the Henle–Koch postulates, the aetiological framework of modern epidemiology in which transition from health to disease is seen to be ‘caused’ by a determinant,10 and the biological context of communicable diseases, it is important to understand the context of agent, host, environment, and transmission, the so-called web of causation.
The agent Mycobacterium tuberculosis is an intracellular pathogen that, like other organisms of this sort (certain systemic fungal infections, Pneumocystis jerovici, Cryptococcus neoformans, and Toxoplasma gondii), can remain in a dormant or latent state, reactivating and causing disease some time remote from the point of infection. The characteristics and mechanisms of latency have been very poorly understood but are key to the prolonged persistence of TB in the individual and the community host in that latent bacilli can reactivate many years after initial infection, meaning that control efforts must be sustained for decades (at least for the lifetime of the last generation infected with M. tuberculosis). A fascinating study, drawing on old observations from the 1920s, of the location of latent bacilli in lung tissue was published in 2000.11 This study, using in-situ PCR on apparently healthy lung tissue obtained at autopsy, identified persistent bacilli in alveolar and interstitial macrophages as well as in type II pneumocytes, endothelial cells and fibroblasts. This startling and important finding has not yet been followed up by other studies, in spite of the importance of understanding latency and persistence in moving forward toward new and more effective means of control of tuberculosis. The virulence of M. tuberculosis has been shown to vary among different strains. Those strains with increased virulence may result in extensive transmission.12 The size of the bacterial population accessible to airways, among other factors, is one of the key determinants of the probability that an exposed individual will become infected by contact with a case of TB.13 This risk is most probably related to the ‘intensity’ of exposure reflected by the concentration of droplet nuclei in the air surrounding the case of TB. This observation has often been considered to imply that it is only the sputum smear-positive case that is infectious. This is clearly untrue. Moreover, the degree of infectiousness of a case is a continuum on a logarithmic scale with the highly sputum smear-positive case (the one with the largest bacterial population accessible to the ambient environment) the most infectious but with virtually all cases (and possibly even individuals without disease but who have been infected—particularly those recently infected) having a certain degree of infectiousness. Thus if one assigns an arbitrary factor of 1,000 for the risk of infectiousness of the sputum smear-positive case, one can extrapolate a risk ten times less for the sputum
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smear-negative but culture-positive case (a factor of 100) and probably a risk 100 times less for the case with previous disease currently inactive but never previously treated (a factor of 1), based on the observation that at any point in time such an apparently inactive case has a probability of 1% to have at least one culture positive.14 These observations have clear implications for priorities in TB control. Although infected humans are the most important environmental reservoir for M. tuberculosis, the bacillus and its close relative, Mycobacterium bovis, which can cause disease indistinguishable from that due to M. tuberculosis, can also be found in various other animal species, most notably cattle. Because the vast majority of human disease arises from transmission of infection from one human to another, the human reservoir has been the focus of attention and of efforts to eliminate the bacillus through the use of treatment of latent infection. Almost no attention has been given to the animal reservoir, even to the point that its distribution in man and in animals is not well characterized.15
The host The probability of developing clinical TB is determined more by characteristics of the host than by those of the causative organism. This view is supported by the fact that the great majority of those who become infected with M. tuberculosis never develop the disease, although they may harbour the bacilli in their bodies for decades. Genetic factors of the host may affect the susceptibility to TB.16 Those most likely to develop disease following infection are those whose immune competence is impaired (for example, those with diminished immune function caused by human immunodeficiency virus (HIV) infection, very small children whose immune systems are not yet fully developed, and those on immunosuppressive treatment). Recent studies have provided new knowledge on ‘immunity’ created by previous experience of tuberculous infection and disease. The understanding of the pathogenesis of TB that emerged as the disease began to decline in western Europe was that previous infection (and disease that had progressed to inactivity) conferred on the individual an element of protection against further (re-) infection.17 Subsequent TB was thus thought to stem primarily from reactivation of remote infection. Recent molecular epidemiological studies have suggested that this is indeed not always the case and that patients previously cured of the disease not only may not have a reduced risk of reinfection but that this risk of developing recurrent TB due to reinfection might actually be increased.18 It is not clear whether this represents an increased risk of the host or a higher risk represented by a subset of the population with enhanced environmental risk. The disease has a characteristic course (natural history) both in the individual host and in the ‘community’ host. The clinical appearance of TB is closely related to the course (timetable) of TB in the individual. The classical picture of the TB timetable was described in a prospective study in Swedish children admitted to an institution for care because their parents had been admitted to an isolation unit because they had active TB.19 A prospective study of these children admitted after exposure to the bacteria that their parents exhaled showed that, among those who became infected, many demonstrated a mild flu-like illness within a few weeks followed by conversion of their tuberculin skin reaction, indicating the clinical correlates of primary infection. The changing clinical picture of disease then emerged with time since infection, with meningitis occurring in small children shortly after infection,
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tuberculous pleurisy within 6 months of infection, tuberculous lymphadenitis within the first year, and other forms appearing later. Genitourinary TB appeared many years (and even decades) after infection. More recent studies of the clinical picture of TB associated with HIV infection have shown a close correlation between the level of immune function in persons living with HIV/acquired immunodeficiency syndrome (AIDS) and the clinical picture of TB.20 The profile of TB in the ‘community host’ varies considerably, depending upon the ‘phase’ of the TB epidemic.21 At the peak, incidence reaches as high as 1% per annum, is greatest in young adults, and is often higher in women than in men; high-risk groups are thought to be absent; most disease follows straightaway after (re-)infection; and almost the entire population has significant tuberculin reactions. When the disease is well on its way to decline, the rates are highest in the elderly and higher in men than in women; high-risk groups account for a substantial proportion of the cases; most disease is related to reactivation of remote infection; and in many previously infected individuals, their tuberculin reaction reverts to non-significant. Indeed, monitoring the median age of cases has been proposed as one means to track the direction of the epidemic.22 The profile of TB when it is rising in the community had been less well studied as there were, until recently, few examples. The effects of the HIV pandemic have afforded such an opportunity, although systematic evaluation, as has been undertaken at the height of the epidemic and on the descending limb, has not been reported. What is clear is that as the HIV-related epidemic takes hold, the median age of cases declines, disease rates rise first in young women, then older men, the probability of dying from the disease and from other causes rises, and extrapulmonary sites increase in frequency among cases. These characteristics clearly impact on the intervention strategies appropriate for a given period and setting.
The environment The physical environment (the density of infectious particles and air exchange in the space where the contact occurs) and the duration of exposure are key determinants in transmission of various communicable diseases. This, however obvious currently, was only relatively recently shown conclusively.23 It is a key predictor of transmission of TB and may explain some variations in TB epidemiology according to location. For example, the historically high rates of TB in adverse climates (in all northern climates but particularly among Inuit) may be partially explained by the prolonged periods spent in tight and closed environments due to the extreme climate around the North Pole.24 Detailed analysis demonstrated how prolonged exposure to an infectious case in a submarine led to infection of numerous contacts.25 More recent refinements of assessment of risk given contact with an active case of TB, using the hourly risk of infection, may explain the wide variation in risk of infection.26 Finally, delay in diagnosis of cases has now been clearly demonstrated to be a determinant of the probability of becoming infected, given contact with an active case.27 The prediction of risk of infection given contact with a case of TB cannot be explained solely by physical aspects of the environment. Social factors have also been demonstrated to be important.28 Moreover, social science approaches to evaluating risks have been proposed as important means for refining strategies for predicting communicable disease transmission with particular examples from HIV/AIDS.29
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Transmission Transmission is determined by the interaction between the agent, the host, and the environment. The transmission of tuberculous infection is not only a function of the virulence of the organism, but also of the intensity and duration of exposure.13 Droplet nuclei have been identified as the most significant mechanism of transmission, the nuclei being many times more frequent among cases with high bacterial loads in their lungs and particularly if they have cavity formation and are likely to create aerosols (for example, by coughing). Aerosols created by butchering infected meat may also transmit infection.30 Transmission through ingestion of infected meat has been very little studied and guidelines on handling meat from infected animals vary widely from one location to another. Transmission through ingestion of infected milk is also clearly possible, but is much less frequent than transmission via aerosol. Mutations associated with drug resistance reduce the biological fitness of M. tuberculosis.31 These observations have led many to believe that drug resistance renders the bacillus less infectious and therefore it contributes little to the TB epidemic. Evidence that this was not the case was put forward, based on mathematical models of TB transmission based on data from Taiwan and Korea which showed that ‘chronic’ cases were more likely to be sources of new cases in a community than were new cases.32 The transmission potential of these cases has been confirmed by molecular studies.33 It seems most likely that the force of infection is determined more by the duration of exposure than by the virulence of the bacilli. Thus it is not reasonable to base assumptions on transmission on a single factor, nor to underestimate, based on inadequate information, the contribution of one factor among many. Indeed, the progressive emergence of increasingly drug-resistant forms of TB (most recently, the ‘extensively drug resistant’, XDR forms) poses a major challenge to the potential for control of TB, resulting from the negligence of those responsible for the care of patients.34 Continuing misuse of the precious and needed medications that will be expected to be produced by the recent investments in ‘tools development’ will risk each of these medications as they are produced, rendering the disease untreatable, even with the new medications. The sum of TB in a community is the result of a series of related transitions.35 The core transitions are those that contribute to the appearance of clinical TB (the transitions from infection to disease, from inactive to active disease) and the disappearance of clinical TB (from disease to death or to inactivity or to cure). Associated with and contributing to these core transitions are those transitions from exposure to infection (feeding into the transition from infection to disease), and those associated with seeking and obtaining appropriate care (feeding those transitions from disease to inactivity). Thus any factor that increases the probability of exposure (especially density of cases) or of infection (intensity and duration of exposure) will increase the transition towards more cases. Any factor that improves access to and quality of care will increase the transition towards fewer cases. PRINCIPLES AND STRATEGY FOR COMMUNICABLE DISEASE CONTROL: THE CASE OF TUBERCULOSIS Maintenance of TB in the human population requires that each case replicates itself with another case; a replication rate of greater than one enhances the disease; a replication rate of less than one diminishes (and eventually eliminates) the disease.
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This:
explains the ‘natural decline’ in TB observed prior to chemotherapy; but does not take into account any reservoir outside humans.
Despite the focus on, and fear of, TB, it remains a rare disease in most settings (less than 1 per 1,000 population). The modern view of TB assumes an inefficient transmission dynamic for M. tuberculosis. Transmission is primarily determined by prevalence of cases and frequency and intensity of exposure. It is assumed that any intervention that reduces the rate of production of new cases or hastens the disappearance of existing cases will tip the balance against the disease. Last defines a strategy as ‘A set of essential measures (preventive and therapeutic) believed sufficient to control a health problem.’2 The modern strategy for control of TB focuses on hastening the disappearance of existing cases (on the theory that reducing duration of a case will drastically reduce transmission potential). It is believed that case detection and successful treatment can reduce transmission of infection by up to ten times. A perverse aspect of this strategy is that if the two interventions (case finding and successful treatment) are not carefully linked, improved case finding with poor treatment outcome can actually worsen the epidemiological situation by keeping patients alive without curing them (prolonging the period of infectiousness).36 Thus, the priority is on improving treatment outcome prior to enhancing case finding. The next component of the modern strategy for TB control, in terms of priority, is the identification of groups at high risk of developing disease—contacts of active cases,13 the immunocompromised (HIV prevention), and those with healed TB never previously treated37—and treating them to reduce their risk of developing disease. The final element in the modern strategy is vaccination of small children who live in communities with a high risk of TB, with the intention of preventing serious disease and death in these vulnerable individuals.38
METHODS FOR COMMUNICABLE DISEASE CONTROL From the framework for communicable disease control, a series of methods generally applied within public health structures have been identified.
Clinical governance and audit The current approach to global TB control focuses primarily on the transition from TB disease to disease inactivity (through efficient treatment and permanent cure of the patient). The intervention to achieve this is a clinical activity. Thus, the result of TB control is a function of the sum of medical interventions with individual patients. The quality of medical intervention is highly dependent upon the establishment, widespread use and maintenance of quality of standard case management. Without careful monitoring of adherence to practice guidelines, the quality of medical care has been consistently shown to be substandard for many conditions, including TB.39,40 As maintaining a high quality of medical intervention for each case is essential to obtain the goal of TB control, mechanisms for ensuring the quality of this care are vital. Within the current guidelines for global TB control, reporting of activities and outcomes of TB treatment and care are key. Indeed, of the five core components of the original model,41 ultimately defined as directly observed treatment, short-course (DOTS), reporting and
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monitoring have been invaluable. This functions as a form of audit and also empowers the care provider with essential information needed to identify challenges and to modify practice accordingly in order to improve the quality of the services provided.
Health protection Among the methods for communicable disease control is a series of elements collectively termed ‘health protection’. They include a variety of activities. Public health legislation Public health legislation has been an historical component of communicable disease control in most industrialized countries and is still used for control of TB in a number of locations. The content of, and procedures for applying, public health law have recently come under critical review.42 Using the example primarily of its use in control of venereal disease and the consequences of this for HIV/AIDS, the author points out a number of limitations of the current laws in the United States and indicated that ‘Future public health statutes should specify that personal control measures must be based on a finding that the person is in an infectious state, and is reasonably likely to transmit the infectious agent, causing a serious risk to the public health.’ Interestingly enough, these conditions are largely met in the application of public health law in the field of TB. The role of public health legislation is a topic that has been pretty much scrupulously avoided (or the subject of invective across the Atlantic) in discussions of global TB control policy. Nevertheless, public health legislation is one of the components of the framework for communicable disease control. In light of the demonstrably harmful role played by medical practitioners in creating drug resistance and of international public health advisors in restricting access to care, international public health legislation should probably focus on accountability and culpability in these areas, rather than focusing primarily on the patient. Quality assurance As noted earlier, the quality of case management is the key to progress in TB control. Consequently, the evaluation, reporting, and analysis of the outcome of treatment, especially for the priority smearpositive patients, are vitally important. This feature has now been adopted by most countries and is an important tool not only for guiding implementation nationally but also for empowering local health service providers in addressing challenges to achieving good results. Quality assurance mechanisms have now been developed for the most basic diagnostic procedure, sputum smear microscopy.43 Implementation of these guidelines remains insufficient with many peripheral laboratories continuing to perform suboptimally. Quality assurance of other diagnostic procedures (chest radiography, mycobacterial cultures, diagnostic algorithms) have not yet been widely or effectively established. Surveillance Surveillance is one of the key elements in TB control. The standardization of data recording, collecting, and reporting has been crucial in moving forward in global TB control. The annual reports of the World Health Organization (WHO) provide information for all nations and force jurisdictions to be accountable for their progress (or lack thereof) in TB control.44 This has been key in engaging political commitment and has been effective in encouraging those countries that are lagging in their efforts to greater diligence.
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Nevertheless, the comprehensiveness of the surveillance remains a matter of concern and continuous efforts must be made to ensure a high level of quality.45–47
Statistics and modelling The WHO has undertaken to estimate the global burden of TB for each country, based on the best available information.48 These estimates have been regularly updated,44 and have been used to monitor progress towards TB control targets and to focus activities for reaching those targets. Recently, however, the reliability of these estimates has been questioned in a number of countries and their value in directing activities may be diminishing if they cannot be more accurately determined. Indeed, the pursuit of targets may become counterproductive in some instances unless the estimates can be improved. Last has defined modelling as ‘a representation of a system, process or relationship in mathematical form in which equations are used to simulate the behaviour of the system or process under study’.2 Mathematical modelling has been widely used to guide communicable disease control activities. In the case of TB, a number of modelling exercises have informed global policy on TB control. One of the first to do so was that of Waaler and Piot, which outlined the transitions in TB epidemiology and control and identified the priority areas for action.49 Results of the model indicated that the highest priority must be placed on case finding. The simple logic of the model was that, of 1,000 existing cases, if one cured 95% but found only 10%, this left 905 cases in the community; alternatively, if one cured 60% but found 80%, this left 520 cases as sources of infection. Clearly the highest priority, in this model, must be case-finding. Unfortunately, this model did not take into consideration the negative impact of poor quality of case management. This was highlighted several years later in a publication that demonstrated the impact of poor treatment in keeping patients alive and infectious but failing to cure them, thus increasing prevalence and transmission.36 Moreover, the failure of control efforts to achieve substantial improvement in the TB situation actually led to a discrediting of these activities and a decline in political commitment, which led to the dismantling of serious efforts at the WHO. The observation that ‘poor treatment is worse than no treatment’ is one of the cornerstones in the revised approach currently employed. Modelling is currently being used to monitor progress towards targets established for The Global Plan to Stop TB 2006–2015 for reduction of prevalence, incidence, and mortality.50 Although this will inform the process of global TB control, it is clearly not sufficient, given the previous negative effects of inadequate models noted above. It is obvious that monitoring must include actual measurements of progress towards targets as well as mathematical modelling.
The impact of international migration is not the whole story. Internal displacement and migration also represents a challenge to TB control. Internal migration brings with it the risk of TB from the community of origin and also the instability of migrant populations, making health services delivery very difficult, especially for a disease like TB that requires long-term treatment.53
Managing incidents and outbreaks Although the occurrence of epidemic TB is a characteristic of when the disease is on the decline,54 the detection and management of outbreaks are relatively poorly organized, as compared with other communicable diseases. The main activities for detection and management have focused on contact investigation and detection and management of nosocomial TB, which have received impetus from incidents where the combination of multidrug-resistant (MDR-)TB and HIV infection have led to fatal outbreaks,55 and more recently, with XDR-TB.34 Advances in molecular genetic techniques should enhance the capacity for detection of such incidents.56 The efficiency of this approach is limited and its major contribution to date has been retrospective evaluation and analysis. Clearly this is an area that requires further attention and development as these techniques should be able to contribute far more in a real-time manner.
Special services In addition to routine care of patients with communicable diseases, a variety of ‘special’ services have been put in place for communicable disease control. They may vary according to the type of communicable disease being considered.
Infection control (nosocomial, occupational) Enhanced transmission of TB within residential facilities has been dramatically illustrated for more than a century. The rapid rise in deaths from TB among aboriginal children placed in boarding schools in western Canada in the early twentieth century has been one of the most dramatic episodes of epidemic TB ever recorded, where death from TB rose from 1% of students to 9% over a decade.57 A similar pattern followed the conscripting of service men from Africa (where TB was uncommon at the time) into European armies during the First World War. The young men rapidly developed TB and many died of their disease.58,59 These experiences have been repeated in recent times in hospital settings where TB patients are admitted together with persons living with HIV/AIDS,60 and in prisons, most notably those in the former Soviet Union, which were overcrowded and the inmates severely malnourished.61 The presence of MDR-TB led to widespread transmission both within the prisons and into the community. As a result guidelines for controlling nosocomial transmission in prisons were developed.62 Although it should be apparent that careful precautions must be taken to control nosocomial transmission of TB in those living with HIV/AIDS, recent visits to ‘day hospitals’ for the care of such persons in Africa revealed an alarming lack of precaution or concern with TB prevention, especially in a setting where pressure to reach the ‘3 by 5’ targets was enormous. Similar observations pertain to the risk of tuberculous infection and, more dramatically, risk of infection with MDR organisms among healthcare workers, particularly in developing countries.63 Although guidelines for control of nosocomial transmission of TB in hospital settings are available,64 the problem continues unabated in many high-burden countries.
Migration and importation For countries where the rates of TB are low, population migration represents the principal source of new cases and delivering effective services for prevention of cases in such populations is challenging.51 Moreover, the migration of TB is not restricted to immigrants and refugees. With the exploding market in overseas travel, risks to visitors to other countries are also measurable.52
Research, development, and innovation In-built research within public health programmes for TB control was recommended as an essential component of national TB programmes,65 but was poorly developed in the modern strategy prior to the establishment of The Stop TB Partnership and the Global Plan to Stop TB. These initiatives have brought back an emphasis on tools development (diagnostics, drugs, and vaccines). However,
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with a gap of some decades, development of these new tools is lagging seriously behind the needs. Operational research, while recognized to be important, still does not receive the priority or resources it needs, thus not allowing the potential for action created by this research to be realized.
ORGANIZATION OF SERVICES Administrative arrangements Since 1993, after several decades of neglect, the WHO has made TB a priority. By recognizing the importance of TB and adopting an approach (the DOTS strategy) for controlling the disease, the WHO has once again endorsed the essential role of government as the vehicle for TB control. By identifying and focusing on the 22 ‘high-burden’ countries, WHO has managed to engage the vast majority of national governments to adopt the National Tuberculosis Programme framework and the DOTS strategy. Coordination The need for wide-ranging partnership in the fight against TB was formally recognized by the establishment, at global level, of The Stop TB Partnership,66 a model for coordinating communicable disease control. Subsequently, WHO has encouraged national programmes to develop mechanisms (interagency coordinating mechanisms, national Stop TB Partnerships, etc.) for enhancing coordination among all players. Diagnostic and reference laboratories The role of microbiological services in the control of TB has been one of the core components of the DOTS strategy. Through the establishment in 1994 of the WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance, a network of supranational reference laboratories has been created to support and strengthen national TB reference laboratories, presently headed by the Institute of Tropical Medicine in Antwerp, Belgium. This network has standardized and monitored drug susceptibility testing for first-line medications and has carried out national surveys of drug resistance in a large number of countries.67 Within the global strategy for TB control, the national TB reference laboratory is a key component.68 Despite this, most high-burden countries do not have efficient or effective national reference laboratories to establish and maintain high-quality diagnostic laboratories accessible to the majority of the population, nor do they systematically provide the specialized services needed by the national public health services. Hopefully this will change now that financing and technical guidelines for the care of drug-resistant cases is becoming increasingly available, but progress to date (despite the declared priority for this type of services) has been extremely disappointing in most countries. Human resources Although strategies and programmes may be in place, a major bottleneck in communicable disease control has been insufficient quantity, quality, and distribution of health services personnel to carry out the work.69 The health workforce crisis is often the result of policies and recommendations from international experts from organizations such as the International Monetary Fund and the World Bank, leading to national policies of staff reductions, freezing of salaries, and limitations of adequate financial compensation, leading to the need for private practice or other sources of revenue on the part of existing personnel. Moreover, human resource development programmes already in place are not enhancing capacity sufficiently to meet the needs.70
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Although the Global Plan to Stop TB 2006–2015 highlights this as a problem,71 the plan lacks a clear analysis of the problem or a way forward to address it.
Public information/media relations The progress in establishing TB as a priority on the agenda for development and for health has been the result, among other factors, of raising public awareness through the media. The presence of TB in international (and particularly in the American) media drew the attention of national policy makers in developing countries in a manner that would never have occurred if the news had been reported only locally. The importance of public information has been underscored by the participation of world leaders such as the Nobel laureates Archbishop Desmond Tutu and, more recently, Nelson Mandela in relating their own personal history and commitment to global TB control. Mobilization of financial resources Key steps in mobilizing resources for global TB control were taken in the late 1980s when the World Bank undertook the Health Sector Priority Review and the subsequent World Bank Report 1993.72 This review compared returns (in terms of disabilityadjusted life-years saved) on investment in various health interventions in developing countries. This analysis showed TB programmes developed through the Mutual Assistance Programme of The Union to be among the most cost-effective of any health intervention in developing countries. Based on this analysis, the World Bank undertook to lend money to various countries (including China, India, and Bangladesh) for developing and expanding TB control programmes along the model developed by The Union. The analysis also provided evidence to convince the WHO to make TB a priority and led to the current global TB control efforts. The G8 summit in Okinawa considered health as an issue for development and identified the need for investment in public health services with an emphasis on AIDS, TB, and malaria. Subsequent steps led to the establishment of the Global Fund to Fight AIDS, Tuberculosis and Malaria which has, as of 2006, committed $6.8 billion in 136 countries to combat the three diseases. This has contributed substantially to move forward global TB control efforts. Financing for TB control is a key issue and sustainable financing an even more vital element. The analysis of the World Bank reported in 1993 was crucial to this argument. It concluded that TB control was so cost-effective that no government could afford not to invest in it. With this argument, it had been possible to convince a number of developing countries to include TB control in their national budgets. This progress has, in some ways, been lost through the impact of international funding mechanisms: policymakers conclude that, if resources can be obtained through other sources, it is unnecessary to include them in national plans.
CRITICAL ISSUES IN CURRENT GLOBAL TUBERCULOSIS CONTROL ACTIVITIES Whereas the framework for global TB control appears to be logical, is relatively well supported from the evidence, and is now being widely and intensively applied, it has not yet succeeded in controlling TB. The failure to achieve the goal was recognized first in industrialized countries where the approach had been official policy for decades. The most dramatic illustration was in New York City in the early 1990s.73,74 This failure was addressed, for example, by public health authorities in England and Wales.5 They identified a series of factors
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Table 77.2 Factors associated with failure to reach goals 76 of tuberculosis control in England and Wales Factor
Specification
1. 2. 3. 4. 5. 6.
Migration of risk groups HIV infection Aging of the population with risk of reactivation of disease Social and economic complexities Lack of awareness in communities and professions Inadequate resources
Table 77.3 Elements for regaining control of tuberculosis 76 in England and Wales Element 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Specification Improving awareness of professionals, community leaders, and the population Ensuring adequate resources (human above all) Adjusting services to the needs of the patients/communities Maintaining screening/case-finding in migrants Rapidly identifying/managing outbreaks Testing TB patients for HIV Achieving and maintaining high levels of successful treatment outcomes Enhancing surveillance Promoting research Contributing to global efforts for disease control
as contributing to this failure (Table 77.2) and identified a series of elements for regaining control of TB (Table 77.3). Will the global TB control efforts following The Global Plan to Stop TB 2006–2015 have poor results similar to those described in England and Wales? Certainly one must not become complacent and just assume that this will not happen. What are some of the pitfalls likely to occur?
LIMITATIONS OF THE CURRENT APPROACH TO GLOBAL TUBERCULOSIS CONTROL The ultimate objective of global TB control must be to reduce the prevalence of the disease with a view to its eventual elimination.2 There are several major challenges to achieving this objective. First, it is abundantly clear that the enhancement of the transition from infection to disease (and consequent increase in prevalence of cases or TB) resulting from HIV infection has tipped the balance markedly away from TB control. There is no doubt that TB cannot be controlled globally if HIV transmission is not also brought under control. Although the Global Plan to Stop TB clearly encourages collaboration between programmes for TB and HIV/AIDS, it needs to be much more explicit and aggressive in engaging everyone involved in TB control in the prevention of HIV/AIDS (not simply in providing care for this pandemic). The two diseases are two sides of a single coin and one cannot be controlled without controlling the other. Second, control of TB through the current approach is dependent on the maintenance of high-quality individual case management. Clearly, great strides have been made in improving the quality of care for large numbers of patients but it remains highly
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variable.75 However, reduction of prevalence and eventual elimination of TB using this approach will require high-quality case management for a full generation. Since this has already proven very difficult in countries with abundant resources (e.g. the USA, England/Wales), it will be all the more so at a global level. Third, standard case management is hampered by inefficient tools. Diagnostic procedures are still quite cumbersome and timeconsuming and their quality is very poor in many locations. Treatment remains long, complex, and costly to the patient and the health service and the drugs are losing their effectiveness as resistance to them emerges.76–78 However, even if these tools can be improved, the intervention is still dependent on maintaining a high-quality case management in health infrastructures that are crumbling and of poor quality. Fourth, the number of drugs available for the treatment of TB is limited. It will take a decade to develop a new antituberculous drug for routine use. As rifampicin has been widely used but the mechanism to protect rifampicin is not strictly in place, an increase of MDR- and XDR-TB cases seems inevitable.
THE NEED FOR A VACCINE-BASED STRATEGY The most successful initiatives for disease control and elimination have been those that have a vaccine-based strategy. Notable in this regard is the eradication of smallpox.79 This strategy will need to be substantially more complex than previous initiatives in that it should address not only primary prevention (prevention of infection) but also secondary prevention (prevention of disease once infected). Clearly, a highly effective vaccine programme (likely with multiple components) must have the highest priority.
THE WEB OF CAUSATION OF TUBERCULOSIS—‘THE POVERTY COMPLEX’ Tuberculosis and poverty are two sides of the same coin: if you would like to find TB, look where there is poverty; if you would like to find poverty, look where there is TB. Even in the richest countries, TB is the shadow of poverty.80–82 The old paradigm of causation (exposure/risk factor/agent leading to disease) as applied to TB may no longer be appropriate. Poverty and TB are so inextricably linked that a new paradigm, where TB, poverty, and environmental/social conditions are part of a complex rather than cause and effect, may be a more appropriate view. Can TB be eliminated/eradicated in the presence of poverty? Clearly, progress can be made to control TB even among poor communities. However, can the disease truly be eliminated/eradicated without dealing with poverty/inequity? We do know that, even without programmes or specific strategies, TB can diminish dramatically when poverty is dramatically reduced.83–85 It must hold that no global strategy for TB control can be effective without taking into account measures to address the context (poverty). It is not at all clear that this has been done effectively in the current approaches.
VARIATIONS IN TRANSMISSION DYNAMICS The current evidence base suggests that there is a ‘balance’ inherent in the transition model for TB and that, given the right balance, TB can be controlled and eliminated.86 This appears to have been true historically in what are now industrialized countries. Does it hold for the whole world?
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There is evidence that what was the case in these locations may not be the case everywhere. For example, previous evidence that individuals who had been infected in the past had a lower risk of becoming (re-)infected and developing disease, given exposure,17 does not appear to hold in some other communities where patients cured of TB actually appear at greater risk of developing recurrent TB due to reinfection.18 While models suggest that achieving a high rate of cure among a high proportion of all existing cases brought under care will ‘tip the balance’ towards TB control, and progress has been demonstrated in some locations,87,88 similar results have not been observed in other locations (such as Vietnam) where the targets for case finding and cure have reportedly been achieved and sustained. Moreover, transmission of TB has been reported to be rising in a community with a low level of HIV infection, despite TB control efforts being in place for many years.89 Do these observations constitute evidence that the model of TB and the strategy for its control may not have universal application?
ADDRESSING THE ANIMAL RESERVOIR Control, elimination, and eradication of a communicable disease requires a full understanding of that disease, including any known reservoirs for the agent. Despite global networks and surveys for
REFERENCES 1. Grzybowski S. Tuberculosis and Its Prevention. St Louis: Warren H Green, 1983:p. vii. 2. Last JM (ed.). A Dictionary of Epidemiology, 3rd edn. New York: Oxford University Press, 1995:37. 3. Webber R. Communicable Disease Epidemiology and Control. Oxford: Oxford University Press, 1996. 4. Hawker J, Begg N, Blair I, et al. Communicable Diseases Control Handbook. Oxford: Blackwell, 2005. 5. Chief Medical Officer. Getting Ahead of the Curve. A Strategy for Combating Infectious Diseases. London: Department of Health, 2002. 6. Davis A. History of Tuberculosis. In: Reichman LB, Hershfield ES (eds) Tuberculosis. A Comprehensive International Approach, 2nd edn. New York: Marcel Dekker, 2000:7. 7. Winkelstein W Jr. A new perspective on John Snow’s communicable disease theory. Am J Epidemiol 1995;142:S3–S9. 8. Villemin JA. De la virulence et de la spe´cificite´ de la tuberculose. Paris : Victor Masson et fils, 1868. 9. Koch R. Die Aetiologie der Tuberculose. Berl Klin Wschr 1882;15:221–230. 10. Enarson DA, Kennedy SM, Miller DL, et al. Research Methods for Promotion of Lung Health. A Guide to Protocol Development for Low-Income Countries. Paris: International Union against Tuberculosis and Lung Disease, 2001:17. 11. Hernandes-Pando R, Jeyanathan M, Mengistu G, et al. Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection. Lancet 2000;356:2133–2138. 12. Valway SE. Sanchez MPC, Shinnick TF, et al. An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998;338:633–639. 13. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc 1975;50(1):90–106. 14. Wang JS, Allen EA, Chao CW, et al. Tuberculosis in British Columbia among immigrants from five Asian countries. Tubercle 1989;70:179–186. 15. Fanning EA. Mycobacterium bovis infection in animals and humans. In: Davies PDO (ed.) Clinical Tuberculosis. London: Chapman and Hall, 1998, 535–552.
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microbiological analysis of TB, very little is known about the extent of distribution and consequences of Mycobacterium bovis in the world. Indeed, the condition is not even discussed in the Global Plan to Stop TB 2006–2015.
CONCLUSION Much progress has been made over the past decade in constructing a framework for global TB control, gaining consensus on policy, strategy, and methods and on mobilizing and coordinating resources to address the problem. A vision, objectives, goals, and targets have been established and a system for monitoring progress is in place. These steps inspire confidence that we may finally see progress in controlling TB throughout the world. Alternatively, there are a number of pitfalls and obstacles that may prevent us from achieving the results we expect. It is important that we neither lapse into complacency nor fall under the spell of dogma to the degree that we suspend critical thinking. Maintaining critical thinking, albeit in a positive spirit, and applying rigorous critical methods remain cornerstones for progress in control of all communicable diseases, not least TB.
16. Bellamy R, Ruwende C, Corrah T, et al. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med 1998;338:640–644. 17. Heimbeck J. Tuberculosis in hospital nurses. Tubercle 1936;18:97–99. 18. Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005;171:1430–1435. 19. Wallgren A. The time table of tuberculosis. Tubercle 1948;29:245–251. 20. Jones BE, Young SMM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Resp Dis 1993;148:1292–1297. 21. Grzybowski S, Enarson D. Tuberculosis. In: Simmons DH (ed.) Current Pulmonology. Chicago: Year Book Medical Publishers, 1985: 73–96. 22. Powell KE, Farer LS. The rising age of the tuberculosis patient: a sign of success and failure. J Infect Dis 1980;142:946–948. 23. Wells W. On air-borne infection: II. Droplets and droplet nuclei. Am J Hyg 1934;20:611–618. 24. Grzybowski S, Styblo K, Dorken E. Tuberculosis in Eskimos. Tubercle 1976;57(Suppl 4):S1–58. 25. Houk VN, Kent DC, Baker JH, et al. The Byrd study: in-depth analysis of an outbreak of tuberculosis in a closed environment. Arch Environ Health 1968;16:4–6. 26. Muecke C, Isler M, Menzies D, et al. The use of environmental factors as adjuncts to traditional tuberculosis contact investigation. Int J Tuberc Lung Dis 2006;10:530–535. 27. Golub JE, Bur S, Cronin WA, et al. Delayed tuberculosis diagnosis and tuberculosis transmission. Int J Tuberc Lung Dis 2006;10:24–30. 28. Veen J. Micro-epidemics of tuberculosis: the stonein-the-pond principle. Bull Int Union Tuberc Lung Dis 1991;61:203–205. 29. McCarthy S. Application of social network analysis to communicable disease research, 2004. [online]. Available at URL:http://www.mala.ca./cch/aded/ documents/McCarthyNetworkTheory.ppt 30. Fanning A, Edwards S. Mycobacterium bovis infection in humans exposed to elk in Alberta. Lancet 1991; 338:1253–1255. 31. Tounggoussova OS, Caugant BA, Sandven P, et al. Impact of drug resistance on fitness of Mycobacterium
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tuberculosis strains of the W-Beijing genotype. FEMS Immunol Med Microbiol 2004;42:281–290. Schulzer M, Enarson DA, Grzybowski S, et al. An analysis of pulmonary tuberculsis data in Taiwan and Korea. In J Epidemiol 1987;16:584–589. Van Rie A, Warren R, Richardson M, et al. Classification of drug-resistant tuberculosis in an epidemic area. Lancet 2000;356:22–25. Van Rie A, Enarson D. XDR tuberculosis: an indicator of public health negligence. Lancet 2006;368:1554–1556. Enarson DA, Ait-Khaled N. Tuberculosis. In: Annesi-Maesano I, Gulsvik A, Viegi G (eds) Respiratory Epidemiology in Europe. Huddersfield: The Charlesworth Group, 2000:67–91. Grzybowski S, Enarson DA. The fate of cases of pulmonary tuberculosis under various treatment programmes. Bull Int Union Tuberc 1978;53(2): 70–75. Nakielna EM, Cragg R, Grzybowski S. Lifelong follow-up of inactive tuberculosis: its value and limitations. Am Rev Respir Dis 1975;112:765–772. WHO Global Tuberculosis Programme and Global Programme on Vaccines. Statement on BCG revaccination for the prevention of tuberculosis. WHO Wkly Epidemiol Rec 1995;70:229–231. Uplekar MW, Shepard DS. Treatment of tuberculosis by private medical practitioners in India. Tubercle 1991;72:284–290. Lee LM, Lobato MN, Buskin SE, et al. Low adherence to guidelines for preventing TB among persons with newly diagnosed HIV infection, United States. Int J Tuberc Lung Dis 2006;10: 209–214. Enarson DA. Principles of IUATLD Collaborative Tuberculosis Programmes. Bull Int Union Tuberc Lung Dis 1991;66:195–200. Gostin L. The future of communicable disease control: toward a new concept in public health law. The Millbank Quarterly 2005;83:1–17. PHL, CDC, IUATLD, KNCV, RIT and WHO. External Quality Assessment for AFB Smear Microscopy. Washington, 2002. World Health Organization. Global Tuberculosis Control. Surveillance, Planning, Financing. Geneva: World Health Organization, 2006. Marais BJ, Hesseling AC, Gie RP, et al. The burden of childhood tuberculosis and the accuracy of community-based surveillance data. Int J Tuberc Lung Dis 2006;10:259–263.
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46. Baussano I, Bugiani M, Gregori D, et al. Undetected burden of tuberculosis in a low-prevalence area. Int J Tuberc Lung Dis 2006;10:415–421. 47. Chiang CY, Enarson DA, Yang SL, et al. The impact of national health insurance on the notification of tuberculosis in Taiwan. Int J Tuberc Lung Dis 2002;6:974–979. 48. Dye C, Scheele S, Dolin P, et al. Consensus statement: Global burden of tuberculosis: estimated incidence, prevalence and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 1999;282:677–686. 49. Waaler HT, Piot MA. The use of an epidemiological model for estimating the effectiveness of tuberculosis control measures. Bull World Health Organ 1969; 41:75–93. 50. The Global Plan to Stop TB 2006-2015. Available at URL:http://www.stoptb.org/globalplan 51. McPherson DW, Gushulak BD. Balancing prevention and screening among international migrants with tuberculosis: population mobility as the major epidemiological influence in low-incidence nations. Public Health 2006;120:712–723. 52. O’Brien DP, Leder K, Matchett E, et al. Illness in returned travellers and immigrants/refugees: the 6-year experience of two Australian infectious disease units. J Travel Med 2006;13:145–152. 53. Zhang L-X, Tu DH, An YS, et al. The impact of migrants on the epidemiology of tuberculosis in Beijing, China. Int J Tuberc Lung Dis 2006;10: 959–962. 54. Lincoln EM. Epidemics of tuberculosis. Arch Environ Health 1967;14:473–476. 55. Frieden TR, Sherman FL, Maw KL, et al. A multiinstitutional outbreak of highly drug-resistant tuberculosis. JAMA 1996;276:1229–1235. 56. Drobniewski F, Gibson A, Ruddy M, et al. Evaluation and utilization as a public health tool of a national molecular epidemiological tuberculosis outbreak database within the United Kingdom from 1997 to 2001. J Clin Microbiol 2003;41:1861–1868. 57. Ferguson RG. Studies in Tuberculosis. Toronto: University of Toronto Press, 1955. 58. Cummins SL. Tuberculosis in primitive tribes and its bearing on tuberculosis of civilized communities. Int J Pub Health 1920;1:10–17. 59. Borrel A. Pneumonie et tuberculose chez les troupes noires. Ann Inst Pasteur 1920;34:7–148. 60. Resende MR, Villares MC, Ramos M de C. Transmission of tuberculosis among patients with human immunodeficiency virus at a university hospital in Brazil. Infect Control Hosp Epidemiol 2004;25:1115–1117. 61. Abraha˜o RMCM, Nogueira PA, Malucelli MIC. Tuberculosis in county jail prisoners in the west of
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Sa˜o Paulo, Brazil. Int J Tuberc Lung Dis 2006;10: 203–208. Centers for Disease Control and Prevention, National Center for HIV/AIDS, viral hepatitis, STD and tuberculosis prevention. Prevention and control of tuberculosis in correctional and detention facilities: recommendations from CDC endorsed by the Advisory Council for the Elimination of Tuberculosis, the National Commission on Correctional Health Care, and the American Correctional Association. MMWR Recomm Rep 2006;55:1–44. Naidoo S, Jhinabhai CC. TB in health care workers in KwaZulu-Natal, South Africa. Int J Tuberc Lung Dis 2006;10:676–682. Jensen PA, Lambert LA, Iademarco MF, et al. Guidelines for preventing transmission of Mycobacterium tuberculosis in health care settings, 2005. MMWR Recomm Rep 2005;54:1–141. National Tuberculosis Association. Recommendations of the Arden House Conference on tuberculosis. Am Rev Respir Dis 1960;81:482–484. The Stop TB Partnership. [online]. Available at URL: http://www.stoptb.org Aziz MA, Wright A. The World Health Organization/International Union against Tuberculosis and Lung Disease Global Project on Surveillance for Anti-Tuberculosis Drug Resistance: a model for other diseases. Clin Infect Dis 2005; 41(suppl 4):S258–264. Rieder HL, Chonde TM, Myking H, et al. The Public Health Service National Tuberculosis Reference Laboratory and the National Laboratory Network. Paris: International Union against Tuberculosis and Lung Disease. 1998. Drager S, Gedik G, Dal Poz MR. Health workforce issues and the Global Fund for AIDS, tuberculosis and malaria: an analytical review. Hum Resour Health 2006:4:23. Villa TCS, Ruffino-Netto A, Andrade RLP, et al. Survey on tuberculosis teaching in Brazilian nursing schools, 2004. Int J Tuberc Lung Dis 2006;10:323–327. Figueroa-Munoz J, Palmer K, Poz MR, et al. The health workforce crisis in TB control: a report from high burden countries. Hum Resour Health 2005;3:2. World Bank. World Development Report 1993: Investing in Health. Oxford: Oxford University Press, 1993. Brudney K, Dobkin J. Resurgent tuberculosis in New York City: Human immunodeficiency virus, homelessness and the decline of tuberculosis control programs. Am Rev Respir Dis 1991; 144:745–749. Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991;144:741–742.
75. Dembe´le´ M, Ouedraogo HZ, Combary AI, et al. Are patients presenting spontaneously with PTB symptoms to the health services in Burkina Faso well managed? Int J Tuberc Lung Dis 2006;10:436–440. 76. Kanavaki S, Mantadakis E, Nikolaou S, et al. Resistance of M. tuberculosis isolates from different populations in Greece, 1993-2002. Int J Tuberc Lung Dis 2006;10:559–564. 77. Quy HT, Cobelens FGJ, Lan NTN, et al. Treatment outcomes by drug resistance, HIV status and treatment regimen among smear-positive tuberculosis patients in Ho Chi Minh City, Vietnam. Int J Tuberc Lung Dis 2006;10:45–51. 78. Sanders M, Van Deun A, Ntakirutimana D, et al. Rifampicin mono-resistant Mycobacterium tuberculosis in Bujumbura, Burundi: results of a drug resistance survey. Int J Tuberc Lung Dis 2006;10:178–183. 79. Henderson DA. The challenge of eradication: lessons from past eradication campaigns. Int J Tuberc Lung Dis 1998;2:S4–8. 80. Thomas MG, Ellis-Pegler R. Tuberculosis in New Zealand: poverty casts a long shadow. NZ Med J 2006;119:U2267. 81. Dahle UR. Tuberculosis and social exclusion: do developed countries need new strategies? BMJ 2006;333:200. 82. Jackson S, Sleigh AC, Wang G-J, et al. Poverty and the economic effects of TB in rural China. Int J Tuberc Lung Dis 2006;10:1104–1110. 83. Grigg ERN. The arcana of tuberculosis. With a brief epidemiologic history of the disease in the USA. Am Rev Tuberc 1958;78:426–453. 84. Collins JJ. The contribution of medical measures to the decline of mortality from respiratory tuberculosis: an age-period-cohort model. Demography 1982; 19:409–427. 85. Wilson LG. The historical decline of tuberculosis in Europe and America: its causes and significance. J Hist Med Allied Sci 1990;45:366–396. 86. Enarson DA. Why not the elimination of tuberculosis? Mayo Clinic Proc 1994;69:85–86. 87. No authors. TB prevalence down 30% after DOTS. Bull World Health Organ 2004;82:716. 88. Zhang LX, Tu DH, He GX, et al. Risk of tuberculosis infection and tuberculous meningitis after discontinuation of Bacillus Calmette-Guerin in Beijing. Am J Respir Crit Care Med 2000;162: 1314–1317. 89. Verver S, Warren RM, Munch Z, et al. Transmission of tuberculosis in a high incidence urban community in South Africa. Int J Epidemiol 2004;33:351–357.
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National tuberculosis programmes and tuberculosis control in developing countries Leopold Blanc and Jeremiah Chakaya
HISTORICAL ASPECTS National TB Control programmes are designed to deliver TB interventions intended to prevent TB transmission (infection) and to prevent and cure TB disease. Until the 1940s no effective interventions were available for these purposes, except Bacillus CalmetteGue´rin (BCG) which, although first used in humans in 1921 and adopted by the health committee of the League of Nations in 1928, did not find widespread use until after the Second World War.1,2 Early national TB control programmes were therefore concerned with the finding of infected and diseased persons and the delivery of BCG.3–5 The early BCG campaigns were concentrated in the rapidly industrializing world of Europe with little activity in other continents.6 The discovery of streptomycin in 1944 ushered in the era of chemotherapy and raised hopes for rapid global control of TB based on the widespread use of BCG vaccination and TB case management with specific chemotherapy. In 1947 the World Heath Organization (WHO) established a TB section and held the first expert committee on TB which recommended that countries should develop TB control programmes based on BCG vaccination and TB case management.7 These two basic elements for TB control have not changed since the 1950s except for changes in treatment including the introduction of multidrug therapy and the discovery of rifampicin in the 1970s which allowed the duration of TB treatment to be reduced to 6–8 months.8 Early treatment of TB was sanatorium-based in which patients were admitted and confined to special TB care units built to provide fresh air, exercise, rest and good nutrition that were, in the pre-chemotherapy era, considered a cure for TB.9 In the late 1950s the Madras Chemotherapy Centre in India demonstrated the efficacy of home-based treatment and suggested that sanatorium treatment was no longer necessary.10 Further simplification in the diagnosis of TB using sputum smear microscopy and in treatment using intermittent therapy made it possible to scale treatment of TB patients further, enabling the evolution of national TB control programmes.11 The basic technical recommendations on case detection, treatment and programme organization were described at a national conference held in the USA in 1960,12 shortly after the convincing demonstration of the efficacy of ambulatory treatment for TB. The new policies were established at the global level in the 8th report of the WHO Expert Committee on Tuberculosis in 1964,13 further refined in the 9th report in 1974,14 and are still valid. They
included integration of TB activities into primary healthcare,15,16 programme management by a single directing authority, the national TB control programme, with responsibility at national level, good planning and operational evaluation.17 Technical aspects included: priority given to passive case detection using direct microscopy of sputum samples; active case detection in high-risk groups; regular ambulatory treatment with direct observation of drug intake; intermittent treatment and bacteriological follow-up of treatment. Publications describing TB control programmes in developing countries began to appear in the mid-1960s. These initial TB control programmes were developed to deliver new and experimental technologies for TB control. They were specialized control programmes with specialized structures, including staff from central to local levels where interventions were delivered.7 The programmes included specialized hospitals, TB clinics and laboratories and X-ray mobile units with staff and teams to carry out diagnostic, treatment and tuberculin tests and to administer BCG vaccination. The TB control programmes carried out independent training, supervision, logistics and health education activities. This specialized approach to TB control demonstrated its efficacy in the rapidly industrializing countries, with declines in TB cases and annual risk of infection as illustrated in Figs 78.1 and 78.2, but similar successes were not evident in the less developed world. The likely reasons for this difference were the lack of resources for the rapid and massive implementation and delivery of interventions which had contributed to the success of the programmes in wealthier countries.18 Specifically, population coverage by the specialized TB services was insufficient to have the desired impact on TB in developing countries. It became clear that to achieve better coverage, use of the general health service was essential for the delivery of TB interventions. This led to attempts to integrate TB services into the general health services in most of the developing world.15–17,19 In the 1960s Mahler promoted the integration of TB control in peripheral health units with a specialized team to support them and supervise activities.20 The refinement of the TB control approaches, based on TB case finding and specific chemotherapy, led to the elaboration of the directly observed treatment, short-course (DOTS) strategy with its five well-defined components.21 This strategy has been vigorously promoted by WHO since 1995. Today almost all countries, rich and poor, have adopted the DOTS strategy as the core of their TB control efforts and have continued to integrate services into the general health service. The DOTS strategy has itself undergone several evolutions since 1995 and on March 24, 2006, a new
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0.6 Case fatality
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Box 78.1 Components of the stop TB strategy and implementation approaches
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Fig. 78.1 Impact of drugs on TB case fatality: England and Wales.
Trend in the annual risk of TB infection: Netherlands, 1955 1965
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Fig. 78.2 Trend in the annual risk of TB infection: Netherlands 1955–1965.
Stop TB Strategy was launched (Box 78.1).22 The new strategy has DOTS as its core element with additional elements addressing challenges and constraints that TB control programmes face nowadays. The new Stop TB Strategy recognizes that TB care and prevention will not be achieved without interventions aimed at strengthening the broader healthcare system in addition to engaging all healthcare providers, empowering TB patients and communities and promoting programme-based operational research to improve the reach, quality and efficiency of TB service delivery.
ORGANIZATION OF NATIONAL TUBERCULOSIS CONTROL PROGRAMMES (NTP) It is currently accepted that to have the desired effect of decreasing the burden of TB in a given population a TB control programme must be able to detect at least 70% of the estimated incident cases of smear-positive pulmonary TB and to successfully treat and or cure at least 85% of these cases and to sustain this level of performance over a prolonged period of time.23 To achieve the goals of high case detection and high cure rates the national TB programme (NTP) must have a presence that is countrywide, permanent and based upon the delivery of inexpensive and simplified technologies through the general health services. Tuberculosis case
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1. Pursue high-quality DOTS expansion and enhancement a. Political commitment with increased and sustained financing b. Case detection through quality-assured bacteriology c. Standardized treatment with supervision and patient support d. An effective drug supply and management system e. Monitoring and evaluation system and impact measurement. 2. Address TB–HIV, MDR-TB and other challenges a. Implement collaborative TB–HIV activities b. Prevent and control MDR-TB c. Address prisoners, refugees and other high-risk groups, and special situations. 3. Contribute to health system strengthening a. Actively participate in efforts to improve system-wide policy, human resources, financing, management, service delivery and information systems b. Share innovations that strengthen systems, including the Practical Approach to Lung Health (PAL) c. Adapt innovations from other fields. 4. Engage all care providers a. Public–public and public–private mix (PPM) approaches b. International Standards for Tuberculosis Care (ISTC). 5. Empower people with TB, and communities a. Advocacy, communication and social mobilization b. Community participation in TB care c. Patients’ Charter for Tuberculosis Care. 6. Enable and promote research a. Programme-based operational research b. Research to develop new diagnostics, drugs and vaccines.
management, including diagnosis and treatment, has been simplified and standardized so that the general health personnel can be trained to diagnose and treat the disease. While this approach is the currently recommended strategy for TB care and prevention, most experts agree that there is need to maintain some form of specialization especially for managerial functions and support of health facilities.7 To implement the managerial functions of TB control most NTPs are currently structured with a central unit (national level) staffed by a national programme manager who takes overall responsibility for the activities of the programme. Depending on factors such as TB disease burden, size of the country, political commitment, financial resources and level of external support, the programme manager may be supported by technical staff coordinating specific areas of the TB control effort as well as support staff such as secretaries, financial and administrative officers and drivers (Box 78.2). In many countries coordination of TB control activities at state, province and ‘district’ levels is carried out by specialized TB control programme staff. The staff responsible for
Box 78.2 Example of common TB control programme structure
Central unit with NTP manager, technical officers and support staff. Regional/provincial coordinators. ‘District’ coordinators. Health service delivery points – TB service integrated into the general health services. Purpose: Programme is countrywide, permanent and delivering TB care and control activities through the general health service.
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National tuberculosis programmes and tuberculosis control in developing countries
coordination of TB control activities at regional and district levels may also be responsible for the coordination of ‘other disease’ control activities. With the increasing need to coordinate activities with other programmes and with local and international partners, country coordination mechanisms (or interagency coordination committees or Stop TB partnerships) are being established in many countries. In particular, TB control programmes are establishing collaborative mechanisms with national human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) programmes. In recent times a patient-centred approach to TB care and prevention has been advocated on the understanding that public health goals can only be achieved if every single individual patient receives the best possible care.24
FUNCTIONS OF NATIONAL TUBERCULOSIS CONTROL PROGRAMMES The NTP has numerous functions shared by different levels of the health system. Core functions at national level and other levels are described in Table 78.1. The overarching function is the organization and delivery of TB care and prevention services to reach, find and cure all persons with TB. Policy formulation, definition of strategies and planning of activities are core functions of the national level. Other functions are carried out by other levels with the stewardship of the national level. The NTP should develop capacity for surveillance, regular supervision and rigorous monitoring of programme performance. The credibility of the programme is often judged by the quality, timeliness, security and supply of the antituberculous drugs it provides. Credibility can be easily damaged by interruptions in the supply or shortage of antituberculous drugs. The key function of NTPs remains the organization and delivery of TB care and prevention services. These services, in particular smear microscopy and antituberculous drugs, are being provided free by most TB control programmes in recognition of the fact that TB is primarily a disease of the poor who are alienated from healthcare services that involve cost recovery schemes.25
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FORMULATION OF TUBERCULOSIS CONTROL POLICIES, STRATEGIES AND TECHNICAL STANDARDS Effective control of TB cannot be conducted without a wellorganized NTP. Based on international policy and strategy recommendations, the national level is responsible for national policy formulation and development of best implementation strategies given the country context. These strategies should facilitate links between primary, district, regional and national levels. To be effective, the NTP must consider all elements of the Stop TB Strategy but adapt the priorities for implementation to the country situation; some elements of the strategy will be more important than others, while some may be applicable only in specific parts of the country. Policies, national strategies and technical standards are usually elaborated in the national TB control guidelines. The recently published International Standards of Tuberculosis Care (ISTC) provides the evidence that supports the common practices promoted by TB control programmes and is a key platform for the engagement of all care providers within a country.23
PLANNING AND BUDGETING TUBERCULOSIS CONTROL ACTIVITIES The Global DOTS Expansion Plan published in 2001 promoted the development of medium-term plans (3–5 years) based on the need to expand or re-enforce DOTS strategy.26 As a result NTPs developed plans that accelerated the expansion of the strategy and increased funding for TB control, from both national and international sources.27 Planning is effective only if it is based on realistic assessment of needs to achieve an objective or a target. With the aim of reaching the TB-related Millennium Development Goals (MDGs) the second Global Plan to Stop TB covering the period 2006–2015 has been formulated.28 Following the same method used to develop the second Global Plan, many NTPs have developed national plans based on defined targets and have estimated the financial requirements to undertake all activities described in the plan. A large gap exists between the current level of TB financing and control efforts and the financing of large-scale TB control activities needed to reach defined targets.
Table 78.1 Functions of national tuberculosis control programmes at different levels National level
Provincial/regional level
District level
Formulation of policies and strategies: national TB control manual Planning and budgeting TB control activities Financing TB control activities Planning human resources development
Planning and budgeting TB control activities Financing TB control activities Planning human resources development
Planning and budgeting TB control activities Financing TB control activities Human resource mapping, quantification and management Conducting training TB disease surveillance Supervision and technical support to health facilities Coordination of activities undertaken by different programmes and partners Supply and distribution of drugs and other commodities Monitoring and evaluation Advocacy, communication and social mobilization Operational research
Conducting training TB disease surveillance Supervision and technical support to provinces/ regions Coordination of activities undertaken by different programmes and partners Procurement, supply and distribution of drugs and other commodities Monitoring and evaluation Advocacy, communication and social mobilization Operational research
Conducting training TB disease surveillance Supervision and technical support to ‘districts’ Coordination of activities undertaken by different programmes and partners Supply and distribution of drugs and other commodities Monitoring and evaluation Advocacy, communication and social mobilization Operational research
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FINANCING AND SUPPORTING TUBERCULOSIS CONTROL PROGRAMMES Governmental commitment is essential for the establishment of effective TB control programmes which promote the provision of TB services that are nationally applicable, socially acceptable and epidemiologically effective. Most NTPs in developing countries are heavily dependent on external donor support to finance crucial elements of the TB control strategy especially drug procurement, training and supervision. In 2007, it was estimated that on average 70% of the available funding for TB control in the 22 high-burden countries was from domestic sources;29 however, most of the funding is channeled to providing the physical infrastructure and human resource budgets. The poorest countries are currently not paying for critical elements of the TB control efforts which include laboratory consumables, antituberculous drugs, training and supervision. Beside the classical support from multilateral financing institutions such as the World Bank and bilateral agreements, the international community has recently created financing and other support mechanisms to ensure that most patients with TB have access to TB care and are successfully treated. These mechanisms include the Global Drug Facility for TB (GDF), the Global Fund to Fight AIDS, TB and Malaria (GFATM) and the recently established UNITAID, which finances antituberculous drugs for children and for multidrug resistant (MDR) TB. While the desired way forward is for governments of endemic countries to increase their budgets for TB care and prevention, it must be recognized that the most affected countries are often those with the least capacity to finance TB care services. External financing of TB control programmes will be required for a considerable time to come.26 A key element for financing is a needs-based plan and a mechanism for the coordination of all interested local and international partners in the country. The national plan forms the basis for regional/provincial and district plans to implement TB control.
HUMAN RESOURCES FOR TUBERCULOSIS CONTROL ACTIVITIES Human resource development is very often limited to training programmes for different categories of health workers. However, the deep human resource crisis for health experienced by many countries calls for a much broader approach which should address the number of staff required in different categories, their qualifications and their distribution at different levels as well as training activities.30 The success of a TB control programme is determined by a number of factors including staffing, staff activities, drug and other supplies management, diagnostic procedures and management of treatment and laboratory services. Of these critical elements human resource for health is the most important.29 NTPs must be staffed with the appropriate number of healthcare workers adequately skilled and motivated to carry out programme activities at all levels. Since patients receive care in general health facilities, NTPs are dependent on the general health system infrastructure and staffing. A large number of high-burden countries, however, do not have data on the available human resource and where these data are available they are often of poor quality and unreliable.31 The insufficient human resource has been a major challenge for NTPs in developing countries. In many countries there are just not enough healthcare workers to carry out the activities required to bring TB
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under control and they are often not motivated enough to do so. In Malawi, for example, it was estimated that only 10% of healthcare facilities had a full complement of the healthcare staff required to deliver the essential healthcare package which includes TB services.32 Malawi has attempted to enhance the performance of programme staff through various methods including the payment of performance-based allowances.33 The long-term sustainability and impact of these approaches has not been evaluated. There is an increasing recognition at the global level that the human resource for health crisis must be addressed if progress is to be made in the delivery of essential health services in poor countries. The restrictions that may previously have been placed by financial regulators on developing countries to limit staff recruitment for the purposes of controlling the wage bill may be relaxing especially in the social service sectors of health and education. In line with this development many poor countries are now undertaking efforts to improve their human resource base in the health service. These efforts include expansion of basic training, recruitment of additional staff and task shifting to lower cadres such as community healthcare workers for tasks that do not require highly trained workers. NTPs, in coordination with the national health planning section in the ministry of health, should therefore formulate plans for human resource development for TB control that encompasses a wide range of activities including but not limited to staff mapping, quantification, training and re-training, improvement of staff motivation and team building efforts.
SUPERVISION AND TECHNICAL SUPPORT Although ‘supervision’ is not always well accepted, this function is indispensable for achieving and maintaining high-quality care and management. Supervision should be seen as an opportunity to provide support to staff working at different levels. Typically, the NTP organizes a programme of regular supervision at three different levels: from central to region/province, from region/province to district and from district to health facilities. Except for the latter, supervision may cover several levels. Various elements are checked during supervision and many programmes have developed checklists and reporting formats to ensure a systematic approach.
COORDINATION OF ACTIVITIES UNDERTAKEN BY DIFFERENT PROGRAMMES AND PARTNERS Tuberculosis control activities cannot be conducted in isolation. The NTP in a country must rely on multiple health actors to ensure good access and minimize missed opportunities to diagnose and treat TB in a person. One of the very demanding tasks of the NTP is to ensure coordination among different programmes of the health services, and particularly with the HIV/AIDS programme, the national public health laboratory service and health facility networks of non-government organizations (NGOs) (including faith-based organizations, FBOs), academic institutions, private health providers and industry. To ensure good coordination, a mechanism headed by the NTP is necessary. This mechanism can be an interagency coordination committee, a national partnership to Stop TB or a national committee to control TB. Its function is to encourage all those interested in TB control to contribute to the national TB control plan and to use national policies and standards defined in the national manual. One of the challenges is to ensure implementation of the same technical standards by all providers.
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National tuberculosis programmes and tuberculosis control in developing countries
DRUGS AND OTHER COMMODITIES SUPPLY AND DISTRIBUTION The national level has the responsibility to ensure the procurement of drugs and other supplies of good quality and their distribution up to the point of care. Different systems are in use based on either a programme model where the NTP ensures procurement and distribution or an integrated model using the essential drugs management system.
MONITORING AND EVALUATION INCLUDING DISEASE SURVEILLANCE Surveillance of TB disease is a critical element of TB control. It is concerned with the measurement of the TB situation and of the control measures applied.34 Surveillance is carried out through a standard recording and reporting system that provides information on number of cases by category (new and re-treatment), type of disease (pulmonary, extrapulmonary) and infectiousness (smear or culture positive or negative). This information is essential for analysing the evolution of TB epidemic. Surveillance of MDR-TB among new and re-treatment cases and of HIV infection among TB patients is also an essential element. Notification of TB cases to the national authority is mandatory in many countries. Some countries also have a system of laboratory-based surveillance where patients are notified to the relevant authority by the laboratory that made the diagnosis. This system is able to report patients diagnosed in the laboratory but who do not report subsequently to the clinic for treatment. Monitoring TB control is based on the standard recording and reporting system used worldwide. Standard indicators such as new cases and treatment outcomes provide adequate information for monitoring quantity and quality of programme activities, from the district to the national level. The expansion of the new strategy to areas such as TB–HIV and MDR-TB has prompted NTPs to adapt their recording and reporting system and include additional indicators for monitoring the evolution of the situation. Tuberculosis case recording and reporting is essential for TB disease monitoring and surveillance which is dependent on case classification and cohort analysis of treatment outcomes.35 In 2006 a revision of recording and reporting system was recommended by WHO in order to include elements of the new Stop TB Strategy. A model recording and reporting system with several options has been proposed by WHO to NTPs.36 As the system is becoming increasingly complex and computers are becoming part of the standard equipment of most health facilities, a number of NTPs have recently moved into electronic TB registers which have the potential to ensure a more complete data entry, easier and better communication and or transmission of the data to other levels and more refined analysis of programme performance. Monitoring and evaluation are conducted through three mechanisms.
National monitoring of planned activities and analysis of data collected from different levels, typically districts and provinces This monitoring is essential to identify high- and low-performing areas and identify causes for low performance. As the basic function of NTPs is to find and treat to cure cases of TB, NTPs are evaluated primarily on the basis of case detection and treatment success rates achieved. To reach high success rates, NTPs must be able to provide quality TB services to every part of the country and to mobilize communities to utilize these
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services. Monitoring includes a recording and reporting system that enables the NTP to obtain disease and treatment information on every TB patient identified. NTPs use several tools for obtaining this information, of which the smear microscopy laboratory register, the TB treatment register and patient individual card are essential. A well-maintained TB recording and reporting system allows health workers and TB programme staff to plan, monitor and evaluate services and drug supplies. The other important purposes of this system are to ensure complete treatment for every patient (and patient observance of treatment) and to identify treatment failure. Records for each TB patient must include results of diagnostic examinations, type of treatment, follow-up results and treatment outcomes.37
External monitoring missions (once or twice a year) These use the national monitoring system with visits to several TB programme levels and care facilities and aim at identifying general problems in the performance of the programme and to identify solutions to poor performance. In these external monitoring missions one or more international experts bring their experience and lessons from other countries. Programme review These are conducted regularly, possibly once every 3–4 years. The objective is to analyse in depth the role, functions, structure and performance of NTP, and to discuss its system environment, the barriers and the opportunities to improve TB control. Tuberculosis programme reviews were intitiated by WHO in the 1990s to strengthen the focus on the DOTS strategy. These reviews are particularly important when a country is in the process of reorienting its TB control policies and re-planning activities. WHO has published guidelines for the conduct of national TB control programme reviews.38 This extensive exercise involves teams of up to 15–35 experts representing a wide range of national and external institutions and includes a 2- to 3-month preparatory period. The review itself may last 2–3 weeks, and the third phase includes discussion of findings and formulation of recommendations. Tuberculosis control programme reviews are an important tool for securing government commitment and providing the basis for reorienting TB control policies and re-planning activities.39 ADVOCACY, COMMUNICATION AND SOCIAL MOBILIZATION (ACSM) INCLUDING COMMUNITY PARTICIPATION AND PATIENT CHARTER ACSM embraces advocacy to influence policy changes and sustain political and financial commitment, communication between care providers and communities to improve knowledge of services and social mobilization to engage society. Community participation implies establishing a working partnership between the health sector and the community. The ACSM working group of the global Stop TB Partnership published its 10-year framework for action to establish and develop programme level ACSM as a core component of TB prevention and treatment efforts.40 The NTP should provide support to frontline health workers to help create an environment where the community mobilizes its members to help patients and facilitate peer education. A patient group has recently published a ‘patient charter’ that describes patients’ rights and responsibilities.41 This is a very important document which NTPs should use to promote the delivery of a high-quality TB diagnosis and treatment services that do not erode the dignity of those afflicted by this disease.
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OPERATIONAL RESEARCH Operational research is an essential and frequently neglected area. National programmes need constant evolution in order to improve performance, introduce new technologies and find solutions to operational problems. All too often the NTP does not have staff or the capacity to conduct operational research. Links with academic institutions within or outside the country are beneficial when mutual respect and good coordination is achieved. The systematic collection and analysis of programme data is required to assist in setting programme priorities, operations planning, and implementing and evaluating programme activities. Attempts have recently been made to boost the capacity of NTPs to carry out operational research.42
TECHNICAL CHALLENGES FACING NATIONAL TUBERCULOSIS CONTROL PROGRAMMES RESPONDING TO THE TUBERCULOSIS AND HIV CO-EPIDEMIC One of the major challenges facing TB control programmes is the impact of HIV on TB. The HIV epidemic has led to a dramatic increase in the burden of TB especially in sub-Saharan Africa where case notification rates have risen more than fivefold since the mid-1980s. The impact on NTPs includes increased case load, impaired NTP performance, increased need for access to ART and difficulties in reaching TB control targets.43 To address this challenge, WHO published the interim policy on collaborative TB–HIV activities for the management of TB in countries or places with various HIV prevalence, identifying 12 TB–HIV collaborative activities for improving TB and HIV control.44 Close collaboration between TB and HIV/AIDS programmes improves the identification and treatment of TB cases and HIV-infected persons.
RESPONDING TO MULTIDRUG- AND EXTENSIVE DRUG-RESISTANT TUBERCULOSIS Multidrug and extensive drug resistance are major and increasing threats to TB control. Many NTPs are already facing the widespread development and dissemination of drug resistance and in particular multidrug and extensive drug resistance, and others will certainly have to deal with a similar situation before long.45 The threat of drug-resistant TB can be mitigated by well-managed TB control programmes that achieve high cure rates in detected cases.46 However, even good TB control programmes cannot eliminate this threat entirely and intensive efforts must be made to equip NTPs to identify and treat drug-resistant TB. Management of MDR- and XDR-TB is part of TB control and requires the establishment of a network of laboratories able to diagnose MDR- and XDR-TB and health facilities able to treat these patients while having in place infection control measures to avoid transmission of drug-resistant strains to healthcare workers, other patients and visitors to the health facility.
INVOLVING ALL CARE PROVIDERS In most settings, patients with symptoms suggestive of TB seek care from a wide variety of healthcare providers. These non-NTP providers, including health facility network of NGOs, FBOs, academic institutions, public and private corporate entities and private
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for-profit healthcare providers, may serve a large proportion of TB patients but may not always apply recommended TB management practices. Their involvement needs a strong mechanism of coordination and monitoring, which is a major challenge facing many NTPs. Evidence suggesting that engaging all care providers, including, where appropriate, informal providers, through public–public and public–private mix approaches, such as linking public hospitals and private NGO networks to NTP, increases TB case detection at no additional cost is accumulating.47–49 This benefit is partly negated by the need for strong coordination and stewardship by the NTP, which is often not feasible due to weak management capacity.
FINANCIAL BARRIERS TO PATIENTS Tuberculosis control must be seen as an element for health system development to increase access to healthcare, a basic human right, and an integral part of poverty alleviation strategies. The development of successful and sustainable approaches to remove financial barriers faced by TB patients is a major challenge for NTPs. Tuberculosis patients face a large financial burden even in programmes where diagnostic and treatment services are free. The financial burden may be larger prior to the diagnosis of TB than after TB diagnosis. In China, for example, it has been reported that total patient expenditure was reduced only marginally, but shifted substantially from after diagnosis to before diagnosis with the adoption of free DOTS services.50
SPECIAL GROUPS AND SITUATIONS Special situations include unexpected population movement as a result of war, natural disasters or man-made disasters. Risk groups that need special attention include the prison populations, refugees, displaced populations, migrants and marginalized minority groups. It is the task of the NTP to link with relevant government ministries and other appropriate groups in the society to guide them and support them in the implementation of TB control activities to ensure that the specially vulnerable groups are reached.
HEALTH SECTOR REFORM AND WEAK HEALTH SYSTEMS Prompted by the persistent poor performance of the health sector and dwindling resources for health a large number of developing countries initiated health sector reforms in the late 1980s and 1990s to increase equity, efficiency and quality of health services. This process involved various approaches including decentralization of authority (local empowerment), managerial integration of programmes and common or basket financing mechanisms. In most countries the reform process was not backed by increased resources and in some countries health sector reform was rapidly and haphazardly implemented, leading to dismantling of specialized programmes including TB control programmes which lead to the weakening of TB control.51,52 Some of the serious consequences of health sector reform included the interruption of supplies of antituberculous drugs (Box 78.3).50 In some countries careful implementation of health sector reform did not harm the NTP. On the contrary TB control may have gained from these reforms. In Kenya the slow transfer of financial and managerial responsibility together with continued donor support and efforts made at protecting the most vulnerable
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National tuberculosis programmes and tuberculosis control in developing countries
Box 78.3 Health sector reform and tuberculosis control Threats effects User fees alienating the poor and other vulnerable groups. Loss of managerial capacity. Interrupted supplies for TB disease control. Loss of TB surveillance data. Opportunities Health system strengthening. Increased human resource available for TB control from use of multipurpose general healthcare workers. Greater ownership of programme by peripheral levels of the healthcare system. Improved access of TB services.
groups from the effects of cost recovery schemes and decentralization of service provision meant that TB control activities continued un-perturbed.53 As part of health sector reform process many developing countries also introduced cost recovery or cost-sharing schemes as part of their health financing strategies. These cost recovery schemes often included social insurance, efficiency measures and private sector development. Even though these schemes led to some increase in revenue, by and large, cost recovery schemes did not achieve the intended objectives and led to a reduction in health service utilization. In Kenya the rapid introduction of user fees in December 1989 led to a significant reduction in outpatient attendance and had to be suspended after about a year of implementation.54 However, a phased implementation of the cost recovery system beginning in 1992, combined with somewhat broader exemptions, was associated with much smaller decreases in outpatient utilization and led to significant increases in revenue.55 The implementation of user fees in Kenya was judged to have had a particularly bad effect on the rural poor including children. Attendance at government fee-charging health facilities for both outpatient and in-patient care was lower during the period when full fees were charged than during the same months of the previous year when there were no fees charged. The utilization of health services by young children, who were exempted from fees, mirrored that of the rest of the population, suggesting that they were not fully protected from the adverse effects of fees. The poorest households made much less use of the fee-charging government facilities than the better-off households.56 While decentralization and user fees have been promoted by some as a means for achieving equity, in Honduras a system of user fees with a decentralized administration was found to be inefficient with regional variation that had created horizontal inequities and had high administrative costs that far outweighed the revenue generated. Additionally since the likelihood of paying for an ambulatory visit was highest at a health post, and lowest at a hospital, individuals from the poorest one-fifth of households were the most likely to have to pay for care.57 The other important effect of haphazardly implemented health sector reform relates to the effect of rapid decentralization of managerial functions on healthcare staff. The transfer of authority to lower levels appears in general to be a desirable goal that should lead to a better design of healthcare delivery services and increased ownership by the peripheral levels. However, without proper training and support, managerial systems may falter and hamper the implementation of TB control activities. Some of the problems that may occur with haphazard transfer of authority include confused lines of authority,
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difficulties of integrated supervision, poor career paths and promotion possibilities, unclear performance management, lack of prioritization of TB control, lack of local accountability, lack of capacity and risk to the drug supply. Thus transfer of authority should be carefully carried out and should preferably be slow and phased. This should be coupled with broad engagement of peripheral healthcare managers for consensus building and management of the change so that central and local responsibilities are clearly defined.58
THE FUTURE OF NATIONAL TB CONTROL PROGRAMMES Most NTPs have focused their efforts on reaching the short-term internationally recommended TB control targets set for 2005, i.e. a case detection of 70% with successful treatment of 85% of the detected cases. These targets were approved by the World Health Assembly (WHA) and agreed upon by international TB technical agencies and progress towards them has recently been evaluated. By the end of 2005, 26 countries had achieved both targets and globally 60% of existing cases were identified and 84% of infectious cases were successfully treated.27 Countries that achieve these targets will have to maintain this level of performance to achieve the MDG target of halting and beginning to reverse the incidence of TB, and the Stop TB Partnership target of halving the prevalence and mortality due to TB by 2015 compared with 1990 levels. For most countries achieving the MDGs and Stop TB Partnership targets will involve going beyond the 70/85 targets. Innovative approaches for finding TB cases and supporting patients on treatment will need to be adopted in order to increase cure rates and hence reduce transmission. This will entail strengthening of many NTPs, as well as closer coordination with HIV/AIDS programmes supported by national advocacy groups.59 Engagement of other sectors beyond health, such as private, educational, and development sectors, will also be important. A higher level of political commitment at the global, national and sub-national levels will be required to provide additional resources for TB care and prevention. Weak health systems constitutes a basic problem in most developing countries and a lot of effort is being placed on health sector reforms intended to address the health system weaknesses. NTPs need to be active participants in this process to ensure that essential TB control activities are not harmed by reform policies that countries may be adopting. By adopting innovative approaches such as Practical Approach to Lung Health (PAL) and supporting the development and implementation of an essential laboratory package among other efforts, NTPs may significantly contribute to the strengthening of the healthcare system.
CONCLUSION Despite the considerable efforts that have been made to control TB in developing countries in the past three decades, the decline in the global epidemic has been slow. Although case management, including bacteriological diagnosis and chemotherapy, is potentially effective for the reduction of mortality and the risk of infection, numerous barriers exist in the efficient application of these apparently simple interventions in developing countries. While full utilization of existing knowledge and available tools can achieve a great deal, a major thrust in research is required to generate additional ways of accelerating TB control in developing countries. Without new technical developments, the goal of worldwide
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control of TB will require tremendous efforts and massive investment in human and financial resources, as outlined in the second Global Plan to Stop TB, with no guarantee that the MDG targets will be reached in some regions of the world. Tuberculosis remains a major cause of morbidity and mortality in developing countries. Four methods for the prevention of TB are currently available: improvement of socioeconomic conditions, case-finding and treatment, chemoprophylaxis and vaccination. Improvement of socioeconomic conditions, partly responsible for the decline of TB in developed countries, must be seen as a long-term solution. Case-finding and treatment is
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the only method expected to have an important short-term impact on transmission.60 Results prove that a high TB case detection of greater than 70% with high cure rates (at least 85%) is feasible in low-income, highburden countries. The main determining factors for success appear to be political commitment, a well-functioning health system, integration of TB control into the general health service at district level, a continuous supply of drugs and effective external support.61 There are valuable lessons to be learnt from the experiences of the more successful countries which must be shared and adopted by other countries for global progress in TB control to be made.62
20. Mahler H. The tuberculosis programme in the developing countries. Bull Int Union Tuberc 1966;37:77–82. 21. World Health Organization. Framework for Effective Tuberculosis Control. WHO/TB/94.179. Geneva: World Health Organization, 1994. 22. World Health Organization. The Stop TB Strategy. WHO/HTM/STB/2006.368. Geneva: World Health Organization, 2006. 23. Styblo K, Bumgarner R. Tuberculosis Can Be Controlled with Existing Technologies: Evidence. The Hague: Tuberculosis Surveillance Research Unit Progress Report, 1991:60–72. 24. The International Standards for Tuberculosis Care. Available at URL:http://www.who.int/tb/ publications/2006/istc/en/index.html 25. Mbugua JK, Bloom GH, Segall MM. Impact of user charges on vulnerable groups: the case of Kibwezi in rural Kenya. Soc Sci Med 1995;41(6): 829–835. 26. World Health Organization. Global DOTS Expansion Plan. WHO/CDS/STB/2001.11. Geneva: World Health Organization, 2001. 27. World Health Organizaton. Global Tuberculosis Control, Surveillance, Planning and Financing. WHO/ HTM/TB/2006.362. Geneva: World Health Organization, 2006. 28. Stop TB Partnership. The Global Plan to Stop TB 2006–2015. WHO/HTM/STB/2006.36. Geneva: World Health Organization, 2006. 29. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO/ HTM/TB/2007.376. Geneva: World Health Organization, 2007. 30. World Health Organization. Working Together for Health. Geneva: World Health Organization, 2006. 31. Figueroa-Munoz J, Palmer K, Poz MR, et al. The health workforce crisis in TB control. A report from high burden countries. Hum Resour Health 2005; 3(1):2. 32. Ministry of Health, Malawi. Report of assessment of Emergency Obstetric Care Services in Malawi, June 17, 2005. 33. Harries AD, Salaniponi FM, Nunn PP, et al. Performance-related allowances within the Malawi National Tuberculosis Control Programme. Int J Tuberc Lung Dis 2005;9(2):145–150. 34. Styblo K. Surveillance for tuberculosis. Int J Epidemiol 1976;5(1):63–68. 35. Dye C, Watt CJ, Blled DM, et al. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence and deaths globally. JAMA 2005;293(22):2790–2793. 36. World Health Organization. The revised TB recording and reporting forms—version 2006. Available at URL:http://www.who.int/tb/dots/ r_and_r_forms/en/index.html 37. World Health Organization. An Expanded Framework for Effective Tuberculosis Control. WHO/CDS/TB/ 2002.297. Geneva: World Health Organization, 2002. 38. World Health Organization. Guidelines for Conducting a Review of National Tuberculosis Programme. WHO/ TB/98.240. Geneva: World Health Organization, 1998.
39. Pio A, Luelmo F, Kumaresan J, et al. National tuberculosis programme review: experience over the period 1990–95. Bull World Health Organ 1997;75(6): 569–581. 40. World Health Organization. Advocacy, Communication and Social Mobilization to Fight TB. A 10 Year Framework for Action. WHO/HTM/STB/ 2006.37. Geneva: World Health Organization, 2006. 41. World Care Council. The Patients’ Charter for Tuberculosis Care. 2006. Available at URL:http:// www.stoptb.org/globalplan/assets/documents/ IP_oms_charte_GB_Epreuve.pdf 42. Laserson KF, Binkin NJ, Thorpe LE, et al. Capacity building for international tuberculosis control through operations research training. Int J Tuberc Lung Dis 2005;9(2):145–150. 43. Maher D, Harries A, Getahun H. Tuberculosis and HIV interaction in sub-Saharan Africa: impact on patients and programmes; implications for policies. Trop Med Int Health 2005;10(8): 734–742. 44. World Health Organization. Interim Policy on TB/HIV Activities: WHO/HTM/TB/2004.330 or WHO/ HTM/HIV/2004.1. Geneva: World Health Organization, 2004. 45. Raviglione MC, Smith IM. XDR tuberculosis— implications for global public health. N Engl J Med 2007;356(7):656–659. 46. Raviglione MC. XDR-TB: entering the postantibiotic era? Int J Tuberc Lung Dis 2006; 10(11):1185–1187. 47. Hamid Salim MA, Uplekar M, Daru P, et al. Turning liabilities into resources: informal village doctors and tuberculosis control in Bangladesh. Bull World Health Organ 2006;84(6):479–484. 48. Balasubramanian R, Rajeswari R, Vijayabhaskara RD, et al. Rural public-private partnership model in tuberculosis control in south India. Int J Tuberc Lung Dis 2006;10(12):1380–1385. 49. Lonnroth K, Uplekar M, Blanc L. Hard gains through soft contacts: productive engagement of private providers in tuberculosis control. Bull World Health Organ 2006;84(11):876–883. 50. Xu B, Dong HJ, Zhao Q, et al. DOTS in China— removing barriers or moving barriers. Health Policy Plan 2006;21(5):365–372. 51. Bosman M. Health sector reform and tuberculosis control: the case of Zambia. Int J Tuberc Lung Dis 2000;4(7):606–614. 52. Kritski AL, Ruffino-Netto A. Health sector reform in Brazil: impact on tuberculosis control. Int J Tuberc Lung Dis 2000;4(7):622–626. 53. Hanson C, Kibuga D. Effective tuberculosis control and health sector reforms in Kenya. Challenges of an increasing tuberculosis burden and opportunities through reform. Int J Tuberc Lung Dis 2000; 4(7):627–632. 54. Mwabu G, Mwanzia J, Liambila W. User charges in government health facilities in Kenya: effect on attendance and revenue. Health Policy Plan 1995; 10(2):164–170. 55. Collins D, Quick JD, Musau SN, et al. The fall and rise of cost sharing in Kenya. the impact of phased implementation. Health Policy Plan 1996;11(1): 52–63.
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National tuberculosis programmes and tuberculosis control in developing countries 56. Mbugua JC, Bloom GH, Segall MM. Impact of user charges on vulnerable groups: the case of Kibwezi in rural Kenya. Soc Sci Med 1995;41(6):829–835. 57. Fiedler JL, Suazo J. Ministry of health user fees, equity and decentralization: lessons from Honduras. Health Policy Plan 2002;17(4):362–377. 58. Newell JN, Collins CD, Baral SC, et al. Decentralization and TB control in Nepal:
understanding the views of TB control staff. Health Policy 2005;73(2):212–227. 59. Walley J, Chukwu J. The tuberculosis emergency in Africa: opportunities and strategies for action. World Hosp Health Serv 1995;31(2):13–16. 60. Rodriugues LC, Smith PG. Tuberculosis in developing countries and methods for its control. Trans R Soc Trop Med Hyg 1990;84(5):739–744.
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61. Huong NT, Duong BD, Co NV, et al. Establishment and development of the National Tuberculosis Control Programme in Vietnam. Int J Tuberc Lung Dis 2005;9(2):151–156. 62. Bull World Health Organ Special issue on TB, 2007 May.
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Implementation of collaborative tuberculosis/HIV activities Policy and programme issues Haileyesus Getahun, Fabio Scano, and Paul Nunn
BACKGROUND Human immunodeficiency virus (HIV) increases the risk of reactivation of latent Mycobacterium tuberculosis infection to active TB by 5–15% annually depending on the degree of immune deficiency.1 It also increases the rate of recurrence,2 both relapse (reactivation of latent TB) and reinfection (newly acquired infection) of TB.3 Countries with high HIV prevalence reported much faster increase in the incidence of TB than countries with low HIV prevalence.1,4 The association between HIV and TB is the chief reason for failure to achieve the TB control targets in high-HIV-prevalence countries and constitutes a global emergency requiring urgent and appropriate measures.5 The TB control targets of detecting at least 70% of all new infectious cases and to cure at least 85% of those detected were first set by the World Health Assembly (WHA) resolution in 1991.6,7 These targets were based on the assumption that achievement of an 85% cure rate and 70% case detection eventually reduces the prevalence of infectious TB cases, the number of infected contacts and the incidence of cases,8 leading to an expected decline in annual TB incidence rate of 6–7% per year.9,10 However, it became clear by 1998 that the year 2000 targets would not be met on time mainly due to the impact of HIV and the emergence of drug-resistant TB,11 and the World Health Organization postponed the target date to 2005.12 Leaders of the eight economic powers of the world (G8) in their summit held in Okinawa, Japan, in 2000 agreed to reduce TB deaths and prevalence by 50% by 2010.13 The Millennium Development Goals (MDGs) embrace the 2005 World Health Organization (WHO) targets and aim to halt and reverse the incidence of TB by 2015.14 These were further consolidated by the Global Plan to Stop TB, 2006–2015, which include the Stop TB Partnership’s targets of halving the prevalence and death rates of TB from the 1990 baseline.15 This chapter will review the global response and progress made in tackling the TB and HIV dual epidemic, describe the programmatic and policy issues and highlight key factors for nationwide scale-up of the implementation of collaborative TB/HIV activities.
THE PROGRAMMATIC RESPONSE The association of TB with HIV was first reported in the early 1980s along with the early descriptions of acquired immunodeficiency syndrome (AIDS).16 Not much later, the challenges posed by HIV for global TB control efforts including the eradication were
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recognized.17–20 However, HIV was estimated to account for less than 4% of the global TB incidence,19 and the inability to diagnose and cure sufficient number of sources of infection (smear-positive pulmonary TB cases) was at that time considered the principal reason for failure of TB control programmes in developing countries.18 With the HIV epidemic in the late 1980s, TB incidence began to rise in HIV-prevalent countries particularly in sub-Saharan Africa where up to 300% increase in TB case notifications was reported over the decade.1 The increase in TB case notifications mirrored the increase in HIV prevalence but often with a 4- to 7-year delay.6,21 Case notifications were increasing despite the implementation of good quality directly observed treatment, short-course (DOTS) strategy in those communities hard hit by the HIV epidemic. The young and productive segments of the community were hardest hit.22 WHO organized an informal meeting in October 1989 to develop guidelines for TB control programmes in view of the HIV epidemic. The meeting concluded that given the difference between the TB and HIV epidemiologies as well as the status of TB control activities in various parts of the world, the intervention strategy cannot be the same in all countries.19 For those countries or regions with poorly developed TB control programmes the emphasis was to improve the treatment and cure of those TB patients detected through the introduction of short-term chemotherapy, with priority given to sputum smearpositive patients. Treatment of smear-negative TB cases was emphasized for well-developed TB control programmes.19 These recommendations focused primarily on DOTS and subsequently there were feeble efforts to respond to the HIV challenge until after the year 2000.23 The failure to include a specific strategy for HIV-related TB along with the DOTS strategy has recently been regretted by the senior WHO Global TB Programme Director at the time.24 However, WHO did launch the ProTEST initiative in 1997 in response as operational research to the unprecedented scale of the epidemic of HIV-related TB. The name ‘ProTEST’ was derived from the promotion of voluntary testing as an entry point for access to the core interventions of intensified TB case-finding and isoniazid preventive treatment (IPT).25 Its aim was to develop a districtbased strategy for a joint TB/HIV programme approach to the problem. The approach entailed the promotion of HIV counselling and testing as an entry point to a package of interventions aimed at reducing the dual burden of TB and HIV. Pilot ProTEST projects were established in Malawi, South Africa and Zambia to evaluate the feasibility, impact and cost-effectiveness of a set of interventions to decrease the burden of HIV-related TB.26
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Evaluation of the ProTEST projects demonstrated that HIV/ AIDS and TB control programmes can work together effectively, from sub-district to national level and results have convinced policy-makers and programme managers in HIV/AIDS and TB that these collaborative activities are necessary and feasible, and that they contribute to improving health services for people living with HIV/AIDS and/or TB.26 Another key milestone in the global response to the TB/HIV problem was the ‘Global DOTS Expansion Meeting’ held in Cairo in November 2000, when participants called for the establishment of a Global Working Group on TB/HIV to address the global burden of HIV-related TB. The Working Group was established and conducted its first meeting in April 2001 with 116 participants coming from 33 countries.27 The goal of the Working Group was to reduce the burden of TB in high-HIV-prevalence populations. The TB/HIV Working Group of the Stop TB Partnership, comprising programme managers, policy-makers, researchers and civil society representatives from the HIV and TB communities, has been coordinating the global response to the epidemic since 2001. Together with its WHO-based Secretariat the Working Group has developed policy and programme guidance,28–32 based on the best available evidence, for reducing the impact of HIV-related TB through collaboration between TB and HIV programmes and their partners. The Working Group has established the basis for collaboration between HIV/AIDS and TB control programmes from global to national level. It aims to expand the evidence-base and promote sharing of information and experiences with the goal of providing for the provision of optimal patient-centred prevention and care.
PROGRAMMATIC APPROACH In the long term, only effective control of the HIV epidemic will switch off the associated increase in TB incidence. However, in the interim, interventions to reduce HIV-related TB morbidity and mortality need to be sought and implemented. Collaboration between TB and HIV/AIDS disease programmes (rather than creating a new separate TB/HIV control programme, or integrating the two programmes completely) should be the basis for delivering such interventions. Evidence on programme collaboration and joint interventions has largely been generated through the ProTEST projects in Zambia, Malawi and South Africa (Table 79.1).26 Similar successful initiatives that build on the collaboration between the two programmes have also been carried out in other parts of Africa and elsewhere.33–36 Strong partnerships were forged within the health system at all levels, which helped to improve health service delivery through improved and expanded referral networks and better use of resources.25 Tuberculosis control services are geared towards controlling the transmission of TB largely with simple, standardized public healthoriented technical procedures built, as far as possible, on sound evidence. HIV/AIDS services, on the other hand, are largely individual patient-oriented and expanding fast, building upon an evolving evidence base. Recognition of such conceptual, practical and cultural differences between the two control programmes and using the primary healthcare system as a platform is important for effective collaboration between the two programmes and in delivering
Table 79.1 Delivery of selected interventions in the top 20 countries with the highest burden of HIV-infected tuberculosis patients accounting for 87% of the global estimated burden in 2006
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Country
Estimate of HIV-infected TB cases
Number of TB cases tested for HIV
Number found to be HIV-infected
Proportion of TB patients HIV-infected
HIV-infected TB patients given CPT
HIV-infected TB patients given ART
PLWHA screened for TB
PLWHA given IPT
South Africa Kenya Nigeria Malawi Zimbabwe Mozambique Zambia India DR Congo UR Tanzania Ethiopia Uganda Rwanda Brazil Coˆte d’Ivoire Thailand Viet Nam Swaziland Cambodia Lesotho
200,693 73,122 42,988 35,781 31,430 27,731 23,875 23,283 21,830 21,653 19,220 17,346 15,270 11,523 10,829 9,961 7,416 7,060 6,841 6,137
110,235 69,290 7,522 17,253 NR 8,631 11,545 59,654 1,314 7,140 3,255 10,826 6,300 54,189 5,810 24,859 14,230 1,847 3,547 2,508
58,249 36,049 1,558 12,064 NR 6,079 7,177 8,785 188 3,604 1,295 6,375 2,561 8,059 2,130 6,493 708 1,476 342 2,222
53 52 21 70 NR 70 62 15 14 50 40 59 41 15 37 26 5 80 10 89
57,053 50,916 NR 11,244 NR 1,058 2,194 NR 170 2,050 1,108 1,481 1,124 4,874 1,185 4,188 NR 1,298 239 1,248
23,344 15,447 5,423 6,863 NR 2,789 2,723 NR 102 935 354 501 789 6,457 994 2,053 NR 287 120 191
103,056 NR NR NR NR 109 NR NR NR NR 1,399 NR NR NR NR 444 NR NR 53 NR
2,512 NR 19,182 NR NR 706 NR 25,055 NR NR 2,760 NR 1,525 NR NR 35,707 NR NR 2,225 NR
ART, antiretroviral treatment; CPT, cotrimoxazole preventive therapy; IPT, isoniazid preventive therapy; NR, not reported or no information available; PLWHA, people living with HIV/AIDS.
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the integrated services. Collaborative TB/HIV activities have a broader goal of decreasing the burden of TB, HIV and AIDS in populations affected by both diseases and rely on effective collaboration between the two disease control programmes.30
IMPLEMENTATION OF COLLABORATIVE TB/HIV ACTIVITIES The best model for the implementation of integrated HIV and TB services is variable from country to country, depending on the epidemiology of HIV and TB, the availability and maturity of HIV and TB control services and the strength of health delivery systems. The implementation should involve the collaboration and communication of the HIV and TB control programmes at national, state/provincial and district/municipality levels, depending on the political structure with the ultimate objective of providing integrated TB and HIV services using the primary healthcare facility as a platform.
ACTIVITIES TO ESTABLISH THE MECHANISM OF COLLABORATION TB/HIV coordinating bodies Coordinating bodies, named as committees, working groups or task forces depending on the specific context in the countries, offer the mechanism for involving TB and HIV stakeholders to promote commitment and sense of ownership.26,37 The coordinating bodies need to have equal or at least a reasonable representation of HIV and TB stakeholders, including TB and HIV patient support groups.30 Assigning focal persons responsible for the coordination of the programme activities was essential to scale up the implementation of collaborative TB/HIV activities. The focal points can be assigned at all levels, including national, provincial, district, municipality or local. By the end of 2006 out of the 63 TB/HIV priority countries (those 58 countries with an adult HIV prevalence 1% in 2005, plus five additional countries: Brazil, China, India, Indonesia and Viet Nam) which together make up 98% of the global TB/HIV burden, 43 countries reported the presence of a national body for coordinating the activities and 40 countries had assigned a national TB/HIV focal point.4 HIV surveillance among tuberculosis patients HIV surveillance among TB patients is critical to understanding the trend of the epidemic,38–40 and informing the development of sound strategies to respond to the problem.41 However, HIV prevalence is not systematically monitored among TB patients, even in industrialized countries with high HIV prevalence rates in TB patients.42 A system for HIV surveillance among TB patients should be in place in all countries irrespective of national adult HIV prevalence rates to ensure continued vigilance and to guide the need for collaboration and delivery of integrated services.30,32 There are three key methods for surveillance of HIV among TB patients:32 periodic surveys (cross-sectional HIV seroprevalence surveys among a small representative group of TB patients within a country); sentinel surveys (using TB patients as sentinel group within the general HIV sentinel surveillance system); and, most desirable, data from routine HIV testing and counselling of TB patients. The surveillance method chosen depends on the underlying HIV epidemic state, the overall TB situation and the availability of resources. However, the current paradigm shift in HIV testing policy in countries, which promotes provider-initiated HIV testing for TB
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patients and TB suspects,43,44 is further enhancing the use of routine data for surveillance. By the end of 2006, 50 of the 63 TB/HIV priority countries had a national policy of offering HIV testing for TB patients and 44 countries had a national surveillance system for measuring the prevalence of HIV in TB patients.4
Joint TB/HIV planning Medium-term national plans with specified budgets and sources of funding are essential elements of effective and comprehensive HIV and TB control efforts and provide the framework for joint TB/ HIV plans.45,46 Successful and systematic collaboration needs joint strategic planning of the national HIV and TB control programmes, which should include either devising a separate joint TB/HIV plan or introducing TB components in HIV strategic plans or HIV components in TB control strategic plans. The joint TB/HIV plans need to clearly define the roles and responsibilities of each programme in implementing specific TB/HIV activities and aim at utilizing existing country-specific opportunities. Joint resource mobilization, making use of traditional and new TB and HIV/AIDS funding opportunities, such as the Global Fund to Fight AIDS, TB and Malaria and the US President’s Emergency Plan for AIDS Relief, is also essential. Adequate deployment of sufficient and qualified human resources, including pre-service and in-service training of health workers on running and managing programmes, is essential. The process of developing the Joint Plans also requires recognition of the burden of HIV-related TB and critical analysis of the respective strengths and weaknesses of the TB and HIV control programmes in implementing collaborative TB/HIV activities.28 The joint plans (either national or sub-national) should give due consideration to all collaborative TB/HIV activities that need to be implemented in the country or setting, depending on the burden of HIV-related TB disease and the HIV epidemic. Countries with generalized HIV epidemics should implement all 12 collaborative TB/HIV activities, whereas countries or settings with low HIV prevalence need to ensure intensified TB prevention, diagnosis and treatment for all HIV positive individuals (Table 79.2).30 Considering geographical variations in the epidemiology of the diseases is also essential while preparing the joint plans. The plans should define priority HIV-prevalent settings (provinces, districts, sub-districts or selected facilities such as referral hospitals and drug rehabilitation centres) as an adult HIV prevalence rate of 1% in the general population or among pregnant women or an HIV
Table 79.2 Recommended collaborative TB/HIV 30 activities A. Establish the mechanisms for collaboration Set up coordinating bodies for TB/HIV activities at all levels. Conduct surveillance of HIV prevalence TB patients. Carry out joint TB/HIV planning. Monitor and evaluate. B. Decrease the burden of TB in people living with HIV/AIDS Establish intensified TB case-finding. Introduce isoniazid preventive therapy. Ensure TB infection control in healthcare and congregate settings. C. Decrease the burden of HIV in TB patients Provide HIV testing and counselling. Introduce HIV prevention methods. Introduce cotrimoxazole preventive therapy. Ensure HIV/AIDS care and support. Introduce antiretroviral therapy.
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prevalence of 5% among TB patients, for full implementation of collaborative TB/HIV activities. The training manual for the management of collaborative TB/HIV activities for managers at national and sub-national levels developed by WHO can help equip trainees with analytical skills to make full use of available data, monitor and evaluate national TB and HIV control programmes and prepare an effective joint plan.47 The other key elements of a joint plan include ensuring two-way communication between the programmes and the general public, ensuring advocacy is targeted at influencing policy at all levels and enhancing the engagement of community members and community-based organizations.30
Monitoring and evaluation The independent monitoring and evaluation systems of TB and HIV programmes may not adequately capture the programme effort expended on collaborative TB/HIV activities.31 Therefore, a core group of simple indicators are essential for the two programmes to work effectively. The core TB/HIV indicators for a given period, usually 1 year, include the number of HIV-infected TB patients identified and the number of people living with HIV screened for TB and started on TB treatment or given treatment for latent TB infection, cotrimoxazole preventive treatment (CPT) or antiretroviral treatment (ART).31 In order to accommodate monitoring and evaluation of collaborative TB/HIV activities, revision of the existing HIV and TB data collection and reporting forms is essential. Revised TB forms and registers are now recommended by WHO.48 Implementation of these revised formats requires development of national guidelines and training materials to adapt these generic formats to the country situation. Use of most of the revised forms and registers with HIV information requires on-the-spot training and supervision. Similarly, adapting and revising the HIV formats and registers with TB information is crucially important, particularly for those key activities that need to be carried out by HIV services (see below). The revised formats and registers for monitoring and evaluating the progress of implementation have already been successfully demonstrated in some countries.4 For example, in Kenya, revising and implementing the recording and reporting formats alongside electronic datacapturing system was crucial to capturing more activities and evaluating progress of implementation. National HIV testing in TB patients increased from 32% to 50%, over three quarters between 2005 and 2006, of whom 56% were HIVinfected in the first quarter of 2006. CPT is provided to 84% of HIV-infected TB patients and ART to a third of the HIV-infected TB patients (Ministry of Health of Kenya, 2007 unpublished). ACTIVITIES TO REDUCE THE BURDEN OF TB AMONG PLHIV Intensified tuberculosis case finding Tuberculosis is generally easier to diagnose in early HIV infection, when there is a higher proportion of patients with typical sputum smear-positive pulmonary TB, than in late HIV infection, when there is a higher proportion of sputum smear-negative pulmonary and extrapulmonary TB.49 However, active TB affects survival of patients in the early stages of HIV infection,50 and the risk of developing active TB increases with advancing immunodeficiency.22,51 A high rate of undetected TB among people living with HIV is common.52,53 Intensified case-finding and treatment of TB among HIV-infected patients interrupts disease transmission by infectious cases and delays mortality, decreases the risk of
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nosocomial TB transmission and offers the opportunity of providing TB preventive therapy to HIV-infected individuals without symptoms and signs of active TB disease.54–58 It is not difficult to implement and can be mainstreamed into pre-existing HIV services with little additional cost.26 Trained counsellors and other lay health workers can administer a brief questionnaire on TB symptoms to screen for active TB. Use of such simple TB screening instruments enabled detection of up to 11% of previously undiagnosed TB among people living with HIV who attended HIV testing and care services.26,52,58,59 The progression of TB infection is fundamentally regulated by the host’s immune system,60 and HIV infection drastically changes the epidemiology and natural history of TB.60,61 For example, weight loss and fever are more common in HIV-infected pulmonary TB patients than in HIV-uninfected patients, and conversely haemoptysis and cough are less frequent in HIV-infected than in -uninfected individuals.49 This must be factored in while developing a simple and standardized screening instrument based on the TB case definition of the national TB control guidelines. The tool needs to incorporate appropriate respiratory and constitutional symptoms applicable to the specific setting and the clinical practice, and needs to be administered by health workers providing TB and HIV services at the lowest service delivery unit. In a study done in South Africa, for example, a simple screening instrument that measured two or more of the symptoms (weight loss, cough, night sweats or fever) and was administered by nurses among people living with HIV had a sensitivity of 100% and specificity of 88% to diagnose TB, and positive and negative predictive values of 44% and 100%, respectively.59 Another study among HIV-infected miners in South Africa found that night sweats, new or worsening cough, weight loss and the inclusion of chest radiographs significantly increased the sensitivity and negative predictive value of the screening process.62 People living with HIV present with smear-negative pulmonary and extrapulmonary TB and are more likely to die during or before diagnosis is established.63 Therefore, expediting the diagnosis of TB in patients with HIV infection or AIDS through strengthening-intensified TB case-finding, including enhancing the role of community members in identification and referral of people suspected to have TB, is crucial and should be encouraged.
Tuberculosis preventive therapy Tuberculosis preventive therapy can be given to HIV-infected individuals with latent M. tuberculosis infection in order to prevent development of active TB. Several randomized trials have shown IPT is effective in reducing the incidence of TB in HIV-infected patients with the greatest reduction observed in positive tuberculin skin test (TST) patients.64 Overall, TB preventive therapy is not associated with a reduction in mortality (RR 0.95, 95% CI 0.85– 1.06), but among TST-positive individuals a beneficial effect was observed (RR 0.8, 95% CI 0.63–1.02). In clinical trials, rifampicin- and pyrazinamide-containing regimens are shown to be as effective as isoniazid (INH)-containing regimens, but they are more likely to be discontinued due to side effects. Treatment of latent TB infection (LTBI) with rifampin and pyrazinamide in HIV-uninfected individuals resulted in more hepatotoxicity than INH.65–67 The risk appears to be limited to HIV-uninfected individuals, as a rigorous re-analysis of a large trial of rifampicin and pyrazinamide in HIV-infected patients confirmed a lack of serious toxicity.67 Nevertheless, these regimens are not recommended by either the Center for Disease Control or WHO.30,65 Preventive
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treatment has resulted in medical care cost savings and reduction of social costs in sub-Saharan Africa.34,66 In a retrospective study from Brazil, it was found that the combined use of IPT with ART in HIV-infected patients is associated with significantly reduced TB incidence and its wider use with expanded access to ART will improve TB control in high-burden areas.68 Excluding active TB disease is essential before putting a patient on IPT. The current international recommendations by WHO and UNAIDS emphasize the importance of excluding active TB disease, including a mandatory chest radiograph, before considering preventive treatment.30,64 However, a pilot study in Botswana, a country with nationwide coverage of IPT, showed that a chest radiograph contributed to high attrition from the programme (18%) and detected TB in only 0.2% of asymptomatic patients with HIV infection,69 and suggested asymptomatic people living with HIV/AIDS (PLWHA) should receive IPT without a screening chest radiograph being required. This finding has been contradicted by a recent finding from the same area (with a larger sample size) in that abnormal chest radiograph was found in 12% of asymptomatic PLWHA seeking IPT, out of which 10% had active TB.70 Similarly, a South African study that used different variables to develop a screening instrument for detecting TB among PLWHA showed that the inclusion of chest radiograph results did not improve the performance of the screening instrument.59 To date, there are no data from programmatic conditions to support the use of screening tools without chest radiograph results for excluding active TB in symptomatic and asymptomatic patients. Partly as a result, at the moment very few countries have large-scale TB preventive therapy programmes. Several additional barriers including concerns of the feasibility of chest radiography to exclude active disease, fear of emergence of drug resistance and lack of suitable structures for monitoring the intervention are mentioned.37
Tuberculosis infection control The respiratory route accounts for the nearly all TB transmission in healthcare facilities, congregate housing and prisons, schools and workplaces.71 The risk of transmission appears to be high when infectious smear-positive pulmonary cases are managed at a healthcare facility.72 Smear-negative pulmonary TB cases can also be infectious, accounting for up to 18% of the TB transmission.73 There are even documented reports of TB transmission in healthcare facilities from patients with extrapulmonary TB.74,75 The outbreak of multidrug-resistant (MDR) TB, particularly affecting HIV-infected patients, in several institutions in the early 1990s helped the understanding of the natural history, clinical presentation, treatment and outcomes of MDR-TB.71 Failure to isolate patients early because HIV-infected patients have atypical clinical presentations was common to all of the outbreaks. The recent outbreak of extensive drug-resistant TB and the associated high casefatality rate among HIV-infected patients, including health workers, calls for strengthening basic principles of TB control including prevention of airborne transmission.76 Therefore, effective infection control measures should be introduced in healthcare and congregate settings where people with TB and HIV are frequently crowded together. Measures should include early recognition, diagnosis and treatment of TB suspects, particularly those with pulmonary TB, and separation of pulmonary TB suspects from others until a diagnosis is confirmed or excluded. Maximizing natural ventilation, protecting the HIV-infected person from possible exposure to TB and offering TB preventive therapy are other
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important interventions.77 Due attention needs to be given to protecting healthcare workers, particularly in low- and middle-income countries, as TB is a significant occupational risk.72
ACTIVITIES TO REDUCE THE BURDEN OF HIV IN PLWHA HIV testing and counselling HIV testing of TB suspects and patients is the gateway to tailored care and support for HIV-infected TB patients, linking prevention activities and adherence support for both HIV and TB.44 Voluntary knowledge of serostatus reduces risk of HIV acquisition or transmission.78 The uptake of HIV testing by TB patients is generally high,79 and simplified techniques such as using sputum for HIV testing are being developed and would further promote it.80 Provider-initiated HIV testing should be offered to all adolescents or children who present to clinical settings with signs and symptoms of TB, including those suspected of having it.43,44 Health providers should recommend HIV testing and counselling for TB patients and suspects as a standard clinical care in order to enable clinical decisions.81 The testing should be offered to all TB patients with respect, protection and fulfillment of human rights norms and standards. In HIV testing of TB patients, the basic conditions of confidentiality, consent and counselling apply but the standard pre-test counselling used in Voluntary Counselling and Testing (VCT) services is adapted to simply ensure informed consent, without a full education and counselling session.43 All patients should receive, or be referred, to post-test counselling tailored to serostatus. HIV and TB prevention, support and care services, including ART must be expanded and made available to eligible HIV-infected TB patients. However, ensuring nationwide universal coverage of highquality rapid HIV testing for TB patients in high-HIV-prevalent and resource-constrained settings poses a serious challenge. It requires availability of knowledgeable, trained and committed health workers at service delivery points, facilities conducting HIV testing in the consulting outpatient department rooms and increased and uninterrupted availability of services and resources.37 Furthermore, the expansion of the testing needs to consider local epidemiological and social contexts, as well as assessment of the risks and benefits, including an appraisal of available resources and prevailing standards of HIV prevention, treatment, care and support, and judgments about the social and legal protections available to those living with HIV or at risk of exposure to it. HIV preventive methods Providing HIV preventive methods to TB patients in TB clinics or through establishing effective referral linkages with HIV/AIDS service outlets (e.g. VCT centre or sexually transmitted infections (STI) clinic) is feasible in high HIV and TB settings.58 Linking prevention and care and support programmes generates synergies and strengthens HIV/AIDS programmes. Directly observed ART for PLWHA modelled on successful TB control efforts has been used to extend moral and social support for patients.82 This could also be a good opportunity to provide integrated services. Condom promotion and screening for STI and their syndromic management were promoted in the ProTEST projects and proved to be feasible.26 However, more data and analysis are still needed on the role of STI screening questionnaires and syndromic management in the context of TB services. Tuberculosis control programmes should implement comprehensive HIV preventive strategies aimed at reduction of sexual, parenteral and vertical
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transmission of HIV.30 Particular emphasis must focus on injecting drug use where it drives the HIV epidemic, namely in Europe and central and east Asia, and TB prevention, diagnosis and treatment need to be integrated with harm reduction strategies, wherever applicable.
Cotrimoxazole prophylaxis HIV-infected TB patients are at higher risk of dying during and after TB treatment than HIV-uninfected TB patients.83 In sub-Saharan Africa about 30% of HIV-infected TB patients die within 12 months of treatment, largely because of other HIV-related infections.84,85 In a 7-year cohort analysis of TB mortality in Malawi, 50% of the cumulative mortality occurred during antituberculous treatment, half of which occurred during the first month of TB treatment.86 This, in the absence of wide availability of ART, implies that adjunct therapies for reducing mortality of HIV-infected TB patients are imperative. Randomized controlled trials of CPT have shown reduction in mortality among HIV-infected, smear-positive TB patients.87 Cotrimoxazole is also shown to be beneficial for CD4 cell count and viral load and to reduce hospitalization and morbidity among PLWHA, including TB patients.79,88–91 Cross resistance of cotrimoxazole with sulfadoxine-pyrimethamine, a widely used antimalarial drug, has also been a concern for its wider use in malariaendemic areas such as in sub-Saharan Africa. However, current WHO recommendations restrict the use of sulfadoxine–pyrimethamine as first-line treatment and countries are increasingly changing their national malaria management policies into combination therapies containing an artemisinin derivative.92 The added benefit in terms of reduction of morbidity and mortality from cotrimoxazole prophylaxis in HIV-infected TB patients on ART is not clear. However, until more evidence becomes available, cotrimoxazole should be an adjunct intervention irrespective of the availability of ART. HIV/AIDS care and support HIV-infected TB patients should have access to comprehensive HIV/AIDS care and support services including effective referral mechanisms.30 Stigma leads people to either hide their TB diagnosis, delay seeking treatment or refrain altogether from getting help out of fear that people will think they have HIV.93 Increasing access to services and treatment will lessen HIV-associated stigma.82,94 Moreover, extending effective and appropriate psychological and social support will be crucial for addressing stigma issues and improving the quality of life of HIV-infected patients. Services should include clinical management (prophylaxis, early diagnosis, rational treatment and follow-up care for opportunistic infections), nursing care (including promoting hygiene and nutritional support), palliative care, home care (including education for care providers and patients’ relatives, promoting universal precautions), counselling and social support.30 Tuberculosis control programmes should provide these services, or, at the minimum, establish an effective referral mechanism for ensuring a continuum of care for their HIV-infected TB patients. Antiretroviral therapy ART improves the quality of life and greatly improves survival for PLWHA.95 It also reduces the incidence of TB in HIV-infected persons,96 although patients with advanced pre-treatment immunodeficiency can have persistently increased risk of TB.97 However, in order to prevent a significant fraction of TB cases, antiretroviral drugs should be initiated early in the course of HIV infection and will need high coverage and high rates of compliance.98,99 Special consideration is needed while administering ART to TB patients
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because of pill burden, overlapping toxicities, drug interactions between rifampicin and antiretroviral drugs, the immune reconstitution inflammatory syndrome (IRIS) and adherence issues.100 IRIS is a clinical condition heralded by the exacerbation of clinical symptoms and signs of active TB in HIV-infected adults started on ART due to the recovery of the immune system. This may be because patients had subclinical TB before the ART began, or because an LTBI has been reactivated. Although there is no standard case definition for TB IRIS, several studies showed that its incidence varies between 11% and 45% in patients receiving ART.101 The risk of IRIS was high in patients with low baseline CD4 count starting ART early in the course of antituberculous treatment. In a community-based ART service in South Africa, among patients with baseline CD4 cell counts < 50, IRIS was developed in 21% of the patients, whereas no IRIS was observed in patients with more than 150 cells/mL. Similarly, although only 12% of patients overall developed TB IRIS, the proportion of patients affected who commenced ART within 2 months of TB diagnosis was much higher (32%).102 Decentralization of ART services in HIV-prevalent settings to the lowest possible primary healthcare unit is also crucial for ensuring access to eligible TB patients. For patients with active TB in whom HIV infection is diagnosed and ART is required, the first priority is to initiate standard TB treatment. When available, CD4 cell counts should be used to determine the eligibility of a patient for ART (Table 79.3). In patients with CD4 counts > 350 cells/mm3, ART can be delayed until after the completion of the TB treatment. Similarly, for patients with CD4 cell counts > 200 cells/mm3 the start of ART may be delayed until after the initial intensive phase of TB treatment has been completed. However, in persons with CD4 cell counts < 200 cells/mm3, ART should be started between 2 and 8 weeks after the start of TB therapy when the patient has stabilized on TB treatment. In circumstances where CD4 cell counts cannot be obtained, ART should be initiated
Table 79.3 Initiating first-line ART in relationship to starting antituberculous therapy CD4 cell count
ART recommendations
Timing of ART in relation to the start of TB treatment
CD4 < 200 cells/mm3 CD4 between 200 and 350 cells/mm3 CD4 > 350 cells/mm3
Recommend ARTa
Between 2 and 8 weeksb
Recommend ART
After 8 weeks
Defer ARTc
CD4 not available
Recommend ARTd
Re-evaluate patient at 8 weeks and at the end of TB treatment Between 2 and 8 weeks
a
An efavirenz-containing regimen is the preferred first-line regimen. Alternative first-line treatment regimens to an efavirenz-based regimen include nevirapine and triple nucleoside reverse transcriptase inhibitors (TDF or ABC-based) regimens. For nevirapine-containing regimens ALT should be checked at 4, 8 and 12 weeks directed by symptoms thereafter. b Start ART as soon as TB treatment is tolerated. c If other non-TB stage 3 or 4 events are present, start ART. d For some TB diagnoses that generally respond well to anti-TB therapy (i.e. lymph node TB, uncomplicated pleural effusion) consider deferring ART.
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between 2 and 8 weeks after the start of TB therapy when the patient has stabilized on TB treatment. For some patients with uncomplicated pulmonary TB disease in whom a good response to TB therapy is seen, ART may be delayed until the initial intensive phase of TB treatment is completed. ART may also be deferred in selected cases of extrapulmonary TB (lymph node TB or patients with uncomplicated pleural disease) where a good response to TB therapy is seen. Otherwise, it is indicated to extrapulmonary TB cases as it represents stage four of HIV disease.100 The recommended standard first-line ART regimen for TB patients comprises two drugs from the class of nucleoside reverse transcriptase inhibitor (NRTIs) plus one drug from the class of the non-nucleoside reverse transcriptase inhibitor (NNRTIs). There are few drug interactions with TB drugs and the NRTI backbone and no specific changes are recommended. However, NNRTI levels (efavirenz (EFV) and nevirapine (NVP)) are reduced in the presence of rifampicin and may require adjustments. Efavirenz blood levels are decreased in the presence of rifampicin and this can be overcome by a dose increase of 600–800 mg daily. However, emerging evidence does not show any benefit in increasing the dose and WHO recommends the use of the standard 600-mg dose in its 2006 recommendations.100 Because of its teratogenic effect, EFV is contraindicated in women of childbearing potential without adequate contraception or in women who are in the first trimester of pregnancy. The use of NVP is recommended along with rifampicin with close clinical and laboratory monitoring of liver enzymes at 4, 8 and 12 weeks of treatment, as it carries the risk of hepatotoxicity, particularly in persons with higher CD4 counts or in those where CD4 counts are not known. Triple NRTIs are considered an alternative regimen in patients undergoing TB treatment. Two triple NRTI regimens (AZT þ 3TC þ ABC and AZT þ 3TC þ TDF) can be used safely with rifampicin.100
SPECIAL CONSIDERATIONS FOR IMPLEMENTATION There are certain groups of patients that need special consideration while implementing collaborative TB/HIV activities. These include injecting drug users (IDUs), prisoners, refugees and internally displaced people and women of reproductive age group.
INJECTING DRUG USERS (IDUS) There is evidence that IDUs are at higher risk of both HIV and TB than the general population and that the risk of TB is greatest in IDUs who are also HIV-infected.103 The principles of addressing TB in IDUs are similar to the overall approach of addressing HIV-related TB. Comprehensive service delivery involves the addition of specific measures for TB control to existing services for drug users, including preventive therapy for TB, intensified TB case-finding and treatment, managing complex drug interactions, the use of incentives to improve adherence, the use of directly observed therapy (DOT), combining DOT with substitution therapy, addressing comorbidities, and considerations for nonopioid drug users. Additional measures for existing TB services are needed to ensure that IDUs are identified and managed appropriately with offer of multiple interventions at the same service delivery point.
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PRISONERS Services in prisons and detention centres require special attention due to the higher incidence of TB, HIV and IDU among prisoners than the general population in many countries.104,105 Prisoners have a right to a standard of healthcare equivalent to that available outside prison. In most cases, prison healthcare is the responsibility of the prison authorities, rather than the national health services. Collaborative TB/HIV services should hence be provided to prisoners with close collaboration and consultation between national TB and HIV control programmes and the prison healthcare service. The local political, social and cultural context need to be taken into account while designing programmes and particular emphasis needs to be given for TB and HIV infection control.
REFUGEES AND INTERNALLY DISPLACED PEOPLE Refugees are at particularly high risk of developing TB.106 The crowded living conditions of most camps for refugees and internally displaced people facilitate the transmission of TB infection. Coexistent illness and the poor nutritional status of many refugees weaken their immune system and make them more vulnerable to developing active TB. The HIV epidemic also affects many countries with large refugee populations, particularly in subSaharan Africa. Tuberculosis treatment and control were successfully implemented with high treatment success rate in a conflict setting with internally displaced populations.107 Local ownership of the programme coupled with reducing the distance travelled to get the services contributed to the success. Collaborative TB/HIV activities need to be provided in an integrated manner wherever refugees and internally displaced people are present.
WOMEN OF REPRODUCTIVE AGE Among notified TB cases of 15–49 years old, the proportion which is women increased over the past decade, particularly in the African region, probably due to the impact of HIV.108 Tuberculosis in pregnant women also results in low birthweight, prematurity and perinatal TB.109 Although women have similar or better TB treatment outcomes than men,21 the high rates of TB in HIV-infected pregnant women require intensified TB screening during routine antenatal care in high-HIV-prevalence settings.110 Those with active TB should be promptly treated with standard TB treatment regimen in accordance with national TB control guidelines. However, the use of IPT in screened pregnant women with no TB symptoms and signs has been a point of controversy. Increased risk of hepatotoxicity following isoniazid has been documented during pregnancy,111,112 suggesting the delay in the treatment until after the pregnancy. However, in a modelling exercise, antepartum treatment of LTBI in pregnant women was shown to result in marginal increase in life expectancy due to the prevented cases of TB, despite more cases of hepatitis and deaths, compared with no treatment or postpartum treatment.113 Moreover, among HIV-infected Indian women, a high incidence of postpartum TB and associated postpartum maternal and infant death was reported.114 Therefore, the decision to treat LTBI during pregnancy should weigh the risk for developing active TB against the consequences to both the mother and her child should active disease develop. There are also other programmatic issues that need to be considered while addressing HIV-related TB among women of reproductive age. For example, EFV-containing regimens are not recommended during
CHAPTER
Implementation of collaborative tuberculosis/HIV activities
the first trimester of pregnancy or in women of childbearing potential unless without ensuring effective contraception. An alternative in women with active TB is a triple NRTI regimen, e.g. AZT þ 3TC þ ABC. A change from an EFV-containing to an NVP-containing regimen can be considered when TB treatment has been completed100
CONCLUSION Implementation of collaborative activities should be a priority for national TB and HIV control programmes, not only in high-HIVprevalence settings but also countries with concentrated or low HIV epidemic state. Experience and best practice from pioneer countries in nationwide expansion of collaborative TB/HIV activities has shown that setting national targets for collaborative TB/HIV activities facilitates implementation and also helps to mobilize political commitment and stakeholders’ engagement from the TB and HIV control programmes. Creating a conducive policy environment with
REFERENCES 1. Raviglione MC, Harries AD, Msiska R, et al. Tuberculosis and HIV: current status in Africa. Aids. 1997;11(Suppl B):S115–123. 2. Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003; 37(1):101–112. 3. Lambert ML, Hasker E, Van Deun A, et al. Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 2003;3(5):282–287. 4. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO/ HTM/2007.376. Geneva: World Health Organization, 2007. 5. Maher D, Harries A, Getahun H. Tuberculosis and HIV interaction in sub-Saharan Africa: impact on patients and programmes; implications for policies. Trop Med Int Health 2005;10(8):734–742. 6. Nunn P, Williams B, Floyd K, et al. Tuberculosis control in the era of HIV. Nat Rev Immunol 2005; 5(10):819–826. 7. World Health Organization. Forty-fourth World Health Assembly. Resolutions and Decisions. Resolution WHA 44.8. WHA44/1991/REC/1. eneva: World Health Organization, 1991. 8. Styblo K BJ. Tuberculosis Can Be Controlled with Existing Technologies: Evidence. Tuberculosis Surveillance Research Unit Progress Report 2, 1991: 60–72. 9. Suarez PG, Watt CJ, Alarcon E, et al. The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru. J Infect Dis 2001;184(4): 473–478. 10. Dye CWB. Criteria for the control of drug-resistant tuberculosis. Proc Natl Acad Science 2000;97: 8180–8185. 11. World Health Organization. Report of the ad hoc Committee on the Tuberculosis Epidemic, London, 17–19 March 1998. WHO/TB/98.245. Geneva: World Health Organization, 1998. 12. World Health Organization. Fifty-third World Health Assembly. Resolutions and Decisions. Resolution WHA 53.1. Geneva: World Health Organization, 2000. 13. GC Information Centre. G8 Communique´ Okinawa 2000: Okinawa 23 July 2000. Accessed on December 12, 2006. Available at URL: http://www.g7. utoronto.ca/summit/2000okinawa/finalcom.htm
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the development of appropriate policy and operational guidelines, training manuals and protocols in line with international guidelines is crucial. Expanding HIV testing facilities by allowing front-line TB clinicians and nurses to test not only TB patients but also those presenting with signs and symptoms of TB (‘TB suspects’) is important to scale up activities in HIV-prevalent settings, backed up by constant supply of HIV test kits, drugs and other important commodities. Implementing revised recording and reporting formats on collaborative TB/HIV activities contributes to the documentation of the progress of implementation and informing the performance of the programmes.48 It is important to include TB components in HIV registers and HIV components in TB registers. There has been a rapid scale of increase in the global implementation of interventions aimed at reducing the burden of HIV among TB patients over the past few years (Table 79.2). Comparably the implementation of interventions intended to reduce the burden of TB among PLWHA such as TB screening, provision of IPT and ensuring TB infection control has been so minimal that it needs urgent attention particularly by HIV policy-makers and service providers.
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62. Day JH, Charalambous S, Fielding KL, et al. Screening for tuberculosis prior to isoniazid preventive therapy among HIV-infected gold miners in South Africa. Int J Tuberc Lung Dis 2006;10(5): 523–529. 63. Getahun H, Harrington M, O’Brien R, et al. Diagnosis of smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resourceconstrained settings: informing urgent policy changes. Lancet 2007;369(9578):2042–2049. 64. WHO/UNAIDS. WHO and UNAIDS Policy statement on preventive therapy against tuberculosis in people living with HIV. Weekly Epidemiological Record 1999;74:385–400. 65. Centers for Disease Control and Prevention (CDC). Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for the treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2003;52:735–739. 66. Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004(1):CD000171. 67. Gordin FM, Cohn DL, Matts JP, et al. Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons? Clin Infect Dis 2004;39(4):561–565. 68. Golub JE, Saraceni V, Cavalcante SC, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIVinfected patients in Rio de Janeiro, Brazil. AIDS 2007;21(11):1441–1448. 69. Mosimaneotsile B, Talbot EA, Moeti TL, et al. Value of chest radiography in a tuberculosis prevention programme for HIV-infected people, Botswana. Lancet 2003;362(9395):1551–1552. 70. Samandari TAT, Arwady A, Yoon J, et al. Asymptomatic pulmonary TB among HIV-infected adults screened for the Botswana isoniazid preventive therapy clinical trial, 2004–2006. Abstract presented at 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007), February 25–28, 2007, Los Angeles, USA. 71. Sepkowitz KA, Raffalli J, Riley L, et al. Tuberculosis in the AIDS era. Clin Microbiol Rev 1995;8(2): 180–199. 72. Joshi R, Reingold AL, Menzies D, et al. Tuberculosis among health-care workers in low- and middleincome countries: a systematic review. PLoS Med 2006;3(12):e494. 73. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999;353(9151):444–449. 74. Frampton MW. An outbreak of tuberculosis among hospital personnel caring for a patient with a skin ulcer. Ann Intern Med 1992;117(4):312–313. 75. Hutton MD, Stead WW, Cauthen GM, et al. Nosocomial transmission of tuberculosis associated with a draining abscess. J Infect Dis 1990;161(2):286–295. 76. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368(9547): 1575–1580. 77. World Health Organization. Guidelines for the Prevention of Tuberculosis in Health Care Facilities in Resource Limited Settings. WHO/CDS/TB/99.269. Geneva: World Health Organization, 1999. 78. De Cock KM, Marum E, Mbori-Ngacha D. A serostatus-based approach to HIV/AIDS prevention and care in Africa. Lancet 2003;362(9398):1847–1849. 79. Zachariah R, Spielmann MP, Chinji C, et al. Voluntary counselling, HIV testing and adjunctive cotrimoxazole reduces mortality in tuberculosis patients in Thyolo, Malawi. AIDS 2003;17(7): 1053–1061. 80. Talbot EA, Hone NM, Moffat HJ, et al. The validity of HIV testing using sputum from suspected tuberculosis patients, Botswana, 2001. Int J Tuberc Lung Dis 2003;7(8):710–713.
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Pulmonary manifestations of tuberculosis in adults Helmuth Reuter and Elvis Irusen
This chapter covers some interesting clinical and radiographic presentations of intrathoracic TB in adults. The cases range from diabetic to human immunodeficiency virus (HIV)-infected patients and demonstrate specific diagnostic or therapeutic aspects of TB in adults.
CASE 1: THE ELDERLY WOMAN A 75-year-old woman presented with 15-kg weight loss and a 3-week history of cough, fever, and night sweats. There was no significant associated medical history, specifically no history of previous TB. She also denied having contact with a TB case. On examination, the weight loss was apparent and there was no palpable lymphadenopathy. The respiratory examination revealed stridor and occasional crackles. A chest radiograph (Fig. 80.1) was requested and was followed by a chest computed tomography (CT) scan as shown in Fig. 80.2. Two sputum smears examined microscopically for acid-fast bacilli were negative. The parenchymal window of the CT scan of the chest showed diffuse nodular changes consistent with miliary TB. Bilateral dependent pleural effusions were also noted. The mediastinal window (at the level of the aortic arch) demonstrated extensive bilateral mediastinal lymphadenopathy with ring enhancement and central hypodensity consistent with liquefaction. The nodes surround the trachea with resulting tracheal stenosis. A percutaneous transthoracic ultrasound-guided parasternal lymph node aspiration yielded caseous material with positive staining for acid-fast bacilli, confirming the diagnosis of miliary TB with bilateral pleural effusions and mediastinal lymphadenopathy. The patient responded well to a 6-month course of directly observed anti-TB therapy.
COMMENT Tuberculosis can present in an atypical manner in elderly patients because of altered immunity. Tuberculosis in the elderly is most often associated with reactivation of endogenous infection.1 Although poverty and poor nutritional status have been blamed for the high rates of TB in the elderly,2,3 ageing itself has been shown to be associated with progressive immune dysregulation and decreased synthesis of interferon gamma (IFN-g), which is an essential cytokine in the antituberculous immune response due to its importance in the activation of macrophages.2,4,5 The delay in diagnosing TB in the elderly is often related to the atypical clinical and radiological features. Although classical symptoms of chronic cough,
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night sweats, weight loss, and haemoptysis may be present, these are often attributed to chronic bronchitis and old age.6,7 Consequently, elderly patients often present with more advanced disease at the time of diagnosis and the treatment outcomes may be worse (higher rates of failure) and the case mortality higher than in younger patients.3,8
CASE 2: THE DIABETIC MAN A 52-year-old man presented with a history of long-standing diabetes mellitus that was recently difficult to control with blood glucose levels ranging from 8 to 15 mmol/L. He experienced some weight loss but had no respiratory symptoms or previous history of TB. His physical examination was essentially normal. Full blood cell count, renal function tests, and liver function tests were normal. A chest radiograph was requested (Figs 80.3 and 80.4), followed by a CT scan (Fig. 80.5). He responded well to a 6-month course of antituberculous therapy and was given an evening dose of long-acting insulin, thereby achieving satisfactory glycaemic control.
COMMENT The radiographic images are consistent with a large conglomerate mass of granulomata surrounded by satellite smaller tuberculous granulomata. The radiographic images would be extremely unusual for pyogenic infection or pulmonary malignancies.
CASE 3: THE DIABETIC FARM WORKER A 40-year-old male diabetic farm worker presented with chronic cough and weight loss and was diagnosed with non-resolving pneumonia. He had been given three courses of antibiotics with no response. Two sputum smears were negative for acid-fast bacilli and Gram stain and bacterial culture had also been negative on three occasions. The chest radiograph is shown in Fig. 80.6. Bronchoscopy with bronchoalveolar lavage yielded Mycobacterium tuberculosis. He responded clinically and radiologically well to a 6month course of anti-TB therapy and was given an evening dose of long-acting insulin, thereby achieving better glycaemic control.
COMMENT Poorly controlled hyperglycaemia is usually considered to be the main factor causing increased susceptibility to infections,9 and the
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Pulmonary manifestations of tuberculosis in adults
Fig. 80.1 The chest radiograph shows diffuse fine nodular parenchymal shadowing. The mediastinum is widened and a mass is projected over an aneurysmal aortic arch. There is blunting of the left costophrenic angle.
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Fig. 80.3 The chest radiograph shows a mass in the left upper lobe surrounded by small nodules; these are better delineated on the close-up radiographic view shown in Fig. 80.4 and on chest CT shown in Fig. 80.5.
Fig. 80.4 The close-up view of the chest radiograph shows the mass in the left upper lobe surrounded by small nodules more clearly.
Fig. 80.2 (A) Parenchymal window. (B) Mediastinal window.
Fig. 80.5 The chest CT scan demonstrates the exact position of the left upper lobe mass and the adjacent smaller nodules, which are suggestive of granulomata.
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She was treated with a 6-month course of anti-TB therapy, oral pyridoxine, and daily cotrimoxazole preventive therapy. After completion of the 2-month intensive phase of anti-TB therapy, highly active antiretroviral therapy was initiated with stavudine, lamivudine, and efavirenz.
COMMENT
Fig. 80.6 The chest radiograph shows left mid-zone opacification with no obvious granulomata or cavitation.
prevalence of TB among diabetics is significantly higher than in the non-diabetic population.10,11 The radiographic manifestations of TB may differ from the findings in non-diabetic controls, including more lower lung-field and multilobar involvement in diabetic patients.10–14 The abnormal radiological presentation and lower lung field involvement seem to be especially associated with female diabetics and also diabetics who are older than 40 years.11
CASE 4: THE HIV-INFECTED DOMESTIC WORKER A 38-year-old domestic worker, known to be HIV-infected (latest CD4 cell count 52 cells/mL), presented with a 3-week history of non-productive cough, night sweats, and weight loss. On physical examination, she was tachypnoeic and had bilateral crackles. Pulse oximetry showed HbO2 saturation of 92%. Her chest radiograph (Fig. 80.7) demonstrated bronchogenic infiltrates and a small right pleural effusion. Two sputum smears examined microscopically for acid-fast bacilli were positive.
The radiographic features observed in HIV-associated pulmonary TB may differ significantly from classical post-primary TB seen in non-HIV-infected individuals. HIV causes a gradual loss of CD4+ T-lymphocytes, and this leads to increased susceptibility to reactivation of latent tuberculous infection, rapid progression following primary infection, increased risk of recurrent disease, increased reinfection rates, and also a change in the clinical picture, including a higher proportion of extrapulmonary TB and involvement at more than one site, a lower rate of tuberculin skin test positivity, a marked increase in mortality, and more frequent atypical chest radiographs, as listed in Box 80.1.15,16 If any of the abnormal radiographic features are seen in an HIV-infected patient, TB should be considered, and, conversely, HIV infection should be suspected in a patient with symptoms of TB and the presence of one or more of these radiographic findings.
CASE 5: THE SECURITY GUARD A 33-year-old male security guard presented with haemoptysis amounting to more than two cups full of light red blood. This had been preceded by 5 days of coughing and production of small amounts of sputum mixed with blood. He had a history of pulmonary TB, which had been fully treated 5 years previously. On examination he was found to be somewhat distressed. He was tachypnoeic (respiratory rate of 20/ minute) and tachycardic (pulse rate of 112/minute) and had a supine brachial blood pressure of 120/75 mmHg. He had decreased chest wall movement on the left, percussion dullness, and crackles in the upper zone of his left lung. His haemoglobin level was 10.6 g/dL, white cell count 11.3 109/L, and his platelet count 376 109/L. The C-reactive protein was 12 mg/mL. A chest radiograph (Fig. 80.8) was requested and demonstrated pleural thickening and a cavity with an endocavitary mass in the left upper zone confirmed by chest CT scan (Fig. 80.9). Sputum smears were negative for acid-fast bacilli. Box 80.1 Atypical radiographic features of HIV-associated pulmonary tuberculosis in adults
Fig. 80.7 Diffuse nodular changes and blunted right costophrenic angle suggestive of pleural effusion.
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Atypical site (not upper lobe). Atypical appearance (no cavitation). Lobar consolidation. Interstitial infiltrates. Simultaneous parenchymal and pleural disease (TB in the immunocompetent usually presents with one or the other, but not both). Hilar and paratracheal lymphadenopathy. Endobronchial disease: Clear lung fields or Lobar collapse. Miliary TB. Clear lung fields (in patients with culture-positive or AFB-positive disease; too few lymphocytes to form a radiologically visible lesion). Pleural effusions pulmonary parenchymal lesions. Pericardial effusions pleural effusions pulmonary parenchymal lesions.
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Pulmonary manifestations of tuberculosis in adults
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CASE 6: THE UNEMPLOYED SHACK DWELLER A 40-year-old unemployed shack dweller presented with recurrent haemoptysis. He was a heavy smoker and known alcoholic and had been treated for TB three times previously. On examination he was found to be pale and malnourished. He was tachypnoeic with a respiratory rate of 22/minute and had bilateral crackles over his upper lung zones. His haemoglobin level was 11.4 g/dL, his white cell count 6.9 109/L, and his platelet count 292 109/L. A chest radiograph (Fig. 80.10) demonstrated fibrotic changes in both upper lobes and a soft-tissue ‘mass’ density in the right mid-zone, simulating a tumour or a mycetoma. A CT scan of the chest (Fig. 80.11) showed that this mass was due to a Rasmussen’s aneurysm.
Fig. 80.8 The chest radiograph shows left-sided pleural thickening, volume loss, crowding of the ribs, mid-zone nodular changes, and a cavity with an endocavitary mass in the left upper zone suggestive of a mycetoma in a patient with previous pulmonary TB.
Fig. 80.10 The chest radiograph shows fibrotic changes in both upper lobes consistent with the patient’s history of previous TB. There is a soft-tissue ‘mass’ density in the right mid-zone simulating a tumour or a mycetoma.
Fig. 80.9 A CT scan of the chest demonstrated features of tuberculous bronchiectasis in the left lung and confirmed significant loss of lung volume, pleural thickening, and a cavity posteriorly with a fungal ball or mycetoma in the dependent position.
COMMENT Endocavitary fungal balls are usually caused by a round mass of hyphae of Aspergillus fumigatus (aspergilloma) or endocavitary infection by actinomycetes of the genera Nocardia, Streptomyces, and Actinomadura (actinomycetoma). Eumycetoma is caused by true fungi of many different genera. Systemic chemotherapy is of no value in endocavitary aspergillosis and patients with severe haemoptysis may benefit from lobectomy. Poor pulmonary function of residual lung and dense pleural adhesions around the cavity can complicate resection.
Fig. 80.11 Contrast-enhanced CT reveals contrast in the great vessels and contrast from the right pulmonary artery leading to the mass that also fills completely with contrast consistent with a Rasmussen’s aneurysm.
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COMMENT Haemoptysis may result from residual post-tuberculous bronchiectasis, endocavitary bacterial or fungal infection (especially aspergillosis in the form of a fungal ball), erosion of calcified lesions into the lumen of an airway (broncholithiasis), or rupture of a dilated vessel in the wall of an old cavity or traversing its lumen. The term Rasmussen’s aneurysm refers to an aneurysm of the small- to medium-sized pulmonary artery branches that develop in the vicinity or wall of a tuberculous cavity. Most patients with massive haemoptysis bleed from bronchial artery neovascularization associated with post-tuberculous
REFERENCES 1. Stead WW. Pathogenesis of first episode of chronic pulmonary tuberculosis in man: recrudescence of residuals of primary infection of exogenous re-infection. Ann Intern Med 1968;68:731–745. 2. Lesourd B, Mazari L. Nutrition and immunity in the elderly. Proc Nut Soc 1999;58:685–695. 3. Gaur SN, Dhingra VK, Rajpal S, et al. Tuberculosis in the elderly and their treatment outcomes under DOTS. Indian J Tuberc 2004;51:83–87. 4. Pedrazzini T, Hug K, Louis JA. Importance of L3T4+ and Lyt2+ cells in the immunologic control of infection with Mycobacterium bovis strain bacillus Calmette Guerin in mice. Assessment by elimination of T cells subsets in vivo. J Immunol 1987;139: 2032–2037. 5. Davies PDO. The effects of poverty and ageing on the increase in tuberculosis. Monaldi Arch Chest Dis 1999;54:168–171.
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bronchiectasis. The management may include resective surgery (such as a pulmonary lobectomy) or bronchial artery embolization (BAE) therapy following bronchial arteriography. BAE may result in immediate control of haemoptysis in 77–82% of patients with massive haemoptysis.17,18 Should haemoptysis recur in these patients, repeat embolization can be performed safely. BAE may help to avoid surgery in patients who are not good surgical candidates. The potential complications of BAE include subintimal dissection or perforation of the bronchial artery and the reflux of embolic material into the aorta with potential embolization sequelae at unintended sites.18
6. Khan MA, Kovnat DM, Bachus B, et al. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Isr J Med 1977;62:31–38. 7. Nagami P, Yoshikawa TT. Ageing and tuberculosis. Gerontology 1984;30:308–315. 8. Chan-Yeung M, Noertjojo K, Tan J, et al. Tuberculosis in the elderly in Hong-Kong. Int J Tuberc Lung Dis 2002;6:771–779. 9. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995;9:1–9. 10. Yamagishi F, Suzuki K, Sasaki Y, et al. Prevalence of coexisting diabetes mellitus among patients with active pulmonary tuberculosis. Kekkaku 1996; 71:569–572. ¨, C 11. Bacakolu F, Baolu O ¸ ok G, et al. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595–600. 12. Chang SC, Lee PY, Perng RP. Lower lung field tuberculosis. Chest 1987;91:230–232. 13. Olmos P, Donoso J, Rojas N, et al. Tuberculosis and diabetes mellitus: A longitudinal-retrospective study
14. 15.
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18.
in a teaching hospital. Rev Med Chil 1989; 117:979–983. Morris JT, Seaworth BJ, McAllister CK. Pulmonary tuberculosis in diabetics. Chest 1992;102:539–541. Chaisson R, Schecter GF, Theuer CP, et al. Tuberculosis in patients with the acquired immunodeficiency syndrome. Clinical features, response to therapy and survival. Am Rev Respir Dis 1987;136:570–574. Havlir DV, Barnes PF. Current concepts. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999;340:376–373. Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results. Radiology 1985;157:637–644. Swanson KL, Johnson CM, Prakash UBS, et al. Bronchial artery embolization—experience with 54 patients. Chest 2002;121:789–795.
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81
Extrapulmonary tuberculosis in adults Helmuth Reuter and Elvis Irusen
This chapter covers some interesting clinical and radiographic presentations of extrapulmonary TB in adults, the cases demonstrating specific diagnostic or therapeutic aspects.
CASE 1: THE FARM LABOURER A 40-year-old male farm labourer presented with a history of a cough accompanied by weight loss and night sweats for about 1 month. During the previous 5 days he had experienced progressively worsening shortness of breath. He had smoked self-rolled cigarettes for more than 20 years and admitted to drinking copious amounts of wine on weekends. He had no previous medical history of lung disease and had never worked in a mine. On physical examination he was found to have dullness on the right side of the chest with decreased air entry. A chest radiograph (Fig. 81.1) showed a large right-sided pleural effusion, which was drained. Fibrin clots developed in the pleural aspirate and the adenosine deaminase (ADA) activity was 86 U/L. Two sputum smears and a smear of the pleural fluid were negative for acid-fast bacilli. The patient tested positive for human immunodeficiency virus (HIV); his CD4 cell count was 364 cells/mL. He started taking daily cotrimoxazole preventive therapy and responded well to a 6-month course of anti-TB therapy.
CASE 2: THE DEPRESSED HIV-INFECTED MOTHER A 26-year-old HIV-infected mother of three children presented with progressive dyspnoea, cough, ankle swelling, and dull retrosternal pain. She had felt depressed for the preceding 3 months and complained of loss of appetite, body pains, and night sweats. On clinical examination she had oral candidiasis and was cachectic, febrile, tachycardic, and tachypnoeic. She had bilateral pitting ankle oedema, distended jugular veins, soft heart sounds, and pulsus paradoxus of 12 mmHg. A chest radiograph demonstrated significant cardiomegaly suggestive of pericardial effusi, which was confirmed by echocardiography (Fig. 81.2). The pericardial effusion was drained by echocardiographically guided aspiration via an indwelling pigtail catheter. The aspirate had a protein content of 58 g/L and an ADA activity of 106 U/L. The patient’s CD4 cell count was 124 cells/mL. She responded clinically and radiologically well to 6 months of antiTB therapy and antiretroviral therapy with stavudine, lamivudine, and efavirenz, initiated 2 months after her anti-TB treatment.
COMMENT Tuberculous pleural effusion can follow post-primary, chronic pulmonary, and miliary disease. Post-primary effusions frequently develop in young adults due to rupture of subpleural collections of mycobacteria into the pleural space. Rupture of caseous material from a pulmonary cavity or an infected intrathoracic lymph node can lead to a tuberculous empyema. Pleural effusions frequently complicate miliary TB (10– 30%) where they may be bilateral and associated with pericardial and/ or peritoneal effusions.1,2 Pleural fluid typically is an exudate with a protein content > 30 g/L, pH < 7.3, lactate dehydrogenase (LDH) > 200 IU/L and, when left standing, fibrin clots usually develop. Lymphocytosis is typical but a minority of patients may have a predominantly polymorphonuclear cellular infiltrate.3 Biochemical markers such as ADA and interferon-gamma (IFN-g) can be used to distinguish between tuberculous and non-tuberculous aetiologies. In high-TB-prevalence settings an ADA > 47 U/L has a sensitivity of 99% for the diagnosis of tuberculous effusions and in low-prevalence settings an ADA < 40 U/L has a high negative predictive value and can be used to exclude tuberculous aetiology.4
Fig. 81.1 The chest radiograph shows a large right-sided pleural effusion.
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Fig. 81.2 Subcostal echocardiographic view demonstrates large
Fig. 81.3 The chest radiograph demonstrates clear lung fields and widening of the mediastinum, suggesting mediastinal lymphadenopathy.
pericardial effusion.
COMMENT HIV prevalence has been shown to be considerably higher in patients with symptomatic pericardial effusions than in the general population in a variety of global settings.5,6 Tuberculous pericardial fluid shares many of the characteristics of tuberculous pleural fluid with low sensitivity of Ziehl–Neelsen staining and moderate sensitivity of mycobacterial culture. ADA and IFN-g levels are elevated and the cellular component is predominantly lymphocytic in effusions from both HIV-infected and uninfected individuals.7 Without specific treatment tuberculous pericarditis has a poor prognosis; the reported average survival being 3–7 months and only 20% survival at 6 months.8 Echo-guided pericardiocentesis with extended intermittent drainage results in effective relief of cardiac tamponade, and in combination with 6 months of antiTB therapy in highly effective prevention of constrictive pericarditis.9 Where pericardiocentesis is not possible, rapid resolution of tuberculous pericardial effusion may be achieved with high-dose prednisone and anti-TB drugs.10
CASE 4: THE YOUNG MAN WITH PREVIOUS TUBERCULOSIS A 21-year-old man with a history of previous pulmonary TB presented with a swelling in the left axilla, which had been present for about a year. On examination he was emaciated with an obvious mass in the left axilla. The mass was not erythematous or warm and two sinuses draining white inspissated material were noted. A chest radiograph was requested (Fig. 81.4). A diagnosis of a cold (tuberculous) abscess was made and he was successfully treated with an 8-month course of anti-TB therapy.
CASE 3: THE YOUNG MALE NURSE A 25-year-old male nurse presented with a 3-week history of fever, night sweats, and about 5 kg weight loss. He had not previously had TB, but had been in contact with TB patients. On examination, he had some temporal wasting and an axillary temperature of 38.6 C. He had small palpable non-tender supraclavicular lymph nodes, but was otherwise well. Three sputum smears were negative. HIV serology was positive twice and his CD4 count 68 cells/mL. A chest radiograph (Fig. 81.3) demonstrated bilateral mediastinal lymphadenopathy. He was treated with a 6-month course of anti-TB therapy, oral pyridoxine, and daily cotrimoxazole preventive therapy. After completing 2 months of the intensive phase of anti-TB therapy the mediastinal lymphadenopathy had subsided, and highly active antiretroviral therapy was initiated with stavudine, lamivudine, and efavirenz.
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Fig. 81.4 The chest radiograph demonstrates a large soft-tissue density in the left axilla. Dystrophic calcification is present scattered in the mass and in the lung parenchyma, suggesting a chronic tuberculous abscess.
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Extrapulmonary tuberculosis in adults
CASE 5: THE ADOLESCENT GIRL WITH DRAINING SINUSES A 15-year-old girl presented with a 2-week history of cervical and supraclavicular swelling. She had associated symptoms of fatigue, anorexia, and weight loss. Two sputum smears were negative for acid-fast bacilli. She was asked to take a course of oral amoxicillin and come back after 1 week. On returning to the clinic after 10 days she felt worse. Physical examination revealed left cervical lymphadenopathy with a discharging sinus in the left cervical region as well as similar lesions in the left supraclavicular region, suggesting a diagnosis of scrofuloderma (Fig. 81.5). A smear of the draining fluid was positive for acid-fast bacilli and culture confirmed a diagnosis of Mycobacterium tuberculosis. Her HIV test was negative.
COMMENT !Tuberculous lymphadenitis is the most frequent form of extrapulmonary TB with cervical nodes being most commonly involved, although inguinal, mesenteric, and mediastinal nodes may also be involved.11,12 The disease is indolent and usually presents as a unilateral cervical painless swelling, although more than one site may be involved in up to 35% of cases.13 Constitutional symptoms are usually mild or absent.14,15 The reported diagnostic yield of fine needle aspiration varies considerably from 42% to 83%,11,12,16,17 with higher yields from excision biopsy with both histology and mycobacterial culture.12,17 Treatment with short-course anti-TB therapy is appropriate for infections with susceptible organisms,11,12,17 although paradoxical expansion of adenopathy may be seen during the first 2 months of treatment in up to 20% of cases.
CASE 6: THE HIV-INFECTED SECURITY GUARD A 56-year-old HIV-infected security guard (CD4 cell count 110 cells/mL) presented with a non-productive cough and weight loss. On examination, he was pale, jaundiced, and tachypnoeic,
Fig. 81.5 Photograph of 15-year-old girl with left-sided cervical lymphadenopathy with a discharging sinus and similar scrofuloderma lesions in the left supraclavicular region caused by infection with Mycobacterium tuberculosis.
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and had tender hepatomegaly with ascites. He did not have a history of previous TB but had a cousin who had received antiTB treatment during the previous year. His haemoglobin level was 6.4 g/dL, his white cell count 2.9 109/L and his platelet count 92 109/L with a low normal MCV and a raised ferritin level (370 mg/L). His liver function tests showed increased globulin (58 g/L) and decreased albumin (28 g/L) levels as well as elevated levels of conjugated bilirubin (61 mmol/L), aspartate aminotransferase (AST), alanine aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP). An ultrasound scan of his abdomen demonstrated splenomegaly, hepatomegaly, para-aortic lymphadenopathy, and a moderate amount of ascites. The intra- and extrahepatic bile ducts were not dilated, but the liver and spleen showed a granular infiltrate consistent with granulomatous lesions. Chest radiograph (Fig. 81.6) demonstrated bilateral nodular shadowing, which was confirmed on chest computed tomography scan (Fig. 81.7). Two sputum smears examined microscopically for acid-fast bacilli were negative. In view of his pancytopenia and the presence of ascites, a bone marrow biopsy was performed, which demonstrated granulomatous lesions (Fig. 81.8), but no acid-fast bacilli and also no features of lymphoma. A diagnosis of miliary TB was thus made and he was treated with a 6-month course of anti-TB therapy, oral pyridoxine, and daily cotrimoxazole preventive therapy. His full blood cell count and liver function tests improved on anti-TB treatment. After completion of the 2-month intensive phase of anti-TB therapy, highly active antiretroviral therapy was initiated with zidovudine, lamivudine, and efavirenz.
COMMENT Miliary TB is a life-threatening disease resulting from haemotogenous spread of M. tuberculosis to a variety of tissues and may lead to a wide range of manifestations, from an acute fulminant illness to a prolonged cryptic illness with subtle clinical findings. The incidence of miliary TB is increased in HIV infection with miliary shadowing identified in up to 38% of acquired immunodeficiency syndrome (AIDS) patients with extrapulmonary TB.18 In HIV-seronegative patients with miliary TB
Fig. 81.6 The radiograph demonstrated miliary shadowing, which is also depicted on the chest CT images shown in Fig. 81.7.
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A Fig. 81.7 (A, B) The contrast-enhanced CT images of the chest demonstrate miliary shadowing and non-enhancing paratracheal masses consistent with enlarged paratracheal lymph nodes.
underlying predisposing conditions such as diabetes mellitus, organ failure, and autoimmune conditions are present in between 41% and 47% of cases.2,19 The disease is characterized by high mortality, reported to be between 18% and 30%. Mortality is strongly associated with age, mycobacterial burden, the delay in initiation of chemotherapy, and laboratory markers indicative of severity of disease such as lymphopenia, thrombocytopenia, hypoalbuminaemia, and elevated hepatic transaminases.2,20,21 Diagnosis can be made by isolation of M. tuberculosis from sputum and gastric washings but the diagnosis is frequently missed and more invasive investigations are required. In retrospective series the diagnostic yield of bronchoscopy, bone marrow biopsy, and liver biopsy were high.2,20,21 Fig. 81.8 Bone marrow biopsy demonstrates granulomatous lesions (arrows) suggestive of TB.
REFERENCES 1. Biehl JP. Miliary tuberculosis: A review of sixty-eight adult patients admitted to a municipal general hospital. Am Rev Tuberc 1985;77:605–622. 2. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: Rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J Med 1990;89:291–296. 3. Epstein DM, Kline LR, Albelda SM, et al. Tuberculous pleural effusions. Chest 1987;91:106–109. 4. Valdes L, Alvarez D, San Jose E, et al. Tuberculosis pleurisy: a study of 254 patients. Arch Intern Med 1998;158:2017–2021. 5. Cegielski JP, Ramiya K, Lallinger GJ, et al. Pericardial disease and human immunodeficiency virus in Dar es Salaam, Tanzania. Lancet 1990;335:209–212. 6. Reuter H, Burgess LJ, Doubell AF. Epidemiology of pericardial effusions at a large academic hospital in South Africa. Epidemiol Infect 2005;133:393–399. 7. Reuter H, Burgess L, van Vuuren W, et al. Diagnosing tuberculous pericarditis. QJM 2006;99:827–839.
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8. Desai HN. Tuberculous pericarditis: a review of 100 cases. S Afr Med J 1979;55:877–880. 9. Reuter H, Burgess LJ, Carstens ME, et al. The management of tuberculous pericardial effusion: experience in 233 consecutive patients. Cardiovasc J South Afr 2007;18:20–25. 10. Strang JIG. Rapid resolution of tuberculous pericardial effusion with high dose prednisone and anti-tuberculous drugs. J Infect 1994;28:251–254. 11. Dandapat MC, Mishra BM, Dash SP, et al. Peripheral lymph node tuberculosis: a review of 80 cases. Br J Surg 1990;77:911–912. 12. Memish ZA, Mah MW, Mahmood SA, et al. Clinico-diagnostic experience with tuberculous lymphadenitis in Saudi Arabia. Clin Microbiol Infect 2000;6:137–141. 13. Geldmacher H, Taube C, Kroeger C, et al. Assessment of lymph node tuberculosis in northern Germany: a clinical review. Chest 2002;121:1177–1182. 14. Chen YM, Lee PY, Su WJ, et al. Lymph node tuberculosis: 7-year experience in Veterans General Hospital, Taipei, Taiwan. Tuber Lung Dis 1992; 73:368–371. 15. Artenstein AW, Kim JH, Williams WJ, et al. Isolated peripheral tuberculous lymphadenitis in adults:
16.
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current clinical and diagnostic issues. Clin Infect Dis 1995;20:876–882. Aggarwal P, Wali JP, Singh S, et al. A clinicobacteriological study of peripheral tuberculous lymphadenitis. J Assoc Physicians India 2001;49: 808–812. Polesky A, Grove W, Bhatia G. Peripheral tuberculous lymphadenitis: epidemiology, diagnosis, treatment, and outcome. Medicine (Baltimore) 2005;84:350–362. Shafer RRW, Kim DS, Weiss JP, et al. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 1991;70:384–397. Hussain SF, Irfan M, Abbasi M, et al. Clinical characteristics of 110 miliary tuberculosis patients from a low HIV prevalence country. Int J Tuberc Lung Dis 2004;8:493–499. Miyoshi I, Daibata M, Kuroda N, et al. Miliary tuberculosius not affecting the lungs but complicated by acute respiratory distress syndrome. Intern Med 2005;44:622–624. Matsumshima T. Miliary tuberculosis or disseminated tuberculosis. Intern Med 2005;44:687.
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Extrapulmonary tuberculosis in children Ben J Marais and Colleen A Wright
A CHILD WITH ENLARGED CERVICAL LYMPH NODES – A CASE REPORT HISTORY A 6-year-old child presented to the hospital with enlarged cervical lymph nodes. The mother reported that she first noticed a neck mass about 3 months ago. Initially there were two small separate masses each about the size of a marble; they slowly gained in size and became attached to each other, forming a single large mass. The mother did not present the child to the clinic initially as he did not complain of tenderness or any other associated symptoms. She presented him to the clinic about 6 weeks after she first noticed the neck masses, because by this time the masses had become clearly visible and other people had started taking notice. At the time, nurses at the clinic noted two enlarged non-tender lymph nodes estimated to be about 2 2 cm, surrounded by many smaller palpable nodes. The child received a course of oral antibiotics (amoxicillin for 5 days), and griseofulvin for 1 month as treatment for a Tinea capitis scalp infection. Despite diligently completing the treatment the mother noticed no reduction in the size of the masses; in fact they continued to increase in size. She took the child back to the primary healthcare clinic, where a second and prolonged course of antibiotics (amoxicillin for 10 days) was prescribed. When no improvement was noticed after completion of the second course of oral antibiotics, the child was referred to the hospital for further management. At presentation to the hospital the child reported minimal symptoms; the mother reported no fever, night sweats, or coughing. On more specific questioning the child complained that he fatigued more easily than usual and his mother said that he had lost most of his appetite. The mother was uncertain whether he lost weight recently, as he has always been ‘very skinny’; no recent weight measurements were available. Regarding possible TB exposure; the child had no known household or other close contact with a TB source case, but there were many people with TB in the neighbourhood.
CLINICAL FINDINGS On examination the child looked pale, chronically ill, and underweight. There was a clearly visible mass within the anterior triangle on the left side of the neck (Fig. 82.1). On closer inspection this large mass (4 8 cm) was made up of multiple lymph nodes
matted together. Two dominant lymph nodes were palpable surrounded by many smaller nodes. The lymph nodes were nontender and solid, with no overlying discoloration of the skin. The mass was mobile and not fixated to any underlying tissue. Apart from the mass in the neck, no other masses or lymphadenopathy was noted and neither the liver nor the spleen was palpable. Table 82.1 contains a list of conditions that were considered in the differential diagnosis, differentiating the most likely from the less likely alternatives.
SPECIAL INVESTIGATIONS The tuberculin skin test (TST) was positive: 18 mm induration after 2 days. A rapid human immunodeficiency virus (HIV) test was negative. The full blood count and peripheral blood smear showed no abnormalities apart from signs of iron deficiency anaemia. The chest radiograph showed no signs suggestive of hilar or paratracheal lymphadenopathy or any other lung involvement. A fine needle aspiration biopsy (FNAB) was performed as an outpatient procedure, using a small 22-G needle. Biopsy material was sent for cytology and for mycobacterial culture, using a liquid broth medium. Microscopic evaluation demonstrated the presence of caseating granulomas with central necrosis (Fig. 82.2). Multiple mycobaterial bacilli were clearly visible, using both fluorescent microscopy (Fig. 82.3) and conventional acid-fast staining (Fig. 82.4). Mycobacterial culture was positive after 12 days of incubation and the presence of Mycobacterium tuberculosis was confirmed by means of a polymerase chain reaction (PCR)-based confirmatory test.
TREATMENT AND OUTCOME The child received directly observed anti-TB treatment, including isoniazid (5 mg/kg/day), rifampicin (10 mg/kg/day), and pyrazinamide (25 mg/kg/day) in fixed-dose combination tablets. In addition, the child was dewormed and received iron and folate supplementation. The response to therapy was slow; initially there was even a small increase in the size of the neck mass before it became smaller. However, after completion of the intensive phase of treatment (2 months) the mass had shrunk in size; two separate masses about 2 2 cm each were still palpable. Within 2 months the child reported complete symptom resolution; both his energy and appetite returned to normal levels. Treatment was continued for a further 4 months (continuation phase) with isoniazid and rifampicin, according to the standard short-course treatment
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Fig. 82.1 A 6-year-old boy with left-sided enlarged cervical lymph nodes. Fig. 82.2 Papanicolaou-stained smear demonstrating epithelioid granuloma with central necrosis.
Table 82.1 Differential diagnosis of isolated, non-tender cervical lymphadenitis Most likely Infections Mycobacterial M. tuberculosis: in TB endemic areas M. bovis: in settings where milk is not routinely pasteurized Environmental mycobacteria: in non-TB-endemic areas; increased in absence of BCG vaccination. Reactive hyperplasia Reactive hyperplasia of undetermined aetiology. Malignancy Non-Hodgkin’s (Burkitt’s) lymphoma: particularly common in certain parts of Africa.
Fig. 82.3 Autofluorescence of Papanicolaou-stained smears in which mycobacteria fluoresce as yellow slightly curved rod-like bacilli.
Less likely Infections Bacterial Bacterial infection: nodes usually red, hot, and/or fluctuant. Mycobacterial M. bovis BCG: usually affects ipsilateral axillary lymph nodes. Fungal Histoplasmosis, coccidioidomycosis, actinomycosis. Viral Mumps: parotid node involvement Infectious mononucleosis, HIV, cytomegalovirus. Other Brucellosis, tuleraemia, toxoplasmosis, cat scratch disease, sarcoidosis. Malignancy Hodgkin’s lymphoma, neuroblastoma, rhabdomyosarcoma, histiocytosis X. Congenital malformations Branchial, thyroglossal, and dermoid cysts Deep cavernous haemangioma.
Fig. 82.4 Ziehl–Neelsen-stained smear demonstrating pink curved mycobacterial bacilli.
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regimen. At the end of treatment the child had gained more than 2 kg in weight and the visible neck masses receded; two small areas of fibrosis < 1 1 cm each remained.
DISCUSSION Tuberculosis lymphadenitis is the most common form of extrapulmonary TB recorded in children from TB endemic areas, and the cervical nodes are predominantly affected.1 However, the mycobacteria responsible for cervical lymphadenitis are highly variable and in developed countries, where both the TB epidemic and bovine TB are well controlled, environmental mycobacteria, also referred to as non-tuberculous mycobacteria (Mycobacterium avium–intracellulare complex in particular), are the most frequent cause of persistent cervical adenopathy.2 Cervical lymphadenitis usually results after lymphatic spread from a primary (Ghon) focus in the lung, but the chest radiograph may be normal in a large percentage of cases. With TB lymphadenitis, isolated involvement of a single node is uncommon; multiple nodes are usually matted together due to the presence of considerable periadenitis. The nodes are rarely painful unless secondary bacterial infection is present, in which case the nodes are usually warm and the overlying skin red. When a node is soft and fluctuant in the absence of secondary bacterial infection it signifies a cold abscess; spontaneous drainage with/without sinus formation may follow. Apart from a visible and/or palpable mass lesion in the neck, the majority of children report minimal symptoms.3 A strongly positive TST and/or radiographic signs suggestive of TB support a diagnosis of TB lymphadenitis. In non-endemic countries, in the absence of routine Bacillus Calmette–Gue´rin (BCG) vaccination and/or known TB exposure, a positive TST may indicate lymphadenitis caused by environmental mycobacteria. The setting usually provides sufficient discriminatory power, as TB would be the most likely diagnosis in TB-endemic areas where disease caused by environmental mycobacteria is relatively rare. FNAB (using a 22-G needle) is a minimally invasive procedure that provides a rapid and definitive tissue diagnosis. Material obtained should be submitted for cytology (rapid cytological diagnosis reduces diagnostic delay) and culture, which would be of particular value if drug susceptibility testing is required. It is not
REFERENCES 1. Marais BJ, Gie RP, Schaaf HS, et al. The spectrum of disease in children treated for tuberculosis in a highly endemic area. Int J Tuberc Lung Dis 2006;10:732–738. 2. Lindeboom JA, Kuijper EJ, Prins JM, et al. Tuberculin skin testing is useful in the screening for nontuberculous mycobacterial cervicofacial
Fig. 82.5 Papanicolaou-stained smear in an immunocompromised child showing dirty necrosis with a few fragmented neutrophils in an amorphous background.
recommended to perform an incision biopsy, as this frequently results in sinus formation, a complication not seen with FNAB.3 In some cases an excision biopsy may be considered, but this is not the preferred therapeutic option for TB lymphadenitis caused by M. tuberculosis, as it shows excellent response to conventional anti-TB treatment. Following treatment initiation there may be some initial nodal enlargement. This is probably the result of increased inflammation as a result of ‘toxin’ release and/or some form of immune reconstitution. Excision biopsy is frequently the best therapeutic option when environmental mycobacteria are responsible, as the response to medical treatment is often suboptimal.4,5 HIV infection complicates the diagnosis of TB lymphadenitis in several ways. Firstly, the TST is frequently negative in HIV-infected children with advanced immune suppression. Secondly, with advanced immune suppression the cyto- and histomorphology is also atypical. The anatomical boundaries of the lesion are poorly demarcated, there is no granuloma formation or central caseation, and the disease process is more diffuse (Fig. 82.5). This increases the importance of establishing a bacteriological diagnosis and also complicates surgical excision.
lymphadenitis in children. Clin Infect Dis 2006; 43:1547–1551. 3. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area. Pediatr Infect Dis J 2006;25:142–146. 4. Hazra R, Robson CD, Perez-Atayde AR, et al. Lymphadenitis due to nontuberculous mycobacteria in children: presentation and response to therapy. Clin Infect Dis 1999;28:123–129.
5. Lindeboom JA, Kuijper EJ, Bruijnesteijn van Coppenraet ES, et al. Surgical excision versus antibiotic treatment for nontuberculous mycobacterial cervicofacial lymphadenitis in children: a multicenter, randomized, controlled study. Clin Infect Dis J 2007;44:1057–1064.
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Tuberculous meningitis Johan F Schoeman
CASE 1: A CASE OF DELAYED DIAGNOSIS AND SEVERE ISCHAEMIC BRAIN DAMAGE DEMONSTRATED BY MAGNETIC RESONANCE IMAGING HISTORY An 8-year-old black girl was referred to our hospital with a 2-week history of coughing and headache. The presenting symptoms were excessive sleepiness and ‘inability to walk’ for the past 2 days. She had been seen at a local clinic 1 week previously where the health worker diagnosed ‘flu’ and prescribed antibiotics for a possible upper respiratory tract infection. The mother had just completed a 6-month course of anti-TB treatment for pulmonary TB. There was no previous medical history of note. According to the ‘Road to Health’ (clinic) card the patient had not received any immunizations.
PHYSICAL EXAMINATION On examination the patient was unresponsive. She was afebrile and her vital signs were normal. The general and systemic examination, apart from the neurological examination, were within normal limits. On examination of the central nervous system the Glasgow coma score was 7/15. Marked neck stiffness was present. The pupils were not equal (left 5 mm, right 3 mm) and responded poorly to light. Fundoscopy was normal. The oculocephalic reflex was present but the gag and cough reflexes were absent. On examination of the motor system the only motor response was a slight withdrawal to pain. The muscle tone was generally decreased. All the deep reflexes were brisk and bilateral sustained ankle clonus could be elicited. The plantar reflexes were flexor but the abdominal reflexes were absent. Shortly after admission the patient developed urinary retention and had to be catheterized.
SPECIAL INVESTIGATIONS The neurological findings (coma and bilateral upper motor signs) in this patient could have resulted from raised intracranial pressure due to obstructive hydrocephalus or ischaemia secondary to tuberculous vasculitis, or both. Since we had access to imaging, a computed tomography (CT) scan of the brain was requested before a lumbar puncture was done. The contrasted CT scan showed moderate hydrocephalus and meningeal enhancement (basal and Sylvian fissures) as well as a single tuberculoma, compatible with a diagnosis of TBM (Fig. 83.1). However, no infarcts were demonstrated by CT. Cerebrospinal fluid (CSF) obtained by lumbar puncture was macroscopically clear. There were 120 lymphocytes/mm3 and 14 polymorphs/mm3 in the CSF. The protein level was 1.9 g/L and glucose level 1.8 mmol/L. The blood glucose level was not done. A limited air encephalogram done at the time of lumbar puncture demonstrated that the hydrocephalus was communicating in nature. The serum sodium level, which was 129 mmol/L on admission, normalized within the first week of treatment without any restriction of fluid intake. The baseline full blood count and liver function tests were normal. In addition to the above, the following tests were done to support a clinical diagnosis of TBM:
TREATMENT A diagnosis of probable TBM was made on account of the following:
PROVISIONAL DIAGNOSIS On account of the subacute onset, positive contact history of TB (the mother) and the neurological signs (neck stiffness and coma) a clinical diagnosis of tuberculous meningitis (TBM) was made. According to the criteria of staging for TBM laid down by the Medical Research Council (1948),1 the patient was classified as having stage 3 disease.
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The tuberculin skin test (Mantoux) showed 20 mm induration after 48 hours. The chest radiograph demonstrated mediastinal lymphadenopathy compatible with a diagnosis of primary TB. Three gastric aspirates and CSF were sent for microscopy and culture. Ziehl–Neelsen stain was negative for acid-fast bacilli and no organism was cultured.
subacute onset of meningitis; positive TB contact (mother); positive Mantoux skin test; typical CSF findings (clear CSF, low cell count, increased protein concentration, and decreased glucose concentration); chest radiograph demonstrating mediastinal lymphadenopathy; and cranial CT compatible with TBM (hydrocephalus, basal meningeal enhancement, and tuberculoma).
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Fig. 83.1 Cranial CT scan on admission showing marked meningeal enhancement in the Sylvian fissures and at the basal cisterns (arrows). Moderate hydrocephalus is present but no infarcts are demonstrated.
Anti-TB treatment was begun in the following single daily dosages: isoniazid (INH) (20 mg/kg), rifampicin (20 mg/kg), ethionamide (20 mg/kg), and pyrazinamide (40 mg/kg). Prednisone (60 mg/day) was added to the treatment regimen. Additional treatment for possible bacterial meningitis (a third-generation cephalosporin) was given for 7 days while awaiting the results of the CSF and blood cultures. Feeds were given by nasogastric tube and daily physiotherapy was introduced. No fluid restriction was implemented even though the patient was suspected of having the syndrome of inappropriate antidiuretic hormone (SIADH) secretion on account of the low serum sodium documented on admission.
Fig. 83.2 T2-weighted axial MRI scan of the brain done 2 days after admission. The hyperintense areas indicate bilateral ischaemic changes in the basal ganglia (short arrows) and thalami (long arrows). The hypointense (black) areas demonstrated in both anterior horns represent air injected during air-encephalography. The position of the air indicates that the hydrocephalus is communicating.
DISCUSSION The following points regarding this case need to be highlighted:
CLINICAL COURSE The patient showed no clinical improvement on treatment. Additional clinical evidence of possible brainstem involvement such as temperature instability, episodes of bradycardia, and hypoventilation became apparent during the first weeks of treatment. Because the level of consciousness decreased even more within 48 hours of admission and more signs of brainstem involvement developed, magnetic resonance imaging (MRI) of the brain was requested. In addition to the features of TBM demonstrated by CT, the MRI scan showed extensive bilateral infarction of the basal ganglia and thalami (Fig. 83.2) as well as ischaemic changes in the pons (Fig. 83.3). The initial hypotonia developed into hypertonia and within the first month of treatment the patient developed a decorticate posture with episodes of opisthotonus when stimulated. These were treated with high doses of baclofen. In consultation with the ethical committee it was decided that apart from anti-TB therapy future management of this patient would be palliative.
TBM could have been prevented if the proper screening procedures were followed after the mother had been diagnosed with pulmonary TB. All children in the household should have been screened for TB at the time. The child already had stage 3 TBM when presenting to us. The one opportunity for early diagnosis was missed when the patient was seen at a local clinic 1 week earlier. Most children with advanced TBM have one or more visits to health workers during the earlier stages of their disease. TBM is, however, rarely diagnosed early because the symptoms are so non-specific. Enquiring about a possible contact history of TB (as in this case) or poor weight gain (crossing of centiles) during the preceding months are valuable clues in the early diagnosis. Although the CT scan was helpful in establishing a clinical diagnosis of TBM, it showed no parenchymal changes that could explain the neurological findings in this patient. An MRI scan of the brain 2 days later showed extensive, bilateral ischaemic changes of the basal ganglia and brainstem. MRI is therefore superior to CT in demonstrating acute parenchymal brain damage in TBM, especially when the brainstem is involved.
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hormone which in itself may result in hypotension and increased risk for thrombosis. This patient had communicating hydrocephalus and only moderately dilated ventricles. In this type of hydrocephalus lumbar pressure accurately reflects intracranial pressure, which can be assessed by measuring the opening CSF pressure. Withdrawal of CSF during lumbar puncture will reduce intracranial pressure in these cases without any danger of cerebral herniation. The moderate degree of hydrocephalus and the fact that it was communicating suggest that raised intracranial pressure did not contribute significantly to this patient’s neurological condition. Cases of TBM with extensive ischaemic brain damage who also need surgery for hydrocephalus (i.e. non-communicating hydrocephalus or communicating hydrocephalus not responding to medical treatment) present an ethical dilemma. One way of assessing whether these cases would benefit from a ventriculoperitoneal shunt is to assess their clinical response to temporary external CSF drainage.
CASE 2: DRAMATIC RESPONSE TO VENTRICULOPERITONEAL SHUNTING IN ACUTE NON-COMMUNICATING HYDROCEPHALUS Fig. 83.3 Multiple T2 hyperintense areas in pons (arrows) representing possible ischaemia (arrows). The ring lesion on the right has the appearance of a small granuloma.
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Although new infarcts can occur on TB treatment, the neurological findings in this patient suggest that the ischaemic changes were already present when the CT scan was performed. CSF findings should always be interpreted in the light of the patient’s neurological condition. With severe neurological involvement such as in this patient, the low cell count in the CSF would not be in keeping with bacterial meningitis, while the low glucose and high protein levels would not favour a diagnosis of viral meningoencephalitis. Since acidfast bacilli are rarely demonstrated by microscopy on CSF and culture, if positive, is only obtained weeks later, the decision to treat for TBM is almost always based on clinical grounds. It is therefore reasonable practice to treat for both TBM and bacterial meningitis and to repeat the CSF after 10–14 days, if the diagnosis is in doubt. In bacterial meningitis the CSF findings will usually normalize within this period of time (with the exception of raised lymphocytes) while the opposite is true in TBM. Positive culture of M. tuberculosis from the CSF can be enhanced by increasing the volume of CSF sent for culture. Because children with TBM are hypercoagulable during the first month of illness and are prone to vasculitis and infarction, we believe that fluid restriction should not be implemented for the associated SIADH secretion. Fluid restriction may increase the risk for thrombosis and infarction, which outweighs the possible consequences of SIADH. Another much less common cause for a low serum sodium in TBM is ‘cerebral saltwasting’ due to presumed increased excretion of natriuretic
HISTORY AND PHYSICAL EXAMINATION AT RURAL HOSPITAL An 11-year-old boy presented to a rural hospital with a 1-week history of headaches that woke him up at night and daily episodes of vomiting which started after hitting his head while wrestling with a friend. During this period he was seen by three independent general practitioners who diagnosed ‘flu’, hay fever, and gastroenteritis, respectively. There was no history of fever, coughing, or diarrhoea. Birth history was normal and there was no previous medical history of note. In the past the patient occasionally visited an aunt who had since died of pulmonary TB. On examination the patient was afebrile and neurologically intact. The only significant clinical finding was faecal loading, which was treated without any improvement in the presenting symptoms. A lumbar puncture was performed, which revealed completely normal CSF findings. A chest radiograph and full blood count were also within normal limits. Shortly after the lumbar puncture the patient had a sudden tonic seizure which resulted in apnoea. This episode necessitated intubation and transfer to an intensive care unit.
CLINICAL COURSE AT TERTIARY REFERRAL HOSPITAL On arrival the patient was stable. He opened his eyes spontaneously and obeyed commands. Speech could not be evaluated because he was intubated. Because of the history of trauma the registrar on call did not check for neck stiffness. An emergency cranial CT scan was done, which showed acute hydrocephalus and basal enhancement compatible with a diagnosis of tuberculous meningitis (TBM) (Fig. 83.4). On returning from the scanner, the patient’s condition suddenly deteriorated. He became unresponsive and the pupils were found to be dilated and non-reactive. Mannitol (0.25 g/kg) was administered intravenously and the patient was rushed to theatre for an emergency ventriculoperitoneal shunt.
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Fig. 83.4 Axial contrasted CT scan of the brain on admission showing marked hydrocephalus (black arrows) and basal meningeal enhancement (white arrow).
Post-surgery the patient was clinically stable and able to obey commands. The pupils were equal and reactive to light. The postoperative course was uneventful. He was started on standard anti-TB therapy and adjunctive prednisone and a follow-up CT scan of the brain 4 days later showed that the hydrocephalus had completely resolved (Fig. 83.5). The patient was discharged home 2 weeks later to complete his treatment by means of a directly observed home-based treatment programme.
Fig. 83.5 A follow-up CT scan of the brain done 4 days after surgery shows that the hydrocephalus has completely resolved.
COMMENTS
This case demonstrates the difficulty in the early diagnosis of TBM. The parents connected the onset of symptoms (headache and vomiting) to the minor trauma. Parents commonly consult a number of different health workers before the diagnosis of TBM is made. As a rule doctors are also not informed of previous medical attention sought by parents. Respiratory symptoms (fever and cough) and gastrointestinal symptoms (vomiting and constipation) dominate the first stage of TBM. Once the classical neurological symptoms and signs of TBM develop, the ‘penny usually drops’ but by then the patient has already progressed to the second and third stages of the disease with a guarded prognosis. The presenting symptoms in this patient should have alerted the attending physician to the possibility of underlying raised intracranial pressure. This applies to both the new onset headache, especially because it woke the child up at night,
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and the episodic vomiting not associated with nausea and diarrhoea. Acute neurological deterioration, especially occurring after lumbar puncture, is highly suggestive of impending cerebral herniation. In the context of TBM, non-communicating hydrocephalus is the most likely underlying cause for this occurrence. Although cranial CT showed marked hydrocephalus, air-encephalography was not performed since the patient’s clinical course suggested that the hydrocephalus was non-communicating. Another lumbar puncture could have been hazardous and delayed surgery. Referring this patient for an emergency ventriculoperitoneal shunt was life-saving. The absence of infarcts on the initial CT scan and the dramatic recovery after surgery further emphasize the role that raised intracranial pressure played in the clinical course of this patient. Apart from the CT findings, the usual special investigations that support a clinical diagnosis of TBM were particularly unhelpful in this case. The chest radiograph, positive for TB in up to 70% of cases of TBM at the time of presentation, was normal. In addition the CSF findings were normal, both with regard to cell count and chemistry. Although completely normal CSF findings have been described in culture-positive TBM, this is very exceptional. The decision to treat for TBM is almost always made on clinical grounds because the organism is only rarely seen on microscopy, and culture takes weeks. A diagnosis of probable TBM can usually be made when clinical signs of meningitis are associated with two or more of the following: history of
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a TB contact, positive Mantoux skin test, typical CSF findings, chest radiograph positive for TB and the presence of classical neuro-imaging findings (CT or MRI). Generally the patient’s clinical response to treatment as well as the results
REFERENCE 1. Medical Research Council, Tuberculosis Trials Committee. Streptomycin treatment of tuberculosis meningitis. Lancet 1948;i:582–596.
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of follow-up CSF and CT findings will provide the answer. A positive culture of M. tuberculosis from the CSF will confirm the diagnosis retrospectively.
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Tuberculosis of the central nervous system in adults Guy E Thwaites
INTRODUCTION The diagnosis and management of central nervous system TB is rarely straightforward and there are few data and little consensus on how best to manage most of the frequently encountered problems. Case reports that illustrate some of these problems can be helpful; they can highlight the natural history of untreated and treated disease and may be more useful than dry tabulations of clinical features and treatment complications. Three adult cases of tuberculous meningitis (TBM) are presented in this chapter. They have been chosen because they highlight the key areas of clinical decision-making and the current controversies in the management of central nervous system TB.
CASE 1: THE VALUE OF REPEATED LUMBAR PUNCTURES AND SIMPLE BACTERIOLOGY HISTORY AND EXAMINATION A 17-year-old man presented to our hospital with a 2-week history of headache, vomiting, and a dry cough. He had no relevant past medical history and was studying at school before the onset of his symptoms. Two days prior to admission he had become confused and his relatives said he appeared more breathless. They had given him an antibiotic – bought from a local pharmacy – but they did not know the name of the drug. On admission he was febrile (temperature 37.8 C), comatose (Glasgow coma score 6/15), and cyanosed, with a respiratory rate of 35 breaths per minute. Air entry was reduced over the mid- and lower zones of the right lung. His right arm and leg were moving less than his left side in response to pain, and reflexes on the right were brisk with an extensor plantar response. His cranial nerves were intact and no other physical abnormalities were found.
INVESTIGATIONS A chest radiograph demonstrated loss of the right hemidiaphragmatic border and reduced volume of the right lung field with mediastinal shift to the right. The appearances were consistent with collapse of the right lower lobe. A full blood count was normal other than an elevated total leucocyte count (21,800 103/mL; 82% neutrophils), and serum sodium was reduced at 122 mmol/L. Computed tomography (CT) of the brain performed without contrast revealed an infarct extending from the left corpus striatum into the caudate nucleus.
Lumbar puncture was attempted but only 1 mL of blood-stained cerebrospinal fluid (CSF) was collected. Analysis of the CSF revealed 10,000 103/mL red cells, 780 103/mL white cells (60% neutrophils, 40% lymphocytes), total protein 160 mg/dL, and CSF–plasma glucose was 0.31 (normal > 0.5). Gram, India ink, and Ziehl–Neelsen (ZN) stains of the CSF were negative. A rapid human immunodeficiency virus (HIV) test was negative.
DIFFERENTIAL DIAGNOSIS AND MANAGEMENT The patient was believed to have either bacterial or tuberculous meningitis. Features in favour of bacterial meningitis were the peripheral blood leucocytosis with neutrophilia, and the high numbers of neutrophils in the CSF. Prior treatment with an unknown antibiotic may have attenuated the total CSF leucocyte response and accounted for the negative Gram stain. Features in favour of TBM included the long history, pulmonary collapse of uncertain cause, a moderate CSF leucocytosis, and evidence of an infarct on the CT scan. The patient was treated with 2 g intravenous ceftriaxone with a plan to repeat the lumbar puncture the following day. The patient remained deeply comatose without significant signs of improvement. A lumbar puncture was repeated; this time 8 mL of clear CSF was obtained. Analysis revealed 600 103/mL white cells (34% neutrophils, 66% lymphocytes), protein 180 mg/dL, and the CSF–plasma glucose was 0.25. Gram stain was negative, but five acid-fast bacilli were seen by ZN stain. Treatment with rifampicin, isoniazid, pyrazinamide, ethambutol, and dexamethasone was started immediately. After 72 hours increased breath sounds were noted in the right lung and repeat chest radiograph showed reinflation of the right lung with marked right hilar lymphadenopathy. Respiratory function improved but the patient remained comatose. After 56 days of treatment the patient died. Fully susceptible Mycobacterium tuberculosis was cultured from the second CSF specimen; no bacteria were cultured from the first CSF specimen.
SUMMARY AND CLINICAL LESSONS This case illustrates some essential principles in the diagnosis and management of TBM, together with some unusual features. Distinguishing partially treated pyogenic bacterial meningitis from tuberculous meningitis is a common and difficult problem. Clinical diagnostic algorithms have been developed in non-HIV-infected adults to help physicians with this problem.1 Conventional
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bacteriology is often thought of as being too insensitive to be helpful, but as this case and recent studies have shown, meticulous and repeated examination of large volumes of CSF can improve the diagnostic yield of ZN stain to 50–70%.2 Sadly, in this case, these efforts were in vain. Outcome from TBM is intimately related to the timing of treatment and anti-TB treatment must not be delayed when the disease is suspected. With hindsight our patient should have received immediate anti-TB therapy, but the unexplained pulmonary collapse and high peripheral blood white cell count had confused the clinical picture. A neutrophilia in both blood and CSF is not uncommon at presentation of TBM. Pulmonary collapse is a rare accompaniment to TBM and we presume the patient also had endobronchial TB. Infarction is a well-described complication of TBM, most commonly affecting the basal ganglia and structures supplied by the small perforating vessels of the middle cerebral artery. The CT scan appearances in this case should have lent greater weight to an initial diagnosis of TBM and prompted immediate anti-TB treatment.
CASE 2: KEEPING AN OPEN MIND HISTORY AND EXAMINATION A 30-year-old man presented with a 3-week history of headaches and increasing confusion. He was known to be infected with HIV, but was not taking antiretroviral therapy, and had no history of previous treatment for TB or any other acquired immunodeficiency syndrome (AIDS)-defining illness. On examination the patient was confused, with a Glasgow coma score of 13/15. A right VIth cranial nerve palsy was found, but the rest of the examination was unremarkable.
INVESTIGATIONS A contrast-enhanced CT scan of his brain which showed diffuse meningeal enhancement was performed. Examination of the CSF revealed 800 103/mL white cells; 40% were reported as neutrophils and the rest were lymphocytes. The CSF total protein was 80 mg/dL and CSF–plasma glucose was 0.45. Gram, India ink, and ZN stain were negative and bacterial and fungal cultures were sterile after 48 hours. CSF and blood cryptococcal antigen tests were negative. Peripheral blood CD4 count was 98 106/mL. Chest radiography was normal.
DIFFERENTIAL DIAGNOSIS AND MANAGEMENT The commonest causes of chronic meningitis in an HIV-infected adult in the developing world are tuberculous and cryptococcal meningitis. The negative predictive value of combined India ink, culture, and cryptococcal antigen tests are high (> 95%) and negative results were used to rule out cryptococcal meningitis in this patient. Tuberculous meningitis was strongly suspected and the history, examination findings, and investigations did not suggest an alternative diagnosis. At presentation, one physician remarked that it was unusual not to see hydrocephalus when the history is long and the coma score reduced; but despite this reservation TBM was considered highly probable and anti-TB therapy was started immediately. After 48 hours the patient did not improve and a lumbar puncture was repeated. The white cell count was 850 103/mL. At first, the laboratory reported 40% of the cells were neutrophils,
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but a senior technician reviewed the slide and revised the report to 30% eosinophils, 10% neutrophils, and 60% lymphocytes. The protein was 1.2 mg/dL and the CSF–plasma glucose was 0.41. The slide of the first CSF was reviewed: it too contained eosinophils (35%) with few neutrophils (5%) and 85% lymphocytes. The diagnosis was revised to parasitic eosinophilic meningitis. Anti-TB drugs were stopped and albendazole and dexamethasone were prescribed. The patient made an uneventful recovery.
SUMMARY AND CLINICAL LESSONS In many centres the CSF white cell differential is performed by junior technicians who rapidly distinguish the multilobed nuclei of neutrophils from mononuclear lymphocytes without difficulty. However, in rare cases, more care and experience is required to differentiate bilobed eosinophils from multilobed neutrophils. Eosinophilic meningitis is rare, except in areas endemic for certain parasites, in particular Angiostrongylus cantonensis (the rat lung worm).3 This infection is relatively common in south-east Asia, where it is contracted after eating raw or undercooked snails or fresh water crustaceans that serve as intermediate hosts for the parasite. The meningitis is usually self-limiting, although the patient can be unwell for several weeks; adjunctive corticosteroids may speed symptom resolution.4 This case highlights the importance of keeping an open mind on the diagnosis, repeating the lumbar puncture when the diagnosis remains uncertain, and liaison with laboratory staff. The limitations of current diagnostic methods for TBM mean that many patients start therapy without microbiological proof of the diagnosis. The physician who commented that it was unusual not to find hydrocephalus on CT of the brain in patients with TBM with similar presentations was correct. Although there was insufficient evidence to reject a diagnosis of TBM, the finding should have prompted further diagnostic questioning. Confusing eosinophils with neutrophils is an easy mistake, but atypical clinical features should prompt discussion between physicians and laboratory staff. Careful CSF cytology is always worthwhile when the aetiology of meningitis remains uncertain. In this case it saved the patient from taking 9 months of unnecessary and potentially toxic anti-TB drugs.
CASE 3: ADVERSE EVENTS, RESISTANCE, AND RELAPSE HISTORY AND EXAMINATION A 26-year-old man with no previous medical history presented with 10 days of headache and vomiting. On examination he was alert and orientated and there were no physical abnormalities other than mild neck stiffness.
INVESTIGATIONS Chest radiograph showed a bilateral diffuse micronodular pattern consistent with miliary TB (Fig. 84.1A). Examination of the CSF showed 180 103/mL white cells (20% neutrophils, 80% lymphocytes), total protein 65 mg/dL, and CSF–plasma glucose 0.25. Bacteria were not seen in the CSF by Gram or ZN stain. An HIV test was negative. Cerebral magnetic resonance imaging (MRI) showed multiple small tuberculomas (Fig. 84.1B).
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Fig. 84.1 (A) Chest radiograph showing diffuse micronodules consistent with miliary TB. (B) T1-weighted MRI following contrast reveals multiple tuberculoma. (C) Contrast-enhanced (near) midline sagittal T1-weighted MRI brain image taken 9 months after the start of treatment, and 7 days after the onset of new symptoms, reveals multiple tuberculomas.
DIFFERENTIAL DIAGNOSIS AND MANAGEMENT The chest radiograph appearance of miliary TB in a patient with meningitis prompted immediate anti-TB therapy. Four drugs were started (isoniazid, rifampicin, pyrazinamide for 9 months, and streptomycin for the first 2 months), with dexamethasone, and the patient’s symptoms resolved over the following 3 weeks. After 4 weeks M. tuberculosis was isolated from the first CSF specimen and the culture was sent for drug susceptibility testing. The patient was discharged without symptoms after 1 month of therapy. One month later the patient remained asymptomatic. However, serum transaminases were elevated (AST 220 IU/mL, ALT 280 IU/mL). Tests for hepatitis B and C were negative, and the patient was told to continue his drugs and return in 2 weeks’ time. The laboratory reported the bacteria from the CSF were resistant
to isoniazid and streptomycin and sensitive to rifampicin and pyrazinamide. The patient failed to attend any appointments for the next 4 months. Eventually, after 6 months of treatment, he returned to the clinic. He said he had felt well and continued to take his tablets (isoniazid, rifampicin, and pyrazinamide), but had noticed his skin and eyes had changed colour over the last month. On examination he was deeply jaundiced. Serum AST and ALT were 550 and 608 IU/mL, respectively, and serum bilirubin was 4.1 mg/dL. Chest radiograph and cerebral MRI showed resolution of all the lesions seen on admission. All anti-TB drugs were stopped. The ultrasound showed hepatomegaly without evidence of biliary tree obstruction or focal lesions.
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Over the next 6 weeks the patient’s jaundice and abnormal liver function tests resolved and anti-TB drugs were not reintroduced. Nine months after first starting therapy, and after 3 months without any anti-TB treatment, the patient was well and was discharged. Three weeks later the patient presented with a 7-day history of headache and vomiting. CSF examination revealed 250 103/mL white cells (20% neutrophils, 80% lymphocytes), protein 120 mg/dL, and CSF–plasma glucose 0.33. Acid-fast bacilli were seen in the CSF. Cerebral MRI showed multiple small tuberculomas, similar to those seen on the first scan but in a different distribution (Fig. 84.1C). Treatment was restarted with isoniazid, rifampicin, ethambutol, and levofloxacin, and the patient made an uneventful recovery. M. tuberculosis resistant to isoniazid and streptomycin was cultured again from the CSF.
SUMMARY AND CLINICAL LESSONS This case highlights three areas of major uncertainty in the management of central nervous system TB: drug-induced hepatitis, the duration of treatment, and drug-resistant TB. Guidelines for the treatment of pulmonary TB from the UK and USA suggest stopping all anti-TB drugs if the AST/ALT rises above five times normal or the bilirubin rises, with sequential reintroduction of drugs once the AST/ALT concentrations improve.5,6 This approach is safe in pulmonary TB, but not in TBM. Alterations in treatment regimens are an independent risk factor for death from TBM and a more cautious approach is required.7 Physicians must judge when the risk of hepatic failure by continuing treatment overcomes the risk of death from TBM by stopping treatment. This is challenging and the published literature on the subject is of little help. Other therapeutic options include stopping the most hepatotoxic drugs (pyrazinamide, isoniazid, rifampicin) and treating with streptomycin, ethambutol, and a fluoroquinolone. Without better clinical data, this approach is probably preferable to stopping all drugs.
REFERENCES 1. Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002; 360(9342):1287–1292. 2. Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol. 2004;42(1):378–379. 3. Lim JM, LeeCC, Wilder-Smith A. Eosinophilic meningitis caused by Angiostrongylus cantonensis: a
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The other issues raised by this case concern the duration of treatment and the management of drug-resistant TBM. A meta-analysis of the limited data on treatment length concluded 6 months of treatment was probably sufficient for most cases of TBM, provided the likelihood of drug-resistance was low.8 Many authorities suggest 12 months of anti-TB therapy for all forms of central nervous system TB, but this is probably a conservative estimate of the time required for bacterial cure. Nevertheless, this case poses the difficult question of what to do if drug-resistant TBM is confirmed? Tuberculous meningitis caused by bacteria resistant to isoniazid and rifampicin is devastating, causing death in most patients before the resistance pattern has been determined and second-line drug treatment can be started. However, the influence of isoniazid resistance upon outcome – either alone or in combination with streptomycin or ethambutol – is far less clear.9 The relapse suffered by this patient may have arisen because the bacteria were resistant to two of the four drugs used in preliminary treatment (isoniazid and streptomycin) and/or because only 6 months of treatment was given. Recent data suggested the pattern of resistance observed in our patient is not detrimental to outcome provided a full course of treatment (at least 9 months) with a rifampicin-containing regimen is given.9 Others may argue that in such cases streptomycin should be replaced with ethambutol and a fluoroquinolone. Uncertainty prevails, and more research is required to determine the best way of rapidly detecting resistant bacteria in the CSF and the role of fluoroquinolones, and other second-line agents, in the management of drug-resistant TBM.
ACKNOWLEDGEMENTS I thank Dr Jeremy Macmullen-Price (consultant neuroradiologist, Leeds General Infirmary, UK) for his help in interpreting the brain images.
case report and literature review. J Travel Med 2004; 11(6):388–390. 4. Chotmongkol V, Sawadpanitch K,Sawanyawisuth K, et al.Treatment of eosinophilic meningitis with a combination of prednisolone and mebendazole. Am J Trop Med Hyg 2006;74(6):1122–1124. 5. BTS. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1998;53(7):536–548. 6. American Thoracic Society; CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1–77.
7. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351(17):1741–1751. 8. van Loenhout-Rooyackers JH, Keyser A, Laheij RJ, et al.Tuberculous meningitis: is a 6-month treatment regimen sufficient? Int J Tuberc Lung Dis 2001; 5(11):1028–1035. 9. Thwaites GE, Lan NT, Dung NH, et al.Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis 2005;192(1):79–88.
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Abdominal tuberculosis: Case study Etienne de la Rey Nel
CASE REPORT A 30-month-old girl presented with a 3-week history of generalized oedema, weight loss, anorexia, and night sweats. She had no abdominal pain, vomiting, change in her stool habit, or respiratory complaints. She had been fully immunized, including Bacillus Calmette–Gue´rin (BCG) shortly after birth. Her mother had tested negative for human immunodeficiency virus (HIV) during pregnancy. There was no household TB contact. On examination she was irritable, appeared pale and chronically ill, and had generalized oedema. Her weight was 12.2 kg (24p) and length 76 cm (20p). There were no clinical signs of vitamin or trace element deficiencies. A BCG scar was present on her right upper arm. Prominent cervical lymph nodes were present with a diameter of approximately 2 cm; they were nontender, of a rubbery consistency, and ‘matted’ together. Her abdomen was distended due to severe ascites. No masses were palpable and the abdomen was non-tender. Respiratory examination was normal except for an increased respiratory rate (54 per minute) that was ascribed to the severe ascites. The rest of her examination was normal.
INVESTIGATIONS A chest radiograph showed some infiltration of the right middle lobe with no obvious enlargement of the hilar or mediastinal lymph nodes. A Mantoux tuberculin skin test was non-reactive. Cultures of gastric aspirates for Mycobacterium tuberculosis were negative. Cytology of a fine-needle aspiration from the cervical lymph nodes showed signs of granulomatous inflammation with necrotic debris suggestive of TB. Acid-fast bacilli (AFB) were demonstrated with Ziehl–Neelsen stain. There were no features suggestive of malignancy. Serum biochemistry showed a total protein of 39 g/L and an albumin of 20 g/L. A full blood count revealed a white cell count of 6.49 109/L with a differential white cell count as follows: lymphocytes 0.97 109/L; neutrophils 4.58 109/L; eosinophils 0.1 109/L; and basophils 0.05 109/L. The haemoglobin was 7.7 g/dL (MCV 67.2fl) and platelets 509 109/L. Ultrasound of the abdomen found gross ascites with no loculations or evidence of enlarged lymph nodes or mesenteric thickening. Computed tomography of the abdomen was not done. Aspiration of the ascites revealed a milky fluid (detailed analysis in Box 85.1).
DISCUSSION The presumptive diagnosis of abdominal TB was made based on the presence of AFB in enlarged cervical lymph nodes and the presence of a chyloperitoneum in a patient living in a TB-endemic area. Although the chest radiograph was not typical of pulmonary TB it was consistent with the diagnosis. An important condition to consider in the differential diagnosis in this patient would be lymphoma. Although the presence of AFB in the cervical nodes supports the diagnosis of TB, the response to anti-TB treatment would still have to be monitored carefully. If her clinical course was not satisfactory or other features suggestive of a lymphoma should be present, a histological and bacteriological diagnosis of abdominal TB should be pursued aggressively. The aetiology of cervical lymphadenopathy in developing countries includes chronic granulomatous diseases, malignancy, and non-specific inflammation. In a review of 1332 children in a TB-endemic area who had lymph node resections the most common histological diagnoses were non-specific reactive lymphoid hyperplasia (47.8%), chronic granulomatous changes (36.3%), and neoplastic lymph node involvement (12%).1 Twenty-five per cent of cases with chronic granulomatous changes had confirmed TB. In another study from the same region, TB was also a common cause of persistent cervical lymphadenopathy accounting for 22.2% of cases.2 A significant number of children in the first study, however, had neoplastic disease, most frequently lymphoma. This emphasizes the importance of confirming the diagnosis by means of a fine needle aspirate or excision biopsy. Extra-abdominal lymph nodes are a common manifestation of extrapulmonary TB. The reported frequency of peripheral lymphadenopathy in children with abdominal TB varies from less than 10% to as high as 50%. In 1982 Davies described the clinical features of 55 children admitted with the diagnosis of abdominal TB in Cape Town, South Africa. Eighteen per cent of these children had cervical lymphadenopathy. Two further studies from the same region reported that 47% and 49% of children with abdominal TB had peripheral lymphadenopathy.3,4 In contrast to these reports, only 7 of 110 (6%) children in India with abdominal TB reported by Sharma et al.5 had cervical or axillary lymphadenopathy. Cervical lymph nodes may also be the only source of M. tuberculosis culture in some children.4 Chylous ascites is a rare complication of abdominal TB. In recent years patients with HIV infection have been reported with tuberculous chylous peritonitis.6,7 Other infections such as filariasis
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Box 85.1 Analysis of ascites
Albumin 14 g/L . Total protein 22 g/L . Lactate dehydrogenase (LDH) 99 U/L . Triglycerides 3.5 mmol/L (serum triglycerides 1.1 mmol/L). Numerous lymphocytes. No malignant cells. Adenosine deaminase (ADA) 42 U/L . Negative cultures for M. tuberculosis.
and Mycobacterium avium complex (in HIV-infected patients) have also been implicated as causes of chylous peritonitis.8 Lymphatic obstruction is thought to account for the leakage of chyle into the peritoneal cavity. Rarely chylous peritonitis may be accompanied by a chylothorax. Chyle is typically a milky odourless fluid. Triglyceride levels are usually greater than 2 mmol/L (200 mg/dL), exceeding the triglyceride level in serum two to eight times. The most important mechanisms of chylous ascites are the following:
congenital abnormalities of the lymphatic ducts that lead to leakage of chyle into the peritoneal cavity; these are often associated with lymphatic abnormalities outside the abdominal cavity; surgical or traumatic injury of the lymphatic system;
REFERENCES 1. Moore SW, Schneider JW, Schaaf HS. Diagnostic aspects of cervical lymphadenopathy in children in the developing world: a study of 1,877 surgical specimens. Pediatr Surg Int 2003;19:240–244. 2. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosisendemic area. Pediatr Infect Dis J 2006;25:142–146. 3. Johnson CA, Hill ID, Bowie MD. Abdominal tuberculosis in children. A survey of cases at the Red Cross War Memorial Children’s Hospital, 1976–1985. S Afr Med J 1987;72:20–22.
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lymph node fibrosis or malignant infiltration; and liver cirrhosis.
The treatment is often challenging and is directed at controlling the production of chyle and treating the underlying cause. The response to diuretics is often disappointing. Dietary support includes a low-fat diet with high medium chain fatty acid content. Care should be taken to meet the essential fatty acid requirements. Some patients may require total parenteral nutrition if the ascites is refractory. Concomitant nutritional deficiencies of protein, minerals, and trace elements also need to be corrected. Although surgical treatment of chylous ascites is well documented after trauma and surgical injury of the lymphatic system it has not been evaluated in tuberculous chyloperitoneum. Somatostatin and octreotide have been used successfully in a variety of patients.9–11 There are, however, no data on its use in tuberculous chylous ascites. The patient was treated with isoniazid, rifampicin, pyrazinamide, and ethambutol. Her diet was modified to provide a low-fat and high-protein intake. During the following 3 weeks the ascites and her general well-being, appetite, and weight gain improved. The culture of the fine needle aspirate grew M. tuberculosis. During the following 4 weeks the glandular enlargement resolved and ascites was no longer clinically detectable. Although histological confirmation of abdominal TB was not obtained, the culture of M. tuberculosis from a site outside the abdomen and the favourable response to treatment provide adequate support for the diagnosis of abdominal TB with a chyloperitoneum.
4. Saczek KB, Schaaf HS, Voss M, et al. Diagnostic dilemmas in abdominal tuberculosis in children. Pediatr Surg Int 2001;17:111–115. 5. Sharma AK, Agarwal LD, Sharma CS, et al. Abdominal tuberculosis in children: experience over a decade. Indian Pediatr 1993;30:1149–1153. 6. Arsura EL, Ismail Y, Civrna-Karalian J, et al. Chylous ascites associated with tuberculosis in a patient with AIDS. Clin Infect Dis 1994;19:973. 7. Ekwcani CN. Chylous ascites, tuberculosis and HIV/ AIDS: a case report. West Afr J Med 2002;21:170–172. 8. Rollhauser C, Borum M. Case report: a rare case of chylous ascites from Mycobacterium avium intracellulare in a patient with AIDS: review of the literature. Dig Dis Sci 1996;41:2499–2501.
9. Andreou A, Papouli M, Papavasiliou V, et al. Postoperative chylous ascites in a neonate treated successfully with octreotide: bile sludge and cholestasis. Am J Perinatol 2005;22:401–404. 10. Berzigotti A, Magalotti D, Cocci C, et al. Octreotide in the outpatient therapy of cirrhotic chylous ascites: a case report. Dig Liver Dis 2006;38:138–142. 11. Hwang J, Choi S, Park W. Resolution of refractory chylous ascites after Kasai portoenterostomy using octreotide. J Pediatr Surg 2004;39:1806–1807.
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Ear, nasal, and ocular tuberculosis W Mulwafu, Nico E Jonas, and Chris A J Prescott
CASE REPORT A 24-year-old female patient was initially referred by her general practitioner to the ophthalmologist with a 3-month history of progressive left-sided proptosis and visual loss (Fig. 86.1). She had no nasal symptoms and she did not report any headaches. There were no constitutional symptoms of fever, weight loss, or night sweats. Her past medical history was unremarkable. Apart from left-sided proptosis and impaired vision the rest of her ophthalmological and general examination was normal. She only had perception of hand movement in her left eye. The ophthalmologist requested a contrasted computed tomography (CT) scan (Fig. 86.2) of her sinuses and orbits, which revealed an expansile destructive lobulated left ethmoid mass with extension into her left sphenoid sinus, left maxillary sinus, and left frontal lobe. There was local bone destruction of the left lamina papyracea, lateral wall of the sphenoid sinus, and greater wing of the sphenoid. The left frontal lobe mass, measuring 24 35 mm, had various densities in keeping with necrosis. There was local mass effect and surrounding oedema.
Fig. 86.1 Photograph of patient illustrating left-sided proptosis.
Human immunodeficiency virus (HIV) rapid test was negative and the rest of her blood results, which included a full blood count, fasting blood glucose, and C-reactive protein, were all within normal ranges. A chest radiograph was performed and reported as normal. Since either a tumour or an invasive fungal infection of the sinuses was suspected, she then underwent endoscopic transnasal biopsy of the lesion. Histological examination revealed extensive fibrocaseous granulomatous inflammation with numerous Langhans giant cells scattered throughout the fibro-inflammatory stromal tissue. No acid-fast bacilli were found and specimens were sent for TB culture. Based on this morphology, a diagnosis of TB was made. Fungal elements with morphology consistent with Aspergillus were also present. The patient was subsequently started on anti-TB and antifungal treatment. Because of the fungal coinfection a more definitive endoscopic debulking procedure was performed. The patient was reviewed 3 months later. She did not have any proptosis and there was no evidence of residual disease in her nose. Tuberculosis culture results were negative after 43 days.
Fig. 86.2 Coronal CT scan of sinuses illustrating the mass.
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COMMENTS Because of the absence of pulmonary disease the most likely route of TB infection was directly via the sinonasal tract. The treatment of sinonasal TB is medical and surgery is reserved for obtaining a biopsy for tissue diagnosis. Examination of the sinuses can be difficult and a CT scan is the best radiological investigation to assess the extent of a sinonasal tumour.
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This is a case report of a very unusual presentation of TB in the ear–nose–throat system to illustrate the ubiquitous nature of this disease. Combined TB and fungal infection of the sinuses has not been previously reported and it remains uncertain which was the primary infection.
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Dermatology case report Papulonecrotic tuberculosis H Francois Jordaan and Johann W Schneider
A 27-year-old man was referred to a department of dermatology with a 1-month history of skin lesions, night sweats, loss of appetite, weight loss and joint pain involving the knees, elbows, ankles and small joints of the feet. The patient was human immunodeficiency virus (HIV)infected with a CD4þ lymphocyte count of 131/mL. He was not receiving antiretroviral treatment. Skin lesions comprised papular, papulopustular and papulonecrotic lesions that involved the ears (Fig. 87.1), limbs, hands (Fig. 87.2) and feet. Atrophic hypopigmented scars were evident on the upper limbs. A clinical diagnosis of papulonecrotic TB
B
Fig. 87.1 Note the numerous small papules and pustules on the external ears: (A) left and (B) right ear. A few papulonecrotic lesions are present (arrows).
was made. A skin biopsy from a papule on the arm showed necrotizing granulomatous inflammation without vasculitis. Special stains showed no organisms. The microscopic features were consistent with a diagnosis of papulonecrotic TB (Fig. 87.3). Clinical examination of the patient revealed generalized lymphadenopathy, hepatosplenomegaly and onychodystrophy of all the nails. Fine needle aspiration cytology of a cervical lymph node was contaminated, rendering interpretation impossible and tissue submitted for mycobacterial culture yielded no growth after 43 days. Nail clippings stained with periodic acid–Schiff (PAS) and diastase showed no fungal elements and culture of nail clippings and shavings were negative for fungi. The nail changes were diagnosed as onychomadesis, the cause of which could not be determined with certainty. Examination of the joints did not reveal swelling, tenderness or limitation of joint movement.
Fig. 87.2 There are numerous papular lesions on the dorsal aspect of (A) the right hand and fingers (close up). (Continued)
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Fig. 87.2—cont’d (B) The numerous papular lesions on both hands. Note the onychomadesis.
The chest radiograph showed mediastinal lymphadenopathy. The C-reactive protein was elevated at 64.7 mg/mL. Rheumatoid factor (23.5 IU/mL) and c-ANCA were positive (titre 1:10). The p-ANCA was negative. The joint pains were diagnosed as HIV-associated arthralgia and responded promptly to treatment with a non-steroidal antiinflammatory drug (ibuprofen). A diagnosis of TB was made in view of the typical skin lesions, lymphadenopathy and chest radiograph findings. The patient responded well to treatment with an intensive four-drug fixed-dose combination drug regimen including rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months followed by a two-drug continuation phase of
Fig. 87.4 Resolution of the skin lesions on (a) the ear and (b) the hand after completion of anti-TB treatment. The nails appear normal.
4 months. All the skin lesions healed without scarring after 3 months. Following completion of the anti-TB treatment the patient was commenced on antiretroviral therapy, namely stavudine, lamivudine and efavirenz. Examination of the patient 9 months after onset of the skin rash confirmed complete resolution of the skin lesions (Fig. 87.4), recovery of his appetite and satisfactory weight gain.
A Fig. 87.3 (A, B) A skin biopsy shows wedge-shaped necrosis of the epidermis and upper dermis (arrows) with surrounding granulomatous inflammation (short arrows).
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Tuberculosis of the hip Gert J Vlok and Martin Storm
CASE REPORT A 10-year-old girl presented with the complaint of low-grade hip pain for a period of 3 months. She resides in a rural area but gave no history of specific TB contact. She was otherwise healthy with no systemic complaints. She did not exhibit any weight loss or night sweats and had no indication of pulmonary TB. Physical examination was unremarkable with the only findings being that of mild pain at the extremes of motion of the hip and mild pain after exercise. The discomfort improved after rest. Special investigations were also unremarkable. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and total white cell count were all within normal limits. Plain radiographs of the hip showed subtle changes on the femoral epiphysis with only slight disuse osteopenia on the acetabular side of the hip joint (Fig. 88.1). The clinical, pathological and radiographic presentation was interpreted as very early Perthes’ disease and was managed with supervised follow-up and instruction to the patient and parents not to participate in sport. The patient defaulted on the 6-week follow-up appointment and only presented 15 weeks later at the clinic. The patient had deteriorated rapidly and presented with a fixed flexion and adduction deformity of the hip and was only able to mobilize with crutches.
Fig. 88.1 Anteroposterior radiograph of the hip at the initial consultation. This picture was interpreted as early Perthes’ disease.
Subsequent clinical evaluation revealed progressive weight loss, generalized lymphadenopathy and hip deformity as described. Blood investigation showed chronic anaemia, raised ESR, CRP and white cell count. On plain radiographs the total destruction of the hip, typical of TB, was evident (Fig. 88.2). The diagnosis of Mycobacterium tuberculosis infection was confirmed by synovial biopsy and culture. The patient was treated with anti-TB chemotherapy and distraction arthrodiastasis. A moderate gain in range of motion was achieved at 6 months but the patient will be left with significant disability.
DISCUSSION This case demonstrates the difficulty of diagnosis of musculoskeletal TB. Regular (and adherent) follow-up and a high index of suspicion are advised in all doubtful cases. The hip is the most common site of musculoskeletal TB after spinal TB. Although it usually has an insidious onset, progression to severe disease may be relatively rapid as shown in this case. Local pain is the most common symptom, with impairment of function also common. Constitutional symptoms such as fever, fatigue, night sweats and weight loss occur in many but not all patients
Fig. 88.2 Rapid progression of femoral head collapse within 3 months of first presentation.
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and usually in advanced disease. Frequently a history of trauma can also be elicited. Diagnosis is by plain radiography and synovial biopsy for culture and histology. The tuberculin skin test (TST) may be positive, but in a high-TB-incidence area, the TST is often positive in children more than 5 years of age and is therefore often not done. However, it remains an important adjunct to the diagnosis especially in lowincidence areas. The goals of treatment in osteoarticular TB are to eradicate the disease while maintaining a mobile and pain-free joint. Anti-TB
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chemotherapy is essential and should be continued for 6–9 months. Some surgeons still prefer to continue treatment for 12–18 months in osteoarticular TB. Traction could be used in the acute phase for pain relief, and physical therapy is used to optimize mobility after treatment has commenced. If a satisfactory pain-free range of motion cannot be obtained by conservative measures, surgery is indicated. In joints such as the hip and elbow spontaneous ankylosis is not well tolerated and surgical arthrodiastasis or osteotomy can be used to stabilize the joint in a functional position.
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Tuberculosis of the thyroid gland associated with thyrotoxicosis Ertan Bulbuloglu and Harun Ciralik
CASE REPORT A 46-year-old Turkish man was admitted with swelling in the neck and symptoms of thyrotoxicosis-like night sweats, palpitations, weakness, weight loss and tremor. The patient was otherwise healthy. On neck examination, there were multiple thyroid nodules and the largest nodules were one in the right lobe measuring approximately 6 5 cm and one in the left approximately 3 2 cm. Both of the nodules were non-tender and firm with well-defined margins. There was no palpable cervical lymphadenopathy. Ear–nose–throat examination including indirect laryngoscopy was unremarkable. Thyroid ultrasonography showed advanced hyperplasia and heterogeneous multiple solid nodules in the thyroid gland, the largest of which were 4.5 3.0 cm in the right lobe and 2.1 1.5 cm in the left. There was atrial fibrillation on electrocardiography, and mild biatrial dilatation and pericardial minimal fluid on echo. Bilateral cervical radiograph showed deviation of the trachea to the left. On chest radiograph, there was no abnormalities in lung parenchyma and pleura. Fine needle aspiration cytology (FNAC) was performed on both right and left nodules, the results of which were consistent with colloidal goitre. Thyroid scintigraphy showed advanced hyperplasia, and multiple hypoactive nodules. Thyroid hormone serum levels were as follows: T3, 12 nm/L (0.87–1.78 nm/L); T4, 2 mg/dL (5.3–11.5 mg/dL); free T4, 0.13 pg/dL (0.58–1.64 pg/dL); free T3, 7.5 pg/mL (2.39–6.79 pg/ml); and thyroid-stimulating hormone (TSH), 0.021 mIU/mL (0.34–5.60 mIU/mL). Other laboratory tests were within normal ranges. Treatment with propylthiouracil was initiated to control the symptoms of thyrotoxicosis. We concluded that the appropriate choice of treatment was bilateral subtotal thyroidectomy because of the multiple nodules on ultrasonography, thyrotoxicosis and pressure symptoms. After thyrotoxicosis was controlled, bilateral subtotal thyroidectomy was performed. Histopathological examination of the left and right thyroid lobes revealed multiple coalescent epithelioid cell granulomas along with Langhans giant cells and caseation (Fig. 89.1). The findings were suggestive of TB. This result was a surprise for us, with an unexpected diagnosis of TB in the thyroidectomy specimen. Ziehl– Neelsen staining was negative for acid-fast bacilli (AFB). Sputum, urine and faeces cultures were negative. Purified protein derivative (PPD; the tuberculin skin test) induration size at 72 hours was 16 mm in diameter and erythrocyte sedimentation rate was 42 mm in the first hour. No evidence of tuberculous involvement of other organs including lung was observed. There was no relevant past or family history of, nor contact with, TB.
For anti-TB treatment, the standard three-drug regimen with rifampicin, isoniazid and pyrazinamide was started and continued for 2 months, then the two-drug continuation regimen with rifampicin and isoniazid was used for 4 months. On an 8-month clinical follow-up, the patient was asymptomatic and euthyroid.
EPIDEMIOLOGY Thyroid TB is a very rare condition, even in countries where the prevalence of TB is high, such as Turkey.1–4 Likewise, the exact reasons for the rarity of this entity is unknown. However, there are two possible explanations: 1. increased physiological activity of phagocytes with destruction of tubercle bacilli and blood flow to the thyroid; or 2. anti-Mycobacterium tuberculosis activity of colloid material and thyroid hormones.1–3 Thyroid TB has been an important problem since the nineteenth century.1,3 Tuberculous infection spreads to the thyroid by a haematogenous route, such as in our case, by a lymphogenous route or directly from adjacent organs.1–4 Although we could not show bacilli, usually M. tuberculosis and sometimes Mycobacterium chelonei and Mycobacterium intracellulare are identified in thyroid TB cases.3 Although the incidence of
Fig. 89.1 Well-formed epithelioid cell granulomas and Langhans giant cells and thyroid parenchyma.
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extrapulmonary TB has increased globally due to the acquired immunodeficiency syndrome (AIDS) epidemic, transglobal immigration, intravenous drug abuse, aging of the population and increasing numbers of immunocompromised patients,1–3 our case did not fall into any of these categories. Thyroid TB is usually primary, such as in our case, but can be secondary to other sites.1–4 According to studies on thyroid TB, there is a slight female predominance with a reported median age of 40 years for men and 43 years for women.1 Our case was male and 46 years old.
SYMPTOMS AND SIGNS The clinical picture may depend upon the type of lesion. If it is a miliary type, there may be very few signs and symptoms. If it is a secondary type of tuberculous infection with caseation and necrosis, it may give rise to a variety of clinical manifestations from mass formation, such as nodules or abscess, to pressure symptoms such as dyspnoea, dysphagia and hoarseness of varying severity. Pain may be present but is never a prominent symptom. Alteration of functional status is very rare.1–4 Our case has the multinodular goitre and symptoms of thyrotoxicosis.
INVESTIGATIONS The diagnosis must be substantiated by histopathological findings and/or identification of AFB either on cytological smears or in cultures prepared from biopsy or FNAC materials.1–4 Since FNAC in our case showed colloidal goitre, the diagnosis of thyroid TB was done postoperatively. If these tests are not enough, polymerase chain reaction is an important aid in diagnosis.1–4 Computed tomography (CT) scan and ultrasonography may be useful. Heterogeneous, hypoechoic lesions are seen on ultrasonography.4 Thyroid ultrasonography showed advanced hyperplasia on the thyroid gland and heterogeneous multiple solid nodules in our case. A multifocal heterogeneous, hypoechoic with ill-defined margins and peripheralenhancing low-density abscess, with several small, oval lymph nodes within the internal jugular chain, has been reported on CT scan.4 Thyroid hormones should be monitored pre- and postoperatively. A high erythrocyte sedimentation rate (ESR) and a PPD may suggest TB.1–3 Retrospectively, we investigated PPD and ESR, and both were positive. For research of other foci, radiography, sputum analysis and stool and urine culture may be useful.1–3 These were negative in our case.
REFERENCES 1. Bulbuloglu E, Ciralik H, Okur E, et al. Tuberculosis of the thyroid gland: review of the literature. World J Surg 2006;30:149–155.
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DIFFERENTIAL DIAGNOSIS Thyroid TB does not have any specific symptoms.1–3 Symptoms of the disease may vary, thus causing difficulty in establishing the correct diagnosis. The disease can cause only non-specific alterations in the thyroid. Thyroid TB should be differentiated from the main diseases of the thyroid such as nodular goitre and thyrotoxicosis as in our case. However, it was noted that most of the previously diagnosed cases were based solely on the findings of lymphocytic infiltration or granulomata that may accompany other conditions such as thyroidal sarcoidosis, granulomatous syphilis, parenchymatous giant cell granulomas, Hashimoto’s thyroiditis, carcinoma and simple invagination of thyroid epithelial rests.3 Also, it is particularly important to distinguish it from thyroid cancer in order to avoid unnecessary thyroid surgery.1,3
PATHOLOGY Several sections on the entire mass were studied and stained with haematoxylin–eosin and AFB stains. All of the sections showed a caseous type of necrosis with epithelioid cells, giant cells and round cell infiltration (Fig. 89.1). The histological picture was typical of TB infection. No AFB could be demonstrated in the sections. However, rarely, AFB has been observed at histopathology in some studies.1
MANAGEMENT Preoperative diagnosis of thyroid TB is important because of the availability of medical treatment and the limited role of surgery.1–3 After diagnosis, anti-TB drugs remain the cornerstone of treatment.1–3 Surgery has only a limited role, with drainage of the abscess, while avoiding total destruction of the thyroid gland and consequential hypothyroidism.1,3 Our patient was diagnosed postoperatively, but for probable remnants of disease after subtotal thyroidectomy anti-TB treatment was given. If we had been sure that we had removed all of the tissue affected by TB, anti-TB treatment would have been unnecessary.3 The patient was followed up periodically and now his general condition is good and there is no evidence of recurrence or generalized infection.
COMPLICATIONS Hypothyroidism, recurrence of thyroid TB, recurrence of thyrotoxicosis and complications due to FNAC and biopsy may be seen.1–4
2. Al-Mulhim AA, Zakaria HM, Abdel Hadi MS, et al. Thyroid tuberculosis mimicking carcinoma: report of two cases. Surgery Today 2002;32:1064–1067. 3. Simkus A. Thyroid tuberculosis. Medicina (Kaunas) 2004;40:201–204.
4. Kang BC, Lee SW, Shim SS, et al. US and CT findings of tuberculosis of the thyroid: three case reports. J Clin Image 2000;24:283–286.
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Renal tuberculosis Adem Fazlioglu and Mete C ¸ ek
CASE REPORT A 15-year-old female patient presented with a right flank sinus, which had been discharging pus for the past 9 years, as well as intermittent low-grade fever and diarrhoea for the past 4 weeks. During the 9-year period, the patient did not seek any healthcare. No significant past medical history was recorded. A physical examination revealed a poorly nourished patient with growth retardation and a pale skin. There was no significant lymphadenopathy and the general physical examination was normal. In the physical examination of the genitourinary system no abnormality was detected. The fistula was not tender on palpation. Laboratory studies showed normochromic, normocytic anaemia, 4800/mL total white cell count, and an erythrocyte sedimentation rate (ESR) of 21 mm in the first hour. Blood urea was normal. The urine test revealed microscopic pyuria and the urine culture tests showed no growing organisms. Five consecutive early morning specimens of urine were cultured on a Lo¨wenstein–Jensen culture medium. These cultures showed no growing organisms. Urine BACTEC test results were not significant. A plain abdominal radiograph revealed no pathological findings. The diameter of the purified protein derivative skin test was 18 mm. An abdominal ultrasound scan revealed the presence of mild free fluid in the abdominal cavity. The left kidney was normal in outline and position with a normal cortical echotexture and maintained corticomedullary differentiation and no obvious abnormality. On the other hand the right kidney was reported to be small, scarred, with loss of corticomedullary differentiation and hydronephrosis. The distal ascending colon showed wall thickening. The spleen and liver had a normal size and echotexture. In the fistulogram that was carried out the fistula tract was revealed to be passing through the kidney and ending at the right ascending colon (Fig. 90.1). The fistulogram revealed the haustra of the ascending colon. The intravenous urogram (IVU) showed a nonfunctioning right kidney, normal functioning left kidney, and a bladder with no irregularities or filling defects. Barium enema study revealed mucosal irregularity in the distal ascending colonic region. In the retrograde ureteropyelogram the ureter was seen to be contracted, straight with no dilatation, and could be followed up to the ureteropelvic junction (UPJ) connection site (Fig. 90.2). Nuclear scintigraphy of the kidney revealed 4% function in the right kidney (Fig. 90.3).
Four weeks of extensive anti-TB chemotherapy was given to the patient. During the chemotherapy period a percutaneous nephrostomy was performed in order to drain the kidney. At the end of the fourth week of chemotherapy no improvement was observed in the right kidney functions. After chemotherapy the patient was operated in order to perform nephroureterectomy, fistula tract excision, and colon reconstruction. Anti-TB treatment carried on for 6 months. In the first 2 months isoniazid (INH) + rifampicin (RMP) + ethambutol (EMB) and in the following 4 months INH + RMP was the choice of treatment regimen. Histological examination of the kidney specimen showed chronic granulomatous inflammation (Fig. 90.4). The specimen special staining for acid-fast organisms was positive. Tuberculosis of the kidney results from haematogenous seeding of Mycobacterium tuberculosis in the glomerular and peritubular capillary bed from the pulmonary and/or bowel focus. Hypertension may occur as a complication of severe unilateral TB and reduced renal blood flow, and two-thirds of patients with extensive unilateral tuberculous nephropathy achieve a substantial fall in blood pressure after nephrectomy. The diagnosis of genitourinary TB is difficult due to the nonspecific symptoms with which it presents. The history of TB in the early life of the patient can be helpful in diagnosing genitourinary TB. In cases such as above this history may be absent or the patient may be young, which may cause hesitation in the diagnosis of TB. Although the patient was young a very important diagnostic clue arousing the idea of TB was the chronic fistula in the right flank region. There is a long latency period between the pulmonary disease and the genitourinary involvement. In some cases a latent period of 30 years has been reported. Voiding problems and chronic dysuria are the typical local symptoms of urinary TB. Other symptoms may include back, flank, and suprapubic pain, nocturia, haematuria, and frequency. In contrast to the information given, diarrhoea caused the patient to seek medical care. The history of not seeking any medical help for a fistula existing for 9 years arouses the question of whether the patient did not consider such symptoms to be important. Microbiological diagnosis is made by isolating M. tuberculosis in the urine or biopsy material. In some cases such as ours this may not be possible and the initial diagnosis may be made on a clinical basis. The patient’s definitive diagnosis of TB became clear after the histological assessment of the specimen. In 25–30% of cases the diagnosis of genitourinary TB is established on the basis of
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ILLUSTRATIVE CASE HISTORIES
Fig. 90.1 Fistulogram showing (A) a hydronephrotic and irregular kidney and (B) right colon haustra.
Fig. 90.2 Right retrograde ureteropyelogram.Obstruction in the UPJ and a straight contracted ureter favour a diagnosis of periureteric fibrosis.
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Fig. 90.3 Nuclear scintigraphy: non-functioning right kidney.
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required for definitive diagnosis. Plain radiograph films of the urinary tract may show calcification in the renal areas and in the lower genitourinary tract. In the early stage of renal involvement IVU may show changes in a single calyx. IVU can also show UPJ and ureteric strictures, kidney functions, and reduced bladder capacity. If the disease is diagnosed at an early stage it may be possible to maintain the function of the remaining kidney tissue by surgical treatments such as double-J administration associated with chemotherapy. If our case had been diagnosed at an early stage such an intervention would be a wise decision, but our case had a nonfunctioning kidney with nearly no remaining kidney parenchyma. A non-functioning or extensively diseased kidney indicates irreversible tuberculous disease. The decision to perform nephrectomy in partly functioning kidneys is controversial. The indications for performing nephrectomy are as follows: Fig. 90.4 Chronic granulomatous inflammation of the kidney. A limited amount of tubular images is due to the destruction of the kidney parenchyma.
the histological pattern and/or by detection of M. tuberculosis complex by polymerase chain reaction (PCR). Purified protein derivative skin test results will be positive in nearly all patients but clearly are not specific for genitourinary involvement. Imaging findings can help in the diagnosis of or suggest genitourinary TB, although cultures, PCR, or histological analysis are
1. a non-functioning kidney with or without calcification; 2. extensive disease involving the whole kidney, together with hypertension and UPJ obstruction; and 3. coexisting renal carcinoma. In all cases of genitourinary TB in which surgery is indicated patients should receive extensive chemotherapy for at least 4 weeks. In cases with periureteric fibrosis, genitourinary TB must always be kept in mind as one of the differential diagnoses. The most important radiological feature that must raise suspicion of genitourinary TB is multiple abnormal findings.
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Tuberculosis of epididymis Fatih O Kurtulus and Mete C ¸ ek
CASE REPORT A 70-year-old man presented with complaints of urinary frequency, nocturia, and hesitancy. The patient had been using alpha-blockers for 2 years; over the past year the symptoms had worsened. The patient’s international prostate symptom score (IPSS) was found to be 28, in which obstructive symptoms were predominant. There were no other constitutional or systemic symptoms. He denied a history of any sexually transmitted or urological disease. His past medical history was not significant with regard to any urological or systemic diseases. Digital rectal examination revealed a prostate of normal size and consistency. Scrotal examination revealed a tender and firm right testicle together with a firm and distinctive epididymis. The left testis was normal on examination. The vasa were normal on both sides. There was no significant lymphadenopathy and the systemic examination was normal. Both total and differential white blood cell counts were within normal limits. The erythrocyte sedimentation rate (ESR) was 60 mm in the first hour. Ultrasonographic evaluation of the scrotum revealed a hypoechoic area of 17 19 23 mm at the posterior of the testis (Fig. 91.1). Testicular tumour markers were as follows: beta-human chorionic gonadotrophin (HCG) 1.02 mIU/mL; AFP 3.26 ng/mL; lactate dehydrogenase (LDH) 350 U/L. Human immunodeficiency virus (HIV) and VDRL were non-reactive. Uroflow showed a decreased maximal flow (7 mL/s). Ureterogram revealed a short stricture of the bulbar urethra. After the results were evaluated in combination with the history and physical findings, the lower urinary tract symptoms were found to be associated with urethral stricture but the pathology of the right testicle could not be distinguished between testicular tumour and chronic inflammation. The patient was operated on and inguinal orchiectomy was performed together with internal urethrotomy. The pathological result of the orchiectomy specimen was reported as necrotic chronic granulomatosis (Fig. 91.2). The patient was diagnosed with genitourinary TB and a 6-month anti-TB treatment was started. During the first 2 months isoniazid (INH) þ rifampicin (RMP) þ ethambutol (EMB) and during the following 4 months INH þ RMP were the choice of treatment regimen. In order to determine other lesions elsewhere in the body, the patient was investigated by chest radiograph, sputum examination for acid-fast bacilli (AFB), ultrasonography of the abdomen, intravenous urography, urine smear and culture for Mycobacterium tuberculosis, etc., but none of these tests revealed positive results.
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DISCUSSION The genitourinary tract is one of the most common sites of extrapulmonary TB. Genital TB is usually a disease of sexually active men and most commonly occurs between the ages of 20 and 40 years, although it has been reported in children also. Extragenital involvement including pulmonary and renal TB can be documented in 50% and 80–85%, respectively, of patients with genital TB. Genital TB in males most commonly involves the epididymis followed by the prostate. Tuberculous epididymitis probably is the result of bloodborne infection because it often is an isolated finding without urinary tract involvement. The spread of TB to the epididymis is also thought to occur by retrocanalicular descent of organisms from the haematogenously infected prostate. Distal spread through the genitourinary tract from a renal source may also occur. A rare possibility of female-to-male transmission (venereal transmission of TB) can be another source of infection which must be kept in mind. It is important to be aware that a high proportion of men with genital TB have radiological abnormalities in the urinary tract. The urinary tract of all such patients with a primary location of tuberculous infection on the epididymis should be investigated. Tuberculous epididymitis is caused by metastatic spread of organisms through the blood stream. The disease usually starts in the globus minor, because it has a greater blood supply than other parts of the epididymis. Tuberculous epididymitis may be the first and only presenting symptom of genitourinary TB. The disease usually develops in young, sexually active men, and, in 70% of patients, there is a previous history of TB. The usual presentation is a painful, inflamed scrotal swelling. The globus minor alone is affected in 40% of cases. The management of tuberculous epididymitis may pose problems if M. tuberculosis cannot be isolated from the urine. In the acute phase, the inflammatory reaction involves the testis, so it is difficult to differentiate the lesion from acute epididymo-orchitis. If there is no sinus and M. tuberculosis organisms are absent from the urine, treatment with an appropriate antibiotic may be started. In the absence of any improvement, within 2–3 weeks, anti-TB chemotherapy should be started. After an additional 3 weeks, if the lesion becomes nodular, firm, and painless, exploration of the testis is mandatory without delay. Testicular involvement is usually the result of local invasion from the epididymis, retrograde seeding from the epididymis, and rarely by haematogenous spread. Genital TB commonly presents as unilateral scrotal swelling, pain, and discharging sinuses. The presence
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Tuberculosis of epididymis
Fig. 91.1 Tuberculous epididymo-orchitis. Ultrasound image shows hypoechoic area showing chronic epididymitis. A small scrotal abscess is also seen.
Fig. 91.2 Histological view of the epididymis specimen.
of abscess or sinus formation indicates advanced widespread scrotal disease. The most characteristic feature is its edge, which is thin, reddish blue, and undermined. There is pale granulation tissue with scanty serosanguineous discharge in the floor and slight indurations at the base, which indicates that the ulcer is a chronic one. The urinary symptoms and sterile pyuria strongly suggest associated renal involvement, which was not evident in our case. High-resolution sonography is currently the best technique for imaging the scrotum and its contents. Tuberculous epididymo-orchitis has a considerable effect on the fertility of man. The sperm counts and motility may be reduced due to blockage of the vas and/or secondary atrophy. Our case demonstrates unusual presentation of genital TB with no evidence of associated pulmonary or renal TB and unilateral involvement of the epididymis with small scrotal abscess. Tuberculous epididymo-orchitis
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must be considered in the differential diagnosis of a scrotal swelling apart from testicular tumour, acute infection, and inflammatory orchitis. All attempts must be made for early diagnosis and treatment of this condition to avoid unnecessary epididymectomy. Diagnosis is often difficult because TB has a variety of clinical and radiological findings. It can mimic numerous other disease entities. A high level of clinical suspicion and familiarity with various radiological manifestations of TB allow early diagnosis and timely initiation of proper management. Tuberculosis involvement of the prostate and seminal vesicles is usually secondary to infection from the upper genitourinary system and may cause a variety of changes such as necrosis, calcification, caseation, and cavitation. In ultrasound (US), TB epididymitis is seen as diffusely enlarged homo -or heterogeneously hypoechoic or nodular enlarged heterogeneously hypoechoic lesions. US features of scrotal TB orchitis include diffusely enlarged homo- or heterogeneously hypoechoic testis, nodular enlarged testis with heterogeneously hypoechoic texture, and multiple small hypoechoic nodules in the enlarged testis producing a miliary pattern. Other US features of scrotal TB include thickened scrotal skin, hydrocele, calcification of the epididymis and tunica vaginalis, scrotal abscesses, and scrotal sinus tract. The US features of TB epididymo-orchitis must be differentiated from non-tuberculous infection and tumour. The presence of skin thickening and epididymal involvement in conjunction with testicular lesions are suggestive of an infection rather than a tumour because orchitis is almost always caused by epididymitis, while even an advanced testicular tumour may only partially involve the epididymis. Non-tuberculous epididymitis is more likely to be homogeneous, whereas TB epididymitis is usually heterogeneous or nodular. Failure of conventional antibiotic therapy with the presence of the abovementioned US features is also suggestive of TB epididymo-orchitis. Tuberculous epididymitis often is not suspected in the management of refractory epididymo-orchitis in developed countries; as a result the ultimate diagnosis of tuberculous epididymitis usually is made when examining the pathological specimen of the epididymo-orchiectomy. Therefore, urologists should always consider the diagnosis of genitourinary TB in a patient presenting with vague, long-standing urinary symptoms for which there is no obvious cause. The diagnosis of genitourinary TB is made based on culture studies. At least three, but preferably five, consecutive early morning specimens of urine should be cultured. Medical treatment is the first-line therapy in genitourinary TB. The duration of medical therapy has been reduced to 6 months in uncomplicated cases. Only in complicated cases (recurrences of TB, immunosuppression, and HIV/acquired immunodeficiency syndrome) is a 9- to 12-month therapy necessary. Early exploration is suggested if a rapid response to antituberculous chemotherapy does not occur in cases of suspected tuberculous epididymitis and orchitis. There are two indications for epididymectomy: a caseating abscess that is not responding to the chemotherapy and a firm swelling that has remained unchanged or has slowly increased in size despite the use of antibiotics and antituberculous chemotherapy. Orchiectomy is seldom required. Ligation of the contralateral vas is not needed. Epididymectomy should be performed through a scrotal incision. Previous tuberculous epididymitis in patients with obstructive azoospermia does not seem to affect the outcome of sperm retrieval and intracytoplasmic sperm injection compared with non-specific infections of the epididymis.
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Congenital tuberculosis Miriam Adhikari and Prakash M Jeena
CASE REPORT Congenital TB is defined according to the criteria of Cantwell and colleagues,1 as described in Chapter 56. Infection may occur during the antenatal (in utero), peripartum, or post-delivery periods. The interaction between TB and human immunodeficiency virus (HIV) infection in pregnancy increases the risk and prevalence of congenital TB. The diagnostic difficulties of TB, HIV infection, and the management of both conditions during early infancy provide immense challenges. The following case illustrates some of these difficulties.
PERINATAL CLINICAL PRESENTATION A 24-year-old pregnant woman NM, para 2 gravida 3, developed eclampsia at 28 weeks gestation. Her male child, weighing 840 g, was delivered by emergency caesarean section. She had received no antenatal care and consequently there were no available results on serological tests for syphilis and HIV. The neonate was wasted and had respiratory distress at birth. The initial chest radiograph revealed hyaline membrane disease and he was placed on 50% FiO2 to maintain an oxygen saturation of between 88% and 92%. The neonate was given penicillin and gentamicin to cover possible intrauterine infection and congenital syphilis. The initial haematological examination and cranial scan were normal and the initial blood culture was negative. Further enquiry into the pregnancy was unhelpful as the mother did not volunteer any risk factors for preterm delivery.
CLINICAL PROGRESS OF THE NEWBORN On day 3, the neonate developed neonatal unconjugated hyperbilirubinaemia, which peaked at a level of 200 mmol/L on day 6. The neonate became sclerematous at this stage, the repeat white blood cell had dropped to 5 109/L, and the blood culture was negative. Antibiotics were changed to tazobactam and amikacin as there was a high nosocomial infection by extended spectrum beta-lactamase producing Klebsiella pneumoniae within the unit. The white blood cell counts returned to normal after 7 days of therapy but results of full blood counts varied over the next 4 weeks. Thus the white blood cells varied from a polymorph predominance to a lymphocyte and monocyte predominance, the haemoglobulin dropped to
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8.0 g/dL, requiring a blood transfusion, and the platelets fluctuated from low to high. No further history was revealed by the mother and a request for HIV testing was refused. On day 30, with a weight of 1010 g, the baby developed abdominal distension and respiratory distress with a decline in platelets to 39109/L but urea and electrolytes were within the normal range. The chest radiograph revealed bilateral patchy opacification and an arterial blood gas assay indicated type 1 respiratory failure. The child was placed on nasal continuous positive airway pressure. An abdominal ultrasound was negative for para-aortic lymph nodes but the abdominal radiograph showed distended bowel loops without air–fluid levels. On day 35 the child developed hepatosplenomegaly with a conjugated hyperbilirubinaemia on liver function test. The blood culture grew K. pneumoniae sensitive to ciprofloxacin, amikacin, and meropenem. The child was therefore started on ciprofloxacin and amikacin, and after 5 days the white cell count improved and blood culture was negative. Nevertheless the child remained ill and deteriorated, requiring ventilation on day 40. The chest radiograph showed deterioration and liver function tests revealed elevated serum bilirubin and gamma GT levels. Urine dipstick testing showed that urobilinogen had increased to 3+. The Mantoux test was negative and an endotracheal aspirate was negative for bacteria and fungi. At this stage the mother spontaneously volunteered that she had been diagnosed with TB and found to be infected with HIV 1 month before becoming pregnant and, on further enquiry, stated that she had been treated with the standard four-drug anti-TB regimen (rifampicin, isoniazid, ethambutol, and pyrazinamide) for 2 months but had defaulted after this period due to excessive vomiting from morning sickness. A bronchoalveolar lavage performed subsequently was negative for acid-fast bacilli on microscopy but positive for M. tuberculosis on polymerase chain reaction (PCR). Tests for other HIV-related pathogens on the bronchoalveolar lavage specimen (cytomegalovirus, herpes, adenovirus, and respiratory syncytial virus) were all negative. Two weeks later a culture of the first endotracheal aspirate from the child yielded M. tuberculosis which was susceptible to ciprofloxacin, ethambutol, isoniazid, kanamycin, rifampicin, and streptomycin. A cerebrospinal fluid sample was also positive for M. tuberculosis by PCR. The child was placed on rifampicin, isoniazid, ethionamide, and PZA although careful attention was paid to the associated hepatic dysfunction. Clinically the baby was wasted and exclusively formula milk was administered by continuous enteral feedings. Total parenteral nutrition was not initiated because of hepatic
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Congenital tuberculosis
dysfunction and septicaemia. Ten days after the commencement of anti-TB therapy, the serum bilirubin and gamma GT decreased and the child began to make steady recovery with weight gain and was able to breathe without artificial ventilation. The child was tested for HIV infection by HIV DNA PCR and was found to be positive with 18% of T-lymphocytes being CD4. The mother was referred to the antiretroviral clinic to determine her TB and HIV status and to obtain anti-TB and antiretroviral therapy for herself and antiretroviral therapy for her infant. Two and half months after commencing anti-TB therapy, a repeat chest radiograph of the infant showed some improvement. Being a live attenuated vaccine, Bacillus Calmette–Gue´rin (BCG) vaccination was not administered because of the HIV status.
DISCUSSION Several issues are raised by this case. First, the need to consider congenital TB as a diagnosis in a chronically ill newborn who is not improving on empiric therapy is highlighted. Furthermore, this case illustrates the difficulties in confirming the diagnosis of TB. The mother did not initially volunteer information indicating that she was the likely source of contact for the disease because of fear of its linkage to HIV disease and its associated stigma. The clinical presentation of TB in the newborn especially associated with HIV infection is atypical. The tuberculin skin test is not reliable in immunocompromised newborns and should be replaced by the use of interferon-g (ESAT6 and CFP10) assays. The use of multiple samples from different anatomical increases the chance of establishing and confirming the diagnosis of TB. The use of PCR requires special mention as it can establish the diagnosis of TB in the newborn when other microbiological and immunological tests are negative.
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Secondly, the management of, and appropriate drugs for, tuberculous meningitis in newborns with hepatitis and HIV disease, the safety of anti-TB agents in newborns with liver dysfunction, and the interaction and adverse effects of these and antiretroviral agents are highlighted. Thirdly, the use of PCR to determine an early diagnosis of HIV infection in the neonate facilitated prompt antiretroviral therapy to prevent rapid progression of HIV disease. The concealment of HIV status until after delivery prevented the use of prevention of mother-to-child transmission (PMTCT) measures, including administration of a single dose of the antiretroviral agent nevirapine to the mother before delivery,2 avoidance of breastfeeding, and cotrimoxazole prophylaxis. Finally the issue of BCG vaccination in newborns who may have congenital TB and be infected with HIV is raised. This case raises several issues regarding the interaction of TB and HIV infection in infancy. Although the problem appears complex, a logical approach to its management is possible.
RECOMMENDATIONS The possibility of congenital TB should be seriously considered in a newborn who is ill and not responding to appropriate antimicrobial therapy even in the absence of a history of exposure to an infectious source case. Both the mother and infant should be tested for HIV infection. If the mother is known to have TB and HIV disease before delivery, appropriate therapy should be given to prevent intrauterine, peripartum, and post-delivery transmission of these infections. The management of infants with congenital TB should be based on guidelines provided in Chapter 56.
2. Stringer JS, Sinkala M, Chapman V, et al. Timing of the maternal drug dose and risk of perinatal HIV transmission in the setting of intrapartum and neonatal single-dose nevirapine. AIDS 2003;17:1659–1665.
1. Cantwell MF, Shehab ZM, Costello AM, et al. Brief report: Congenital tuberculosis. N Engl J Med 1994; 330:1051–1054.
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Deteriorating tuberculosis in a HIV-infected man despite treatment Immune reconstitution, resistance, or drug malabsorption? Graeme Meintjes and Gary Maartens
CASE REPORT A 27-year-old human immunodeficiency virus (HIV)-infected man presented with symptomatic sputum smear-positive pulmonary TB. He had a background history of having been treated for pulmonary TB twice in the past. He reported full adherence to treatment in both episodes. He was commenced on rifampicin, isoniazid, pyrazinamide, ethambutol, and streptomycin (World Health Organization (WHO) anti-TB treatment regimen II) dosed according to weight. His CD4 T-helper lymphocyte count was 2 cells/mm3. Four weeks later he reported symptomatic improvement, he had gained weight from 49 to 55 kg, and his C-reactive protein (CRP) had decreased from 139 to 21 mg/L. He was commenced on combination antiretroviral therapy (zidovudine, lamivudine, and efavirenz). Three months later he reported recurrence of night sweats and cough with mucopurulent sputum production. He also complained of left pleuritic chest pain and had symptoms and clinical signs suggestive of a right sacroiliitis. His weight had increased further to 61 kg. He was found to have a fever and his CRP was again elevated at 133 mg/L. His chest radiograph showed right middle lobe consolidation and left hilar adenopathy (no chest radiograph had been done at diagnosis for comparison). Streptomycin had been discontinued a month previously. He reported 100% adherence and his clinic card confirmed this. Sputa were sent for mycobacterial culture and susceptibility testing. A clinical diagnosis of paradoxical deterioration of TB due to the immune reconstitution inflammatory syndrome (IRIS) was made and he was commenced on corticosteroids at a high dose (prednisone 90 mg daily). His respiratory symptoms resolved and his night sweats and joint pain improved. The prednisone dose was reduced, but a week later he had markedly deteriorated with severe left flank pain and lumbar backache, clinical features of a left sacroiliitis, right upper quadrant pain, a dry cough, and recurrent night sweats. The prednisone dose was increased again and his symptoms improved. However, 2 weeks later his symptoms again worsened despite the prednisone dose remaining at 90 mg daily. He had such severe left sacroiliitis that he was unable to weight-bear and he had lost 6 kg weight. An ultrasound demonstrated a 2-cm-diameter hypoechoic lesion in the liver consistent with an abscess. Mycobacterium tuberculosis was cultured from his sputum, which was susceptible to rifampicin and isoniazid. Prednisone was rapidly weaned. Plasma concentrations of isoniazid were therapeutic, but rifampicin concentrations were markedly sub therapeutic
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(undetectable 2.5 hours post-dose and 1 mg/L 4 hours post-dose; therapeutic range 8–24 mg/L). His rifampicin dose was increased from 600 to 900 mg daily. His liver function tests were closely monitored but did not rise. Within 2 weeks his symptoms had resolved completely and over the next 2 months he regained all the weight he had lost. A follow-up ultrasound showed marked reduction of the liver lesion. Anti-TB treatment was continued for a further 8 months with the higher dose of rifampicin, and he did not experience a relapse of his TB following TB treatment. After 7 months on antiretroviral therapy his CD4 lymphocyte count was 294 cells/mm3 and viral load was below the level of detection.
DISCUSSION Deterioration of symptoms or signs on anti-TB therapy is a common problem in HIV-infected patients (Box 93.1). Although TB-IRIS is probably the commonest cause in patients who commence antiretroviral therapy when being treated for TB, the diagnosis of TB-IRIS is a diagnosis of exclusion.1 There are a number of important differential diagnoses. TB-IRIS occurs in HIV-infected patients who have been diagnosed with TB and are improving on treatment, but who develop a paradoxical worsening or recurrence of TB manifestations (symptoms, signs, or radiological features) shortly after commencing antiretroviral therapy (ART). TB-IRIS occurs in 29–36% of patients started on ART while on TB treatment.2 This patient’s deterioration occurred 3 months after starting ART. Typically paradoxical IRIS occurs 1–4 weeks after the initiation of ART, but it has been reported to occur many months after patients commence ART.2,3 Although there are no randomized controlled trials supporting the use of corticosteroids for TB-IRIS, there are case reports and small series reporting favourable responses to corticosteroids.4 There are several potential dangers of corticosteroids: steroid adverse drug reactions, additional immunosuppression in an already immunosuppressed patient, and delayed diagnoses (as in this case) by causing transient improvement by suppressing fever and inflammation. For these reasons and because of the lack of good evidence of benefit, corticosteroids should probably be reserved for more severe cases of IRIS in whom the diagnosis is certain. The culture of M. tuberculosis from the sputum in this patient indicated that deteriorating TB was the cause of his symptoms
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Deteriorating tuberculosis in a HIV-infected man despite treatment
Box 93.1 Causes of deterioration on antituberculosis therapy
Diagnosis of TB incorrect. Poor adherence to TB treatment. Immune reconstitution inflammatory syndrome (IRIS). Drug-resistant TB. Sub therapeutic concentration of anti-TB drugs. New opportunistic disease. Adverse drug reaction.
and signs. Drug resistance was an important consideration in this patient with his previous episodes of TB, but this was excluded.
REFERENCES 1. Meintjes G, Lawn SD, Scano F, et al. International Network for the Study of HIV-associated IRIS. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8(8):516–523. 2. Lawn SD, Bekker L-G, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–373.
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Although there have been contradictory reports in the literature, several studies have reported low concentrations of anti-TB drugs, notably rifampicin, in HIV-infected patients.5–7 Low concentrations occur more commonly in advanced HIV disease, with or without concomitant diarrhoea.5,7 The mechanism appears to be due to malabsorption.7 The significance of these findings at the population level is doubtful, given that HIV-infected patients generally respond well to rifampicin-based anti-TB therapy. However, in individual cases, as in the patient reported here, low concentrations can result in failure of therapy. Therapeutic drug monitoring of anti-TB drugs is only available in a few centres. It should be considered in patients deteriorating on therapy despite good adherence after exclusion of drug resistance.
3. Olalla J, Pulido F, Rubio R, et al. Paradoxical responses in a cohort of HIV-1 infected patients with mycobacterial disease. Int J Tuberc Lung Dis 2002;6: 71–75. 4. Breen RA, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004;59: 704–707. 5. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, et al. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 2004;48:4473–4475.
6. McIlleron H, Wash P, Burger A, et al. Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob Agents Chemother 2006;50:1170–1177. 7. Sahai J, Gallicano K, Swick L, et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997;127: 289–293.
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Unusual cases Guillaume Breton
The management of TB in human immunodeficiency virus (HIV)infected patients is complicated by overlapping toxicity profiles, by drugs interaction, and by immune reconstitution inflammatory syndrome (IRIS) when both anti-TB and antiretroviral therapies (ARTs) are associated.
CASE REPORT A 27-year-old man originating from the Ivory Coast was hospitalized in November 2001 for prolonged cough and fever. Clinical examination revealed fever (40 C), peripheral axillary adenopathy (3 4 cm), and oral candidiasis. Computed tomography (CT) scan revealed multiple mediastinal and abdominal adenopathies, hepatomegaly, splenomegaly, and ascites. Sputum smears were positive for acid-fast bacilli. C-reactive protein (CRP) was 224 mg/L. HIV serology was found to be positive, CD4 cell count was 4/mm3 (1%), and HIV-RNA was 181.153 cp/mL. The patient was initially treated on 23 November with anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol), trimethoprim– sulfamethoxazole, and fluconazole with a rapid cessation of fever in 2 days, and a progressive decrease in axillary adenopathy and oral and probably oesophageal candidiasis. On 17 December, the patient was asymptomatic. CRP was 3 mg/mL, CD4 cell count 5/mm3 (1%), and HIV-RNA 166.059 cp/mL. ART (zidovudine, lamivudine, indinavir, ritonavir) was initiated and concomitantly rifampicin was switched to rifabutin.
FIRST EPISODE OF IRIS On 26 December, the patient presented with fever (39 C), painful axillary adenopathy reappearance, abdominal pain, headache, and vomiting. Neurological examination was normal. Blood tests showed anaemia (9.0 g/dL); liver, pancreatic, and renal tests were normal. CRP was 128 mg/L, CD4 cell count 64/mm3 (12%), and HIV-RNA 2633 cp/mL. Multiple blood and urine cultures were performed and found to be negative. Three sputum samples were negative for direct smear microscopy. Cryptococcal antigen was negative. Polymerase chain reaction (PCR) for cytomegalovirus (CMV) and ophthalmic fundus examination were negative. Blood culture for mycobacteria was negative. Stool examination for parasites was negative. The search for histoplasmosis, leishmaniasis, and malaria was negative. Cerebral CT scan was normal and cerebrospinal fluid (CSF) examination, culture, and PCR for bacteria, mycobacteria, and virus were negative. Thoracic and
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abdominal CT scans were similar to the previous examination. Cardiac echocardiography was normal. The search for dental and sinus infection was negative. The results from initial (20 November) mycobacterial culture from sputum and urine identified Mycobacterium tuberculosis and drug susceptibility testing showed a susceptible strain. On 2 January, he presented with a localized oedema of the lip. Dermatological examination was normal. Eosinophil count and liver test were normal, and creatinine concentration was 177 mmol/L. CRP was 190 mg/L. An allergy to trimethoprim–sulfamethoxazole was thus suspected and this drug was stopped. On 5 January, all symptoms were persisting. Haemoglobin was 7.6 g/dL and platelet count was 71,000/mm3. Haptoglobin was low. Myelogram was normal. An immunoallergic haemolytic anaemia was suspected and rifabutin and pyrazinamide were then stopped. The lip oedema disappeared but the fever persisted at 38–38.5 C. On 13 January, the patient presented with dyspnoea and cough, and examination revealed crackling rales. Chest radiograph was compatible with a diagnosis of left base pneumonia associated with a minimal pleural effusion. A diagnosis of bacterial pneumonia was considered and a treatment with cefotaxime and ofloxacin was initiated. However, all symptoms and fever were persisting. Serologies for Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae were negative. Bronchoalveolar lavage was haemorrhagic; culture remained negative. Pulmonary scintigraphy showed bilateral pulmonary embolism with pulmonary infarct. On 19 January, all treatments were interrupted and heparin (later switched to fluindione) was administered. The high fever persisted but renal function, anaemia, and thrombopenia normalized. Antituberculosis therapy was reinitiated on 25 January (isoniazid, ofloxacin, ethambutol) in association with pyrimethamine and pentamidine aerosol (rifampicin, pyrazinamide, and trimethoprim–sulfamethoxazole were avoided due to possible allergies). Four days later, the outcome was favourable with cessation of fever and decrease in axillary adenopathy, CRP was 18 mg/L, and CD4 cell count was 48/mm3 (3%). On 11 February, ART was reinitiated (didanosine, lamivudine, efavirenz); protease inhibitors were avoided due to interaction with fluindione.
SECOND EPISODE OF IRIS One week later, on 18 February, fever and painful adenopathy reappeared. CD4 cell count was 112/mm3 (11%). After negative sputum smears, blood, urine culture, and normal chest radiograph, steroids (prednisone 40 mg/day, 0.7 mg/kg/day) were initiated after treatment with ivermectin in this patient originating from
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an intertropical area. However, steroids did not give any improvement. Because of high fever and vomiting, ART was finally stopped on 26 February; CD4 cell count was 180/mm3 (22%). Apyrexia was progressively obtained on 13 March. Finally steroids (0.7 mg/kg/day) were reinitiated on 19 March. At this time, the CD4 cell count was 74/mm3 (8%), ARN-VIH 1,300,000 cp/mL, and CRP 10 mg/mL. A genotypic resistance test was performed and revealed a K103N mutation (resistance to efavirenz). Two days later ART was reinitiated (didanosine, lamivudine, lopinavir/ritonavir). Because of the interaction between fluindione and ritonavir, the fluindione dose was progressively increased until 50 mg/day but it was impossible to adapt the international normalized ratio and low-molecular-weight heparin was used. On 2 April, the CD4 cell count was 185/mm3 (33%) and HIV-RNA was 17,000 cp/mL. On 5 April, pyrazinamide was reintroduced.
THIRD EPISODE OF IRIS On 19 April, the patient presented with shivering, abdominal pain, and headache but he remained afebrile. CRP was 91 mg/L. Abdominal CT scan showed necrotic adenopathies and multiple spleen abscesses (Fig. 94.1); cerebral magnetic resonance imaging (MRI) detected a T1-weighted round lesion with partial gadolinium enhancement but without oedema, suggestive of a diagnosis of brain tuberculoma (Fig. 94.2). Treatment was unchanged and a progressive favourable outcome was observed. Steroids were progressively tapered until 20 mg/day, whereas CT scan and CRP remained unchanged on 22 May. In June, the patient presented with foot paraesthesia. A peripheral neuropathy was diagnosed. Isoniazid and didanosine were interrupted, zidovudine was initiated, and anti-TB therapy with pyrazinamide and ethambutol was continued. Steroids were stopped on 15 July. Anti-TB therapy was stopped on 2 June.
FOURTH EPISODE OF IRIS On 25 July, the patient presented with a new increase in size of axillary adenopathy. The clinical examination and biological test were unremarkable. Sputum smear and culture remained negative.
Fig. 94.2 Cerebral MRI during IRIS: T1-weighted round lesion with partial gadolinium enhancement suggestive of tuberculoma.
Lymph node punction showed caseum without acid-fast bacilli (AFB) and culture remained negative. The CD4 cell count was stable and HIV remained undetectable. Considering the minor symptom, no treatment modifications were made and a favourable clinical outcome was observed. As of January 2007, the patient remained asymptomatic without relapse of IRIS or of TB.
DISCUSSION Antiretroviral therapy for HIV infection induces a reconstitution of the immune response and has led to a decrease in the frequency and mortality of opportunistic infections.1 However, this immune reconstitution is sometimes deleterious and may cause IRIS. This syndrome includes all pathological manifestations attributed to an exaggerated immune response to various infectious or non-infectious antigens.2
DIAGNOSIS OF IRIS (BOX 94.1)
Fig. 94.1 Abdominal CT scan during IRIS: necrotic intra-abdominal adenopathies and spleen abscesses.
The diagnosis of IRIS is suggested by the temporal association of worsening TB symptoms without evidence of TB relapse or resistance immediately after initiating antiretroviral therapy whereas TB symptoms initially improved after anti-TB treatment. The efficacy of antiretroviral therapy is documented by the rapid decrease in HIV viral load (1.8 log10 in 10 days). The immune reconstitution is suggested by the rapid increase in CD4 cell count (þ60/mm3, þ11%) within 10 days of initiating ART. The conversion of a tuberculin skin test, not documented in this case, can also be suggestive of the reconstitution of the immune response against TB.3
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Box 94.1 Proposed criteria for the diagnosis of IRIS associated with tuberculosis The diagnosis of IRIS requires the following three criteria: 1. Atypical or inflammatory clinical manifestations after ART initiation. 2. Active antiretroviral therapy HIV viral load decreases > 1 log 10 cp/mL; increase in CD4 cell count (frequently observed but not required). 3. Clinical manifestations not explained by: TB relapse or resistance; non-adherence to treatment; drug side effects; or new infection or other diagnoses.
The main differential diagnosis to exclude is a relapse of TB or drugresistant TB. Even if the initial favourable outcome is suggestive of a microbiological control of TB, this hypothesis can only be excluded after the results of culture and drug susceptibility testing are known, which can take several weeks. Other differential diagnoses must be excluded. In this case an allergy to rifabutin is probably associated with the first IRIS episode considering the dermatological reaction and the haemolytic anaemia. An allergy to trimethoprim–sulfamethoxazole is less probable but is difficult to exclude even if the timing (> 1 month) is not suggestive. This illustrates the association of IRIS with potential differential diagnoses and the difficult diagnosis procedure in such cases. In this observation, all identified risk factors for IRIS were present: low CD4 cell count, disseminated TB, and short interval time (< 4–8 weeks) between initiation of anti-TB drugs and initiation of ART.3–11 Even if these risk factors remain controversial, their presence would have prompted a diagnostic procedure faster than than the one we used. In this observation, the relapse of IRIS observed after the reinitiation of ART is probably a very strong argument for positive diagnosis. However, the interruption of ART should not be used as diagnostic evidence when one considers, first, its inefficacy demonstrated by the relapse of IRIS after each ART reinitiation and, second, the risk of new acquired immunodeficiency syndrome (AIDS) events in deeply immunocompromised patients.12 Moreover, the interruption of non-nucleoside reverse transcriptase inhibitors (NNRTIs) can also induce very rapid resistance when NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs) are interrupted at the same time irrespective of the very long half-life of NNRTIs, as demonstrated here with efavirenz. Considering the high frequency of IRIS in HIV/TB-coinfected patients and the sometimes severe IRIS manifestations, clinicians should be aware of the risk of interrupting ART if they choose an antiretroviral regimen containing NNRTIs. Even if it is not recommended, the comparison of CT scans performed when TB has been diagnosed with CT scans performed when IRIS has manifested can be useful in order to determine the initial aspect and size of the lesion. The outcome of necrotic abdominal adenopathies and the appearance of spleen abscesses during the third IRIS episode are highly suggestive of this diagnosis. The appearance of an intracranial tuberculoma is probable considering the occurrence of headaches and vomiting; however, because of the lack of initial cerebral MRI it is difficult to confirm.
TREATMENT OF IRIS (BOX 94.2) Because of a lack of clinical studies into the management of IRIS the recommended treatment remains uncertain. Steroids
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Box 94.2 Proposal for IRIS treatment 1. Try not to stop ART. 2. Continue anti-TB treatment. 3. According to severity of symptoms: wait and see; use non-steroidal anti-inflammatory drugs; try high-dose, short-term corticosteroid (i.e. prednisone 1 mg/kg/day 2 weeks); or in life-threatening cases, stop ART and add steroids.
are, however, the most frequently administered drugs and are thus suggested by expert opinion.13,14 Other therapeutic options include non-steroidal anti-inflammatory drugs and a wait-and-see attitude in the less severe forms. In this observation, the last IRIS episode with recurrence of a painful axillary adenopathy with caseation had a spontaneous favourable outcome without treatment modification. In contrast, the second IRIS episode illustrates that IRIS can sometimes be severe and difficult to control even if steroids are used. The dose of 0.7 mg/kg used here was insufficient to control IRIS symptoms and the occurrence of intracranial tuberculoma with vomiting led to an interruption of ART. The use of a higher dose steroid (1 mg/kg), as recommended, should be able to control IRIS symptoms. The use of steroids in immunocompromised patients can also be deleterious with a major increased risk of CMV infection. In a case–control study of 279 patients with fewer than 50 CD4 cells/mm3, the use of steroids was the main predictive factor of CMV retinitis (odds ratio 6.41).15 Thus a control of CMV PCR and ophthalmic fundus examination at least once a month if negative is recommended. At minimum, before steroid administration, ivermectin should be administered systematically in patients originating from endemic areas in order to avoid a rare but severe disseminated strongyloides infection.
DRUGS MANAGEMENT: INTERACTION, CROSS SIDE EFFECTS The association of antiretroviral drugs with anti-TB drugs, especially rifamycin, is associated with major drug interaction and toxicity.12 Anti-TB therapy should include rifamycin in order to decrease the rate of relapse and failure.16 Current ART regimens usually include two NRTIs and one NNRTI or one protease inhibitor (PI). NNRTIs and PIs are metabolized by cytochrome p450. Rifamycins induce the activity of cytochrome p450 and significantly decrease the serum concentration of NNRTIs and PIs. The use of efavirenz in association with rifampicin is, however, possible with an increased dose of efavirenz from 600 to 800 mg/day, except perhaps in patients with low weight.17 In such cases a monitoring of efavirenz serum concentration is highly recommended if possible. The association with nevirapine is not recommended. However, since nevirapine has been widely used, this association has been studied. A prospective study of 140 patients in Thailand showed a low nevirapine concentration (< 3.4 mg/L) in 29.7% of the patients treated with rifampicin versus 6.8% of the patients with other anti-TB drugs ( p = 0.001). However, the virological response did not differ after 6 months of ART.18 The association of PIs with rifampicin is a strong contraindication, with a major reduction (up to 95%) of serum concentration of most PIs, leading to a lack of antiretroviral activity and to the
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rapid emergence of resistant viruses. Low-dose rifabutin (150 mg/day to 150 mg thrice weekly), which is the least potent cytochrome inducer, is recommended in association with PIs.13 In this observation, rifamycin was stopped because of a possible allergy; however, the strong cytochrome inhibitor effect of lopinavir/ritonavir led also to the impossibility of adapting the fluindione dosage. The association of antiretroviral and anti-TB drugs in HIVinfected patients has been associated with an increase in side-effect frequency. In our observation the occurrence of peripheral neuropathy was predictable due to the association of isoniazid with
REFERENCES 1. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;338:853–860. 2. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002;81:213–227. 3. Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157–161. 4. Breen RA, Smith CJ, Bettinson H, et al. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 2004; 59:704–707. 5. Navas E, Martin-Davila P, Moreno L, et al. Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 2002;162:97–99. 6. Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during higly active antiretroviral therapy. AIDS 2005;19:399–406.
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didanosine, one of the more neurotoxic antiretroviral drugs. In a retrospective control study of anti-TB treatment in 156 HIVinfected and 156 non-HIV-infected patients treated for TB, the most frequent adverse effects in HIV-infected patients were peripheral neuropathy (14%), hepatotoxicity (13%), rash (13%), and persistent vomiting (10%), leading to anti-TB treatment interruption in 13% of cases. Peripheral neuropathy and persistent vomiting were significantly more frequent in HIV-infected patients.19 The choice of ART regimen should take into account these side effects.
7. Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39:1709–1712. 8. Kumarasamy N, Chaguturu S, Mayer KH, et al. Incidence of immune reconstitution syndrome in HIV-tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr 2004;37:1574–1576. 9. Michailidis C, Pozniak AL, Mandalia S, et al. Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis. Antivir Ther 2005;10:417–422. 10. Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1 responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS 2006;20:F1–F7. 11. Manosuthi W, Kiertiburanakul S, Phoorisri T, et al. Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculous and antiretroviral therapy. J Infect 2006;53(6):357–363. 12. Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002; 16:75–83. 13. Treating opportunistic infections among HIVinfected adults and adolescents. MMWR Morb Mortal Wkly Rep 2004;53(RR-15):1–112.
14. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected indivuduals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–373. 15. Hodge WG, Boivin JF, Shapiro SH, et al. Iatrogenic risk factors for cytomegalovirus retinitis. Can J Ophthalmol 2005;40:701–710. 16. Jindani A, Nunn A, Enarson D. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004;364:1244–1251. 17. Patel A, Patel K, Patel J, et al. Safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with tuberculosis and HIV 1. J Acquir Immune Defic Syndr 2004;37:1166–1169. 18. Manosuthi W, Sungkanuparph S, Thakkinstian A, et al. Plasma nevirapine levels and 24-week efficacy in HIV-infected patients receiving-based highly active antiretroviral therapy with or without rifampicin. Clin Infect Dis 2006;43:243–245. 19. Breen RAM, Miller RF, Gorsuch T, et al. Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection. Thorax 2006;61:791–794.
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Unusual images of tuberculosis in children Nicky Wieselthaler and Savvas Andronikou
IN THE DIFFERENTIAL DIAGNOSIS OF A POSTERIOR FOSSA MASS
on computed tomography (CT) and a hyperintense centre on T2weighted magnetic resonance imaging (MRI).1,2 The differential diagnosis is pyogenic abscess. Tuberculosis abscesses are known to develop in patients who are adequately treated for TB.3 They require drainage for treatment. In comparison tuberculomas may develop in patients who are not on TB treatment and have no history of TB. The classic feature of a tuberculoma is that the centre has low signal intensity on T2-weighted MRI versus the high signal intensity centre seen in an abscess2 (Figs 95.2 and 92.3).
See Fig. 95.1.
MIMICKING A BRAIN TUMOUR
ABSCESS VERSUS TUBERCULOMA
Tuberculous lesions may take on bizarre appearances as shown in the following unusual cases and they are often initially misdiagnosed as neoplasms (Figs 95.4–95.7).1,4
The images in this chapter were confirmed by culture, a positive test for acid-fast bacilli (AFB) highly suggestive cerebrospinal fluid (CSF) or positive Mantoux test or a combination thereof.
BRAIN
Abscesses are rare, particularly in the posterior fossa. They are larger than 2 cm, are ring-enhancing, and have a hypodense centre
Fig. 95.1 T1 axial MRI with contrast demonstrating multiple ring-
Fig. 95.2 Axial CT with contrast demonstrating right cerebellar ring-
enhancing tuberculomata as a cluster in the periphery of the right side of the posterior fossa with surrounding oedema.
enhancing abscess with hypodense centre and surrounding oedema. Note the left Sylvian fissure discoid enhancing tuberculoma.
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Fig. 95.4 Axial CT with contrast demonstrating irregular enhancing right Fig. 95.3 T2 axial MRI demonstrating left cerebellar tuberculoma with
frontal lesion. Differential diagnosis: glioblastoma multiforme.
low signal intensity centre and surrounding oedema.
Fig. 95.5 Axial CT (A) and T1 axial MRI (B) with contrast demonstrating irregular enhancing right thalamic tuberculous lesion. Differential diagnosis: thalamic glioma.
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Fig. 95.6 Axial CT showing mixed cystic and solid mass with calcification. TB confirmed. Differential diagnosis: ganglioglioma, oligodendroglioma.
Fig. 95.7 T1 axial (A), with contrast (B), and T2 MRI
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PARADOXICAL RESPONSE TO ANTITUBERCULOSIS TREATMENT Some patients may show worsening of symptoms and paradoxical expansion or new formation of multiple granulomas while on anti-TB treatment (Fig. 95.9).6
Fig. 95.7—cont’d (C) demonstrating enhancing choroid plexus lesion. Patient improved on anti-TB treatment. Differential diagnosis: choroid plexus papilloma.
TUBERCULOUS MENINGITIS (TBM) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) The typical features of TB meningitis are seen less in HIV-infected patients (Fig. 95.8).5
Fig. 95.8 Axial CT of HIV-infected patient with culture-confirmed TB meningitis demonstrating atrophy only but no features of basal enhancement, hydrocephalus, or infarction.
Fig. 95.9 Axial CT with contrast demonstrating paradoxical increase in the size of a tuberculous lesion. Note the change in density at the centre of the lesion.
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SPINE AND SPINAL CORD CERVICAL SPINE TUBERCULOSIS Tuberculosis of the cervical spine is rare, constituting 3–5% of all TB spondylitis. Only 1% of cases occur at the craniocervical junction (Fig. 95.10).7–9
Fig. 95.10 T2 sagittal (A), T1 with contrast midline sagittal (B) and parasagittal (C) MRI of the craniocervical junction demonstrating destruction of C1 and C2 with large enhancing paravertebral mass, cord compression and parapharyngeal abscess (C).
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TUBERCULOUS ARACHNOIDITIS
EXTRADURAL ABSCESS
The radiological appearances include partial or complete encasement of the cord by an enhancing exudate with adhesions and features of cord compression (Fig. 95.11).10,11
Abscesses confined to the epidural space result in cord compression with or without meningeal inflammation (Fig. 95.12).10
Fig. 95.12 T1
Fig. 95.11 T1 sagittal MRI with contrast demonstrating enhancing irregular arachnoid membrane encasing the cord and ‘shaggy’ nerve roots in keeping with exudates and adhesions.
sagittal MRI with contrast demonstrating extradural enhancing abscess with cord compression at T8–9. Note also enhancing mediastinal nodes anterior to the proximal vertebral column.
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INTRAMEDULLARY ABSCESS See Fig. 95.13.
MUSKULOSKELETAL SYSTEM SPINA VENTOSA12 See Fig. 95.14.
Fig. 95.14 Anteroposterior radiograph of the right hand demonstrating an expansile bone lesion of the second metacarpal with periosteal reaction and soft-tissue swelling. Note the coexistent healing rickets.
Fig. 95.13 T1 sagittal MRI without (A) and with (B) contrast demonstrating multiple intramedullary enhancing tuberculous abscesses.
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TUBERCULOSIS OF THE LONG BONES The differential diagnosis is the same as for any aggressive bone lesion in the paediatric age group (Fig. 95.15).
Fig. 95.15 (A) Anteroposterior radiograph demonstrating proximal diaphyseal sclerosis with periosteal reaction. (B) Axial CT demonstrating right tibial cortical sclerosis and thickening with new bone formation. (C) T1 sagittal MRI of tibia demonstrating medullary lesions. Note the difference in signal between the lesions and hyperintense fatty marrow.
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TUBERCULOSIS OF THE ANKLE JOINT AND FOOT Tuberculosis of the foot and ankle is rare. Most commonly there is osteoporosis, and disease most often involves the calcaneus. Treatment is usually medical (Figs 95.16 and 95.17).13
Fig. 95.16 (A) Anteroposterior radiograph of the ankle demonstrating erosion in the medial cortex of distal fibular metaphysis. (B) T1 fat saturation axial MRI with contrast demonstrating periarticular synovitis with fibular bone destruction.
Fig. 95.17 (A) Lateral radiograph of the foot demonstrating subtalar joint space narrowing and irregularity with cortical sclerosis. (B) Coronal CT demonstrating joint space narrowing and irregularity on the left. (Continued)
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CALVARIAL TUBERCULOSIS14 See Fig. 95.19.
Fig. 95.17—cont’d T1 coronal MRI without (C) and with contrast fat saturation (D) demonstrating enhancing subtalar synovial thickening.
HIV AND TUBERCULOSIS See Fig. 95.18.
Fig. 95.18 Anteroposterior radiograph of the tibia in a patient on highly active antiretroviral therapy demonstrating multiple expansile lytic lesions confirmed on biopsy to be TB.
Fig. 95.19 Axial CT on bone window (A) and axial CT without contrast (B) demonstrating bilateral but asymmetrical frontal lytic/destructive bone lesions with associated extracranial soft-tissue masses. Biopsy-proven TB.
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ADULT-TYPE POST-PRIMARY TUBERCULOSIS CAVITATION IN A CHILD
CHEST CHEST WALL INVOLVEMENT BY COLD ABSCESSES
See Fig. 95.22.
15
Primary TB of the chest wall is rare. Differential diagnosis includes pyogenic abscess and tumours (Fig. 95.20).
Fig. 95.22 Zoomed and cropped frontal radiograph of the chest in an
Fig. 95.20 Axial CT with contrast demonstrating left rim-enhancing subcutaneous abscess with intrathoracic but extrapleural extension.
adolescent. Multicystic change is seen in the right apex, a feature considered diagnostic of pulmonary TB in an adult. This type of postprimary or reactivation TB is rarely encountered in children.
AIRWAY COMPRESSION BY TUBERCULOUS SPONDYLITIS16 See Fig. 95.21.
Fig. 95.21 Axial CT (A) and T1 axial MRI with contrast (B) in two different patients – the trachea is displaced anteriorly and compressed against the sternoclavicular joint by a large prevertebral soft-tissue mass associated with thoracic TB spondylitis.
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OESOPHAGEAL PERFORATION BY TUBERCULOUS LYMPHADENOPATHY17 See Fig. 95.23.
Fig. 95.23 (A) Anteroposterior view during a contrast upper gastrointestinal tract fluoroscopic examination demonstrating localized leakage of the contrast and communication with the trachea in the form of a tracheo-oesophageal fistula. (B, C) Axial CT with contrast in the same patient as (A) demonstrating large paratracheal low-density rim-enhancing lymphadenopathy, locules of gas, and a fluid collection surrounding the oesophagus, some of which is extraluminal. There is also extensive consolidation and an effusion. The oesophageal perforation was confirmed at surgery and necrotic nodes were seen to have eroded the oesophagus.
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REFERENCES 1. du Plessis J, Andronikou S, Wieselthaler N, et al. CT features of tuberculous intracranial abscesses in children. Pediatr Radiol 2007;37(2):167–172. 2. Andronikou S, Wieselthaler N. Modern imaging of tuberculosis in children: thoracic, central nervous system and abdominal tuberculosis. Pediatr Radiol 2004;34(11):861–875. 3. Schoeman JF, Ravenscroft A, Hartzenberg HB. Possible role of adjunctive thalidomide therapy in the resolution of a massive intracranial tuberculous abscess. Child Nerv Syst 2001;17:370–372. 4. Brismar J, Hugosson S, Larsson C, et al. Imaging of tuberculosis III. Tuberculosis as a mimicker of brain tumour. Acta Radiol 1996;37:496–505. 5. Van der Weert EM, Hartgers NM, Schaaf HS, et al. Clinical diagnosis of tuberculous meningitis: comparison of diagnostic criteria in HIV-infected and
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6.
7.
8.
9. 10. 11.
HIV-uninfected children. Pediatr Infect Dis J 2006; 25(1):65–69. Schoeman JF, Morkel A, Seifart HI, et al. Massive posterior fossa tuberculous abscess developing in a young child treated for miliary tuberculosis. Pediatr Neurosurg 1998;29:64–68. Bhojraj S, Shetty N, Shah PJ. Tuberculosis of the craniocervical junction. J Bone Joint Surg (Br) 2001;83B:222–225. Krishnan A, Patkar D, Patankar T, et al. Craniovertebral junction tuberculosis: a review of 29 cases. J Comp Assist Tomog 2001;25(2):171–176. Lukhele M. Tuberculosis of the cervical spine. S Afr Med J 1996;86:553–556. Leonard JM, Des Prez RM. Tuberculous meningitis. Infect Dis Clin North Am 1990;4:769–787. Dastur DK. Neurosurgically relevant aspects of pathology and pathogenesis of intracranial and intraspinal tuberculosis. Neurosurg Rev 1983;6:103–110.
12. Andronikou S, Smith B. ‘Spina ventosa’— tuberculous dactylitis. Arch Dis Child 2002;86(3):206. 13. Dhillon MS, Nagi ON. Tuberculosis of the foot and ankle. Clin Orthop Related Res 2002;398:107–113. 14. Pantakar T, Varma R, Prasad S, et al. Radiographic findings in tuberculosis of the calvarium. Neuroradiology 2000;42:518–521. 15. Paik H, Chung K, Kang J, et al. Surgical treatment of tuberculous cold abscess of the chest wall. Yonsei Med J 2002;43(3):309–314. 16. Andronikou S, Wieselthaler N, Kilborn T. Significant airway compromise in a child with a posterior mediastinal mass due to tuberculous spondylitis. Pediatr Radiol 2005;35(11):1159–1160. 17. Goussard P, Sidler D, Kling S, et al. Esophageal stent improves ventilation in a child with a bronchoesophageal fistula caused by Mycobacterium tuberculosis. Pediatr Pulmonol 2007;42(1):93–97.
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Spinal tuberculosis in children A report of a complicated case H Simon Schaaf, Peter R Donald, and Gert J Vlok
CASE PRESENTATION A 23-month-old girl presented from a rural town with a history of cough for the past 2 weeks and that she had been less active than usual. She had lost weight, and this was confirmed on her ‘roadto-health card’. On further enquiry the grandmother, who lived in the same house, had been diagnosed with microscopy smearpositive pulmonary TB 2 years earlier, but no further information was obtained. On clinical examination her weight was less than the third percentile for her age (National Center for Health Statistics). Her respiratory examination was normal. She was neurologically intact, but a gibbus was noted in the lower thoracic spine. The tuberculin skin test result was not documented. Her chest radiograph showed a segmental right upper lobe opacification with some volume loss and a broad mediastinum for a malnourished child. A mass lesion was observed behind the cardiac shadow (Fig. 96.1). A previous lateral radiograph of the spine, done at a rural hospital 9 months earlier when the child was aged 14 months, was brought to the referral hospital and this already showed loss of volume in the anterior part of thoracic vertebral bodies 10–12 (Fig. 96.2). The diagnosis of TB was not considered and the treatment and course over the following 9 months is not known. No other radiographs were available. The erythrocyte sedimentation rate was 20 mm/h. No further investigations were done and a clinical and radiographic diagnosis of spinal TB was made. She was started on a three-drug anti-TB regimen of isoniazid, rifampicin, and pyrazinamide. No surgical procedures were done and no specimens for culture were obtained. The three-drug treatment regimen was continued for 8 months, during which time she remained in hospital, after which she was discharged home to continue treatment at the local clinic. Because of the slow response to treatment, however, the three-drug treatment was continued for a further 2 months and isoniazid plus rifampicin thereafter for another 12 months. The total duration of treatment was therefore 22 months. Her clinical outcome at the end of treatment was not known, as she did not return to the referral hospital. Fifteen months after completion of her TB treatment, at the age of 5 years, she was again referred. She had developed a chronically draining fistula in the area of the gibbus, which had now become much worse. She was still neurologically intact. The angle of the kyphosis was about 90 (Fig. 96.3). The chest radiograph showed poor lung volumes secondary to the severe kyphosis with an impression of right hilar lymphadenopathy (Fig. 96.4).
A pus swab was sent for mycobacterial culture; Mycobacterium tuberculosis resistant to isoniazid, rifampicin, and streptomycin and susceptible to ethambutol, ethionamide, ofloxacin, and kanamycin was cultured. The drug susceptibility test results were the same as those of the grandmother’s isolates. She was again admitted for treatment, this time to a TB hospital. She was supplied with a brace and was treated with high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, and ofloxacin for 18 months. Although her spinal defect did not improve, it remained stable. During treatment she was referred for an orthopaedic opinion, but surgery was not recommended until after completion of her medical treatment as she had normal neurological function and reasonable lung capacity. Further enquiry was made about the grandmother or other possible source cases. It was only then discovered that the grandmother was initially treated with regimen I as for drug-susceptible TB. Her sputum smear remained positive for acid-fast bacilli at the end of treatment (before the child was diagnosed the first time), and culture and drug susceptibility testing at the time yielded M. tuberculosis
Fig. 96.1 Segmental opacification of right upper lobe with raised horizontal fissure. Arrows indicate paravertebral mass behind cardiac shadow.
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Fig. 96.4 Lung volumes and chest compressed due to severe kyphosis of the thoracic spine with possible right hilar lymphadenopathy.
resistant to isoniazid, rifampicin, and streptomycin. She refused further treatment, remained smear-positive, and stayed in the same house until her death 2 years later. Fig. 96.2 Collapse of anterior vertebral elements seen in the thoracic spine from T10 to T12.
DISCUSSION
Fig. 96.3 Severe kyphosis with collapse of several lower thoracic vertebrae.
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Skeletal TB occurs in 1–3% of all TB patients and makes up 5–10% of all extrapulmonary TB. Spinal TB makes up half of all skeletal TB. Haematogenous spread from a primary lung focus is the main mechanism of spread, although overt lung pathology on chest radiograph is found in only 30–50% of cases by the time that skeletal TB is diagnosed. Spinal TB is mainly a disease of children, although this case presented at a very early age and was probably missed because it was not considered as a possibility. We did not get an explanation as to what treatment the child received. The slow development of the disease is demonstrated also in the long time that lapsed between the first and second presentation. This case is an example of an anterior pattern of spinal involvement. In this type the pus and the necrotic tissue dissects beneath the anterior longitudinal ligament. Devascularization of the vertebral body and surrounding structures ensues with necrosis and abscess formation along the spinal column, which in this case can be seen on the first anteroposterior chest radiograph as a dense opacification behind the cardiac shadow. Further progression leads to collapse of the vertebral body and kyphotic deformity. Although it took many years because of inadequate treatment, sinus formation eventually occurred. Only spinal radigraphs were done. The ideal is to also evaluate the extent of the disease with magnetic resonance imaging (MRI), but this was not available at the time. In many developing countries with high TB burdens, this is still the case, but the absence of such investigations should not cause treatment to be withheld if TB is suspected. This case demonstrates the importance of taking a complete history, even if it means that the health worker must contact the local clinic. At the time of this child’s first diagnosis, multidrug-resistant
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Spinal tuberculosis in children
(MDR) TB was seldom considered in children. However, the grandmother was at the time already known to have MDR pulmonary TB, was living in the same house and was not taking her treatment and no other source case was identified. No culture was obtained from the child, but it has been shown in several studies that MDR-TB is as infectious and causes as much disease as drug-susceptible TB. Because the child presented with very early kyphosis, the severe progression of her disease could probably have been prevented had she been started on the correct MDR anti-TB treatment regimen according to the drug susceptibility test results of the grandmother. A minimum of three drugs to which the source case is susceptible or naı¨ve should be included in such a regimen, and preferably an aminoglycoside should also have been added for the first 4–6 months of treatment. Treatment of MDR-TB should continue for a minimum of 18 months or 18 months after the first negative culture. Kyphotic deformity is an important complication of spinal TB. As in this case, it is usually the result of collapse of the anterior spinal elements. The regions of the thoracolumbar junction and lumbar spine are more prone to these deformities. The deformity is more severe in children or where two or more vertebrae are involved. Although chemotherapy may eradicate the infection, vertebral collapse may continue for some time thereafter. Neurological compromise is the most serious complication of spinal TB. Despite a severe kyphosis on follow-up this child was fortunate not to develop neurological problems. The incidence of complete or
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incomplete paraplegia ranges between 12% and 43% and it is most common following a lesion in the mid- and low thoracic region. The current recommended medical treatment for spinal and other osteoarticular TB is a four-drug intensive phase (isoniazid, rifampicin, pyrazinamide, and ethambutol) followed by a continuation phase with isoniazid and rifampicin. The optimal duration of treatment for osteoarticular TB has not been established, but most orthopaedic surgeons recommend a treatment regimen of between 9 and 18 months for spinal TB, as it has been shown by MRI that response to treatment is often incomplete at 6 months duration. The role of bedrest in spinal TB has not been established. Bracing, with mainly three pressure points, could prevent further progression of the kyphosis during treatment and help to stabilize the spinal column. Because of initial severe discomfort, the brace is initially fitted for short periods (15–30 minutes/day for the first 1–2 weeks) and gradually increased over weeks. The aim of bracing is to arrest curve progression, provide pain relief (although initially it is often quite painful to wear), and encourage early ambulation. This patient had no surgery, but surgical treatment is indicated in the following circumstances: 1. uncertain diagnosis; 2. draining of large abscesses; 3. failure of conservative treatment; 4. progression of neurological deficit; and 5. impending or progressive kyphosis. In these circumstances surgery is mandatory.
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Sarcoidosis and tuberculosis A study in mimicry Om P Sharma
INTRODUCTION Sarcoidosis, a multisystem disease, occurs world-wide. It has a high prevalence in Scandinavian countries, England, Ireland, North America and Japan. In the developing countries of Asia and in Africa, the prevalence of the disease is not known because it remains hidden under the blanket of TB and other tropical granulomatous and non-granulomatous diseases. In the past syphilis was known as a great masquerader; in the twenty-first century, however, sarcoidosis, because of its chameleon-like presentations, can safely be dubbed la petitite simulatrice.
DEFINITION It is hard to define a disease whose cause is yet to be discovered. Scadding and Mitchell1 recommended the following: ‘Sarcoidosis is a disease characterized by the formation in all of several affected tissues of epithelioid-cell tubercles without caseation though fibrinoid necrosis may be present at the centre of a few, proceeding either to resolution or to conversion into hyaline fibrous tissue.’ This definition emphasizes only the histological features of the illness. The knowledge of the disease is so extensive now that we need to include not only the clinical, but also the radiological, immunological, biochemical and genetic aspects of the illness.2 The following descriptive definition is provided in the American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders Statement on Sarcoidosis in 1999:3 Sarcoidosis is a multisystem disorder of unknown cause. It commonly affects young and middle-aged adults and frequently presents with bilateral hilar adenopathy, pulmonary infiltration, ocular and skin lesions. The liver, spleen, lymph nodes, salivary glands, heart, nervous system, muscles, bones and other organs may also be involved. The diagnosis is established when clinico-radiographic findings are supported by histological evidence of noncaseating epithelioid cell granulomas. Granulomas of unknown causes and local sarcoid reactions must be excluded. Frequently observed immunological features are depression of cutaneous delayed typehypersensitivity and a heightened Th-1 immune response at sites of disease. Circulating immune-complexes along with signs of B-cell hyperactivity may also be found. The course and prognosis may correlate with the mode of the onset, and the extent of the disease. An acute onset with erythema nodosum or asymptomatic bilateral hilar adenopathy usually heralds a selflimiting course, whereas an insidious onset, especially with multiple extrapulmonary lesions, may be followed by relentless, progressive fibrosis of the lungs and other organs.
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WHO GETS SARCOIDOSIS? Occurrence of familial sarcoidosis is well known. The likelihood of developing sarcoidosis ranges from 26% to 73% in individuals with a first- or second-degree family member with sarcoidosis. Spurred by the earlier studies that had shown association between class II major histocompatibility complex (MHC) alleles and sarcoidosis, Schurmann et al.4 investigated 138 individuals in 63 German families. They used microsatellite markers to identify an area of genome linked to sarcoidosis and found the linkage to a section within the MHC on the short arm of chromosome 6.4 There are several alleles that confer susceptibility to disease (human leucocyte antigen (HLA) DR 11, 12, 14, 15, 17) and there are other alleles that offer protection (HLA DR1, DR4, and possibly HLA DQ 0202). Sarcoidosis is a genetically complex disease involving not a single gene but multiple genetic polymorphisms.5–8
WHAT CAUSES SARCOIDOSIS? In the last quarter of the nineteenth and the earlier decades of the twentieth century, sarcoidosis and TB were considered closely related. It was not uncommon for sarcoidosis patients to be treated in TB sanatoriums in the belief that they had pulmonary TB. In 1899, Boeck considered it a harmless new growth of connective tissue. He, however, soon realized that the histology of the disease resembled a tuberculoid granuloma. In 1914, Schaumann introduced the term ‘lymphogranulomatosis benigna’ and regarded sarcoidosis as a proliferative disease of the lymphatic tissue, analogous in some ways to Hodgkin’s lymphoma, but probably related to an infection either by a non-acid-fast variant of tubercle bacillus or an attenuated form of bovine tubercle bacillus. Pinner was convinced that sarcoidosis was ‘non-caseating’ TB. When the relationship between Mycobacterium tuberculosis could not be established, many clinical scientists turned their attention to phage-infected mycobacteria and atypical mycobacteria. Mankiewicz and Van Wallbeck proposed that sarcoidosis resulted from invasion of the tissues by phage-infected mycobacteria in individuals who lacked the capacity to form phage-neutralizing antibodies, but the hypothesis died without any confirmatory support. Many assiduous researchers have failed to find any acid-fast or non-acid-fast bacteria, cell wall defective L-forms, fungi and Mycoplasma from sarcoid granulomas.9,10 Hosoda and his colleagues11 have analysed health surveillance data in a Japanese work population of 460,000 employees who were annually radiographed and tuberculin tested. They found no causal relationship between TB and sarcoidosis.
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Sarcoidosis and tuberculosis
Propionibacterium acnes and Propionibacterium granulosum, which are ubiquitous organisms, are found in the skin, gut, lymph nodes and lung tissues of a large number of healthy individuals. Is the organism able to form systemic granulomas in humans and satisfy Koch’s postulates? We do not know.12,13 A viral cause of sarcoidosis was proposed by Lofgren and Lundback, who isolated the mumps–influenza–Newcastle group of viruses from six cases of cutaneous sarcoidosis. Hirshaut et al. found significantly high serum titres of antibody to herpes-like virus (HLV or Epstein-Barr virus) in 131 patients with sarcoidosis. The significance of the presence of human herpesvirus (HHV)-6 DNA in bronchoalveolar lavage fluid from a patient with sarcoidosis is uncertain because HHV-6 is also found in healthy controls. Biglino et al. failed to detect circulating interferon in any of the 45 patients with sarcoidosis. They concluded that a viral cause of sarcoidosis was unlikely. Nilsson et al.14 found genetic material from Rickettsia helvetica in the samples obtained at autopsy from two patients with sarcoidosis. Electron microscopic examination identified Rickettsia-like organisms within the granuloma, suggesting ongoing infection. A number of non-infective granulomatous agents have been considered as possible causes of sarcoidosis.1,14 There is a high incidence of sarcoidosis in the south-eastern area of the USA where, coincidentally, there is a high content of beryllium in the soil; however, the clinical, radiological and immunological differences between chronic beryllium disease and multisystem sarcoidosis are many. In the past, because of an interesting distribution of sarcoidosis in the pine region of south-eastern USA, allergy to pine pollens was considered to be the causative agent of the disease. The pine pollen is acid-fast and contains lipid components capable of inciting localized foreign body granulomas in animals.1 Epidemiological observations from countries other than the USA failed to support the relationship between the distribution of sarcoidosis and pine forests. Likewise, the role of clay eating, inhalation of peanut dust and hair-spray, and burning and chewing pine products were not found to play any role in causing sarcoidosis. Refvem demonstrated that silica and phospholipids from hen’s eggs showed no abnormal granulomatous reactivity in patients with sarcoidosis. Hurley and Shelley demonstrated that zirconium caused local granulomas, but not systemic sarcoidosis.1 Other elements, except beryllium, do not have granuloma-producing properties. The histological and clinical similarities between berylliosis and stage III sarcoidosis have led some to believe that a causal relationship between the two exists. Chronic berylliosis, however, lacks most of the features of acute sarcoidosis and almost all the features of extrapulmonary sarcoidosis. A recent major US study, ACCESS (A Case Controlled Etiologic Study of Sarcoidosis), found no evidence of association of sarcoidosis with exposures to wood, inorganic dusts, metals or pine pollens and closed the chapter on the possibility of any relationship between inorganic or organic antigens causing sarcoidosis. The search for the cause of sarcoidosis continues.15–17
CLINICAL FEATURES OF SARCOIDOSIS Lungs are the most commonly involved organs; more than 95% of the patients have an abnormal chest radiograph. In many of these patients the chest radiograph abnormalities resemble the
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changes caused by TB. Other commonly involved organs include the skin, liver, eyes, lymph nodes and the brain; however, no organ is exempt from sarcoidosis. The common clinical features of the disease are dyspnoea, cough, blurring of vision, red-eye, photophobia and joint pains. Lofgren’s syndrome, a combination of erythema nodosum and hilar adenopathy, is a manifestation of acute sarcoidosis and is commonly seen in Caucasian patients. Bilateral parotid gland enlargement, uveitis and facial palsy constitute Heerfordt’s syndrome. Lupus pernio, a special skin lesion of chronic sarcoidosis, may easily be confused with lupus vulgaris of TB. Fatigue, polyuria, thirst, heartblock, mono- or poly-neuritis, muscle weakness and anaemia may also complicate the disease.18
DIAGNOSIS The criteria for establishing the diagnosis of sarcoidosis include: 1. a compatible clinical or radiological picture (Fig. 97.1); 2. histological evidence of non-caseating granuloma (Fig. 97.2); and 3. negative bacterial and fungal stains and cultures of biopsied tissue, sputum and appropriate body fluids. If all the three steps are not carried out, the diagnosis of sarcoidosis remains in doubt since the clinical or radiological picture presents
A
B
C
D
Fig. 97.1 Chest radiograph features of sarcoidosis are conventionally classified into four stages. (A) Stage I: bilateral hilar adenopathy; (B) stage II: bilateral hilar adenopathy and parenchymal infiltrates; (C) stage III: parenchyma infiltrate with small lungs indicating fibrosis; and (D) stage IV: extensive destruction of the lung with fibrosis and bullae formation.
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Table 97.2 Differences between sarcoidosis and tuberculosis Features Age (years) Fever, weight loss Erythema nodosum Uveitis Skin involvement
Fig. 97.2 A typical non-caseating granuloma of sarcoidosis. This granuloma is solitary, compact, oval and solid. It is surrounded by a scanty layer of lymphocytes and has only a few giant cells. There are no eosinophils.
Table 97.1 Causes of granuloma formation Bacteria Mycobacterium tuberculosis Environmental mycobacteria Mycobacterium leprae Brucella species Spirochaetes Viruses Rickettsia Fungi Histoplasma capsulatum Coccidioides immitis Cryptococcus neoformans Blastomyces dermatitidis Paracoccidioidomycosis Parasites Toxoplasma Leishmania Schistosoma Trichinella
Minerals Beryllium, zirconium, cobalt Talc, silica Organic antigens Thermophilic actinomycetes Avian antigens Local sarcoid reactions Lymphoma, carcinoma Crohn’s disease Primary biliary cirrhosis Necrotizing sarcoid granulomas Vasculitis
too wide a differential diagnosis and histological evidence of non-caseating granulomas can be produced by many bacteria including tubercle and lepra bacilli, fungi, parasites and organic dust diseases (Table 97.1). Mycobacterium tuberculosis, one of the most frequent causes of an infective granulomatous response, produces granulomas with areas of caseation. In those patients with good resistance against the organism the granulomas remain discrete and non-caseating and may be indistinguishable from those seen in sarcoidosis. In these circumstances it is essential to detect the organism by special staining and culture.19 Strict adherence to the three-step diagnostic work-up presents practical problems particularly in developing countries. First, the patient, particularly when asymptomatic, may not be willing to have any invasive procedure carried out. Second, biopsy procedures depending on the site and technique carry a definite, albeit small, risk of morbidity and even mortality. Finally, trained personal and well-equipped laboratories and bronchoscopy facilities required to carry out these procedures are not available to the majority of the world’s population. Consequently, sarcoidosis
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Pleural effusion Involvement of small intestine Granulomas Acid-fast bacilli Tuberculin test Kveim–Siltzbach test Serum angiotensinconverting enzyme (ACE) Hypercalcaemia/ hypercalciuria Hilar adenopathy Pulmonary infiltrate Ghon focus Anti-TB drugs Corticosteroids World-wide distribution
Tuberculosis Common Uncommon Uncommon Rare (lupus vulgaris) Common Common
Sarcoidosis 20–50 Rare Common Common Common (lupus pernio, plaques) Rare Rare
Caseating Present Positive in most Negative Elevated in 5–10%
Non-caseating Absent Negative in most Positive Elevated in 60%
No
Yes
Unilateral Usually unilateral Yes Treatment of choice May be harmful alone Shrinking
Bilateral Usually bilateral No Unhelpful Helpful Increasing
patients are misdiagnosed and inappropriately treated as TB and vice versa. Nevertheless, clinical, radiological and laboratory difference between the two disorders are many and an accurate diagnosis can be made (Table 97.2).
TREATMENT As yet, we do not know the cause of sarcoidosis. This basic ignorance is reflected in the multiplicity of the therapeutic agents that have been used since the infancy of the disease. Throughout the history of sarcoidosis many extravagant, unsubstantiated and unconfirmed claims of benefit from a variety of treatments have been made. Many of these therapies have been recommended because of their use in the diseases thought to be, in some way, similar to sarcoidosis. Among these are chaulmoogra oil derivatives because of their effectiveness in treating leprosy; anti-TB drugs because of the hypothesis of a relationship to TB; gold, in part, on the same hypothesis; vitamin D preparations, in part by analogy to lupus vulgaris, a type of tuberculous skin lesion; chelating agents, probably by analogy to berylliosis and zirconium; radiotherapy, possibly by analogy to Hodgkin’s disease; chemotherapeutic agents, possibly by analogy to lymphoma; and paraaminobenzoic acid because of reported favourable results in scleroderma. On the other hand some agents have been used not on the basis of any established hypothesis, but on a trial basis. These drugs have included arsenic, sodium morrhuate, bismuth, vitamin C, colchicine, levamisole and melatonin.1 The natural course of spontaneous remission in many cases of sarcoidosis complicates the assessment of any therapy. There is no
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Sarcoidosis and tuberculosis
CASE 1: TUBERCULOSIS MISDIAGNOSED AS SARCOIDOSIS A 40-year-old Asian woman presented with a 3- to 4-month history of fatigue, low-grade fever, cough, anorexia and a weight loss of about 2–5 kg. She denied chills, haemoptysis, ‘red-eye’, skin lesions or joint pains. Physical examination was normal. A chest radiograph showed a left upper lobe infiltrate. Three good samples of sputum showed no acid-fast bacilli and fungi. The erythrocyte sedimentation rate (ESR) was 60 mm in the first hour. An intermediate strength tuberculin test showed 35 mm of induration and erythema. The patient was given isoniazid 300 mg/day, ethambutol 1 g/day, pyrazinamide 750 mg twice a day and streptomycin 750 mg/day for 3 months. The treatment was prescribed for 6 months, but the patient, after a few weeks, discontinued therapy. Six months later her symptoms returned. A chest radiograph showed no infiltrate but mediastinal lymph nodes were seen. A chest computed tomography (CT) scan confirmed the presence of mediastinal adenopathy; hilar nodes were not enlarged. A gallium 72-hour chest scan showed uptake in the mediastinal lymph nodes. The serum angiotensin-converting enzyme level was normal. The ESR was 42 mm in the first hour. Broncho alveolar lavage fluid analysis showed 42% lymphocytes. A transbronchial biopsy showed a non-caseating granuloma. The diagnosis of sarcoidosis was entertained. She was given prednisone 20 mg/day and isoniazid 300 mg/day. After 3 months, the patient experienced low-grade fevers and fatigue. She was examined by a specialist who recommended another mediastinal biopsy and culturing the tissue for tubercle bacilli.
Why did the specialist insist on repeating a biopsy? If a patient with sarcoidosis has a positive tuberculin test (15 mm induration) then there is a strong possibility that the patient either has TB masquerading as sarcoidosis or both diseases. The diagnosis of TB cannot be excluded if the patient has not had cultures of sputum, appropriate body fluid or tissue biopsy specimens. Second, the patient either did not strictly adhere to the anti-TB regimen or her recurrence was a manifestation of the paradoxical response to anti-TB therapy. Finally, sarcoidosis patients do not have persistent fevers and weight loss, high ESR or mediastinal adenopathy in the absence of hilar involvement. For these reasons the specialist was justified in recommending a second mediastinal biopsy. It showed non-caseating and caseating granulomas; cultures grew M. tuberculosis. The patient responded to aggressive, supervised anti-TB treatment.
At the age of 21 years this previously healthy African American patient developed low-grade fever, night sweats and neck pain. His grandfather had died of pulmonary TB. Otherwise, family, past and social histories were not helpful. Physical examination did not reveal tenderness of the neck, cervical adenopathy or localized neck swelling. Complete blood cell count, serum electrolytes, liver function tests, calcium and serum proteins were normal. An intermediate tuberculin skin test was positive with a 20-mm induration. Chest radiograph was normal. The cervical spine film showed a lesion consistent with TB of the spine. He was treated with three anti-TB drugs for 18 months. Fever, night sweats and neck pain subsided. Soon after, the patient developed a diffuse maculopapular rash over his trunk and extremities. The rash did not itch or ulcerate and did not bother the patient much. He had no fever, weight loss, night sweats or neck pain. Biopsy of one of the lesions showed noncaseating granulomas. Special stains and cultures of the tissue showed no tubercle bacilli or fungal elements. His chest radiograph showed diffuse nodular infiltrate. The tuberculin test now was 7 mm erythema and 5 mm induration. He also developed hyper-gammaglobulinaemia and severe hypercalcaemia (Fig. 97.3). The diagnosis of sarcoidosis was entertained and he was given prednisone 20 mg/ day. His chest radiograph became normal, the skin lesions disappeared, and the hypercalcaemia subsided. Prednisone was reduced and slowly discontinued over a period of 18 months. The patient remained free of TB and sarcoidosis when last seen in 1980.
Did this patient have both sarcoidosis and tuberculosis or only tuberculosis? The cause of sarcoidosis remains unknown. There are two schools of thought: one believes that sarcoidosis is a syndrome, like bronchial asthma, with many causative agents, whereas the other is of Diagnosis
TB Cervical spine
Sarcoidosis: skin, liver, granuloma Prednisone
Treatment
Antituberculosis drugs: INH, STM, PAS
Chest radiograph Intermediate tuberculin Serum proteins (g/100 mL)
CASE DISCUSSION
CASE 2: SARCOIDOSIS AND TUBERCULOSIS OCCURRING IN THE SAME PATIENT
Normal
Mil. infil.
20 mm
10 mm
Normal
5 4
Albumin
3
Globulin
17 16 Serum calcium (mg/100 mL)(N: 911)
single cure for sarcoidosis. Corticosteroids are effective. The usual dose is 20–40 mg of prednisone daily for 6–12 months gradually reduced to maintenance levels of 5–10 mg daily. Hydroxychloroquine is useful in chronic skin lesions, hypercalcaemia and neurosarcoidosis. Methotrexate, azathioprine, cyclophosphamide and chlorambucil have been used. Thalidomide, pentoxifylline, etanercept, cellsept and infliximab have been found to be effective in selected patients with sarcoidosis who do not respond to corticosteroids or who develop severe side effects to the therapy.20
15 14 13 12 11 10 9
1968
1969
1970
1971
Fig. 97.3 Clinical course of sarcoidosis and TB in a 21-year-old African American patient (case 2).
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the opinion that sarcoidosis is a single disease, the causative agent of which is unknown. The theory of tuberculous aetiology continues to have a lingering support because of: 1. the histological similarity between sarcoidosis and TB; 2. the occurrence of TB before, during, or following clinical sarcoidosis; and 3. occasional identification and isolation of both M. tuberculosis and environmental mycobacteria from non-caseating granulomas from a few patients with sarcoidosis. This patient had both; sarcoidosis was followed by TB. Both illnesses not only showed their distinct clinical, laboratory and radiological features but also responded appropriately to the respective treatments.
CASE 3: TUBERCULOSIS MISDIAGNOSED AS SARCOIDOSIS A 25-year-old African American man was admitted to hospital with right upper-quadrant abdominal pain. His pain subsided overnight and no longer remained a problem. Complete blood count, liver and renal function tests and ESR were normal. A chest radiograph, however, showed hilar adenopathy (Fig. 97.4). The differential diagnoses of hilar adenopathy in an otherwise asymptomatic man includes sarcoidosis, coccidioidomycosis, histoplasmosis, lymphoma and TB. Because he was asymptomatic the diagnosis of sarcoidosis/lymphoma was considered and a mediastinal biopsy was performed. The lymph node biopsy showed caseating granulomas with acid-fast bacilli. Later, his tuberculin test was found to be positive at 20 mm induration. Had the tuberculin been performed earlier, mediastinoscopy could have been avoided, because it is unusual to have such a strongly positive tuberculin test in either sarcoidosis or lymphoma.
Fig. 97.4 A chest radiograph showing hilar adenopathy in a 25-year-old African American man with no pulmonary symptoms (case 3).
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CASE 4: LUPUS VULGARIS MISDIAGNOSED AS CHRONIC SARCOID PLAQUE A 39-year-old African American man presented with chronic annular lesion with peripheral thickening and nodules consistent with the diagnosis of sarcoidosis (Fig. 97.5). A chest radiograph showed no active disease but an old Ghon focus. The patient had no symptoms and the diagnosis of cutaneous sarcoidosis was entertained. A biopsy showed a non-caseating granuloma. However, cultures showed M. tuberculosis. His lesion resembled chronic sarcoidosis plaques, but his positive tuberculin and the positive culture for M. tuberculosis established the correct diagnosis.
CONCLUSION Sarcoidosis is a multisystem granulomatous disease of unknown cause(s). The diagnosis is established most securely when wellrecognized clinical–radiological findings are supported by histological evidence of widespread non-caseating epithelioid granulomas in more than one tissue system. Multisystem sarcoidosis must be differentiated from TB because the two diseases may present with similar radiological and histological features. The tuberculin test is negative in the majority of patients with sarcoidosis. A strongly positive tuberculin tests rules out active sarcoidosis.
Fig. 97.5 An unusual annular lesion in a patient whose chest radiograph showed a Ghon focus.
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Sarcoidosis and tuberculosis
REFERENCES 1. Scadding JG, Mitchell D. Sarcoidosis, 2nd edn. London: Chapman and Hall, 1985: 36–42. 2. Sharma O. Definition and history of sarcoidosis. Eur Respir Mon 2005;32:1–12. 3. Hunninghake GW, Costabel U, Ando M, et al. ATS/ ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/ World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:149–173. 4. Schurmann M, Lympany P, Reichel P, et al. Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med 2000;162:861–864. 5. Foley P, McGrath D, Petrek M, et al. HLA-DRB1 position 11 residues are a common protective marker for sarcoidosis. Am J Respir Cell Mol Biol 2001;25:272–277. 6. Maliarik M, Chen K, Major M, et al. Analysis of HLA-DPB1 polymorphism in African-Americans
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with sarcoidosis. Am J Respir Crit Care Med 1998;158:111–114. Rutherford R, Staedtler F, Kehren J, et al. Functional Genomics and prognosis in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004;21:10–18. Silverman E, Palmer J. Case-control association studies for the genetics of complex respiratory diseases. Am J Respir Cell Med Biol 2000;22:645–648. Almenoff P, Johnson A, Lesser M, et al. Growth of acid-fast L forms from the blood of patients with sarcoidosis. Thorax 1996,51:530–533. Brown S, Brett I, Almenoff P, et al. Recovery of cell-wall deficient organisms from blood does not distinguish between patients with sarcoidosis and control subjects. Chest 2003;123:413–417. Hosoda Y, Sasagawa S, Yamaguchi T. Sarcoidosis and tuberculosis: epidemiological similarities and dissimilarities. Sarcoidosis Vasc Diffuse Lung Dis 2004;21:85–93. Ishige I, Usui Y, Takemura T, et al. Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet 1999;354:120–123.
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13. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Cin Microbiol 2002;40:198–204. 14. Nilsson K, Pahlson C, Lukinius A, et al. Presence of Rickettsia helvetica in granulomatous tissue from patients with sarcoidosis. J Infect Dis 2002; 185:1128–1138. 15. Moller D, Chen E. What causes sarcoidosis? Curr Opin Pulm Med 2002;8:429–434. 16. Newman L. Aetiologies of sarcoidosis. Eur Respir Mon 2005;32:23–48. 17. Drake W, Newman L. Mycobacterial antigen may be important in sarcoidosis pathogenesis. Curr Opin Pulm Med 2006;12:359–363. 18. Mihailovic-Vucinic V, Sharma O. Atlas of Sarcoidosis. London: Springer-Verlag, 2005. 19. Gal A, Koss M. The pathology of sarcoidosis. Curr Opin Pulm Med 2002;8:445–451. 20. Baughman R. Therapeutic options for sarcoidosis: new and old. Curr Opin Pulm Med 2002;8:464–469.
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Management of an HIV-positive patient with smear-negative pulmonary tuberculosis Anthony D Harries
This chapter describes the course and management of an African patient who becomes ill, is tested and counselled for the human immunodeficiency virus (HIV), is found to be HIV-seropositive, and some time later is diagnosed with smear-negative pulmonary TB. This is a common scenario, and reflects the huge burden of HIV and TB faced by communities and individuals living in many countries in sub-Saharan Africa. This region, home to 10% of the world’s population, bears the brunt of the global HIV and TB epidemic. At the end of 2005, of 40.3 million adults and children living with HIV/acquired immunodeficiency syndrome (AIDS) in the world, 25.8 million (64%) were residing in sub-Saharan Africa, the most severely affected countries being in southern Africa.1 Each year, an estimated 9 million people around the world develop TB for the first time and over 1.5 million die with or from the disease.2 Although the TB incidence rate is falling or stable in five out of six World Health Organization (WHO) regions in the world, the global TB incidence rate is still growing at 1% per annum. This growth has been fuelled from the WHO Africa region where a third of new TB patients were infected with HIV in 2003.3 Good management of HIV and TB in sub-Saharan Africa is crucial for global HIV and TB control, and the important Millennium Development Goals will not be reached in 2015 unless due attention is paid to the details of such management. This chapter will take the reader through the illness and management of an HIVpositive patient from Malawi, drawing attention to details of prevention, diagnosis, and treatment that, if properly implemented, could result in good outcomes for the patient and indirectly for the community.
THE FIRST ILLNESS AND DIAGNOSIS OF HIV INFECTION A 26-year-old African woman living in one of the semi-urban townships in the southern region of Malawi presents to the local hospital with a complaint of mild weight loss over the previous 4 weeks and pain over the left cheek. The previous year her 35-year-old husband died of a ‘chronic illness’ and her 1-yearold son died of a respiratory condition. Her past medical history includes an episode of ‘shingles’ (herpes zoster) in the previous year, and a similar episode of pain over the left cheek several months previously that responded to antibiotics. On examination, she has a left maxillary sinusitis and mild malnutrition. The attending clinician prescribes a course of oral amoxycillin for the sinusitis, and refers the patient to the HIV testing and counselling unit of the
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hospital. She is duly counselled, tested, and found to be HIVseropositive. She is given information about safe sex and positive living, and is referred to the antiretroviral clinic for further assessment and clinical staging. She is assessed by the clinician and classified correctly as being in WHO clinical stage 2. She is advised to continue with the medication and report back to the hospital in case of other illnesses.
COMMENT In view of the patient’s medical and social history, she is appropriately referred for HIV testing and counselling and is found to be HIV-seropositive. She is also referred for clinical assessment and has been correctly staged by WHO criteria.4 HIV-positive patients in WHO clinical stage 2 are not eligible for antiretroviral therapy (ART). However, she is potentially eligible for two important prophylactic interventions, cotrimoxazole preventive therapy (CPT) and isoniazid preventive therapy (IPT), which her caregivers have failed to assist her with.
Cotrimoxazole preventive therapy (CPT) Cotrimoxazole is a cheap, broad-spectrum antibiotic that has important activity against a range of HIV- and non-HIV-related pathogens. It is used in industrialized countries mainly for primary and secondary prophylaxis in HIV-positive persons to prevent Pneumocystis jiroveci pneumonia and Toxoplasma gondii encephalitis. Its use in sub-Saharan Africa was almost non-existent, until a seminal randomized placebocontrolled study in Cote d’Ivoire in 1998 showed that cotrimoxazole in HIV-positive patients with TB was associated with a 48% reduction in deaths.5 There were significantly fewer hospital admissions due to septicaemia and enteritis in the cotrimoxazole group than in the placebo control group, and the drug was also well tolerated with only 1% of patients reporting skin reactions. The results of this study were an important factor in persuading the WHO and UNAIDS in 2000 to issue provisional recommendations that cotrimoxazole be given to all patients in Africa living with AIDS including HIV-positive patients with TB. Despite this blanket recommendation, its routine use in most African countries remained minimal because of: 1. concerns about efficacy in areas with high rates of bacterial resistance to the antibiotic; and 2. a fear that widespread use of cotrimoxazole would cause malaria parasites to become cross-resistant to sulphadoxine–pyrimethamine (Fansidar, SP), a drug that is still first-line therapy for malaria in several endemic countries.
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However, the past 5 years have seen a number of published studies from Uganda, Zambia, South Africa, and Malawi on the efficacy, effectiveness, safety, and feasibility of cotrimoxazole preventive therapy: these studies, well summarized in a recent review paper, have all shown significant benefits in terms of a reduction in morbidity and mortality in HIV-positive patients, including those with TB.6 In children aged 5–15 years in Mali, CPT has also not selected for sulphadoxine–pyrimethamineresistant malaria parasites, thus providing some reassurance that the efficacy of sulphadoxine–pyrimethamine in treating falciparum malaria will be maintained. In 2004, an expert WHO consultation on CPT firmly recommended the use of cotrimoxazole in HIV-positive adults and children (Table 98.1). The patient is HIV-positive, is classified as being WHO stage 2, is eligible for CPT, and would have benefited from this intervention.
Isoniazid preventive therapy (IPT) HIV, by targeting CD4 T-lymphocytes and reducing cellular immune function, is the most important risk factor for development of active TB. Not only does HIV increase the risk of reactivating latent Mycobacterium tuberculosis (MTB), but it also increases the risk of rapid TB progression soon after infection or reinfection with MTB. In persons infected with MTB only, the risk of clinically significant disease within the first year after infection is approximately 1.5%, and it thereafter decreases to reach after 5 years, a fairly stable risk of 0.1% per annum. Conversely, in persons coinfected with MTB and HIV, the annual risk of active TB is 5–15%. The risk starts within the first year of HIV infection,7 increases as the immune system becomes more compromised, and over the course of an infected person’s life is approximately 50%. The risk can be considerably reduced by isoniazid preventive therapy (IPT). Several randomized trials have shown that IPT is effective in reducing the incidence of TB in HIV-infected patients. A Cochrane review of 11 trials showed that overall IPT reduced the risk of active TB by 33%.8 Among individuals who were tuberculin skin test positive, IPT reduced the risk of active TB by 62%. Isoniazid is more effective, safer, and cheaper than rifampicin- and pyrazinamide-containing regimens, and is the preferred drug for this intervention. IPT for the prevention of TB in HIV-positive individuals is policy both internationally and nationally for many Table 98.1 Use of cotrimoxazole preventive therapy (CPT) in adults and children Policy recommendations Adults CPT for all symptomatic HIV-positive adults (stages 2, 3, and 4) CPT for HIV-positive adults with CD4 count 500 cells/mm3 Children CPT for all children born to HIV-positive mothers CPT for all HIV-positive children < 5 years, regardless of symptoms CPT for all symptomatic HIV-positive children 5 years Dosages of CPT Adults 480 mg twice a day (1 tablet twice daily) Children Children aged 6–14 years: 480 mg once a day (1 tablet daily); children aged 6 months–5 years: 240 mg once a day (1/2 tablet daily); children aged 6 weeks to 6 months: 120 mg once a day (1/4 tablet daily) Contraindications for CPT Adults and children Known allergy to cotrimoxazole; first trimester of pregnancy for pregnant women
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industrialized countries. WHO and UNAIDS also issued a joint policy statement on preventive therapy in 1998 that recommended that IPT should be part of a package of care for people living with HIV/AIDS, and the use of IPT has since been emphasized in the WHO Interim Policy on TB and HIV.9 Despite these policies, few countries in sub-Saharan Africa have adopted widespread use of IPT. This is because: 1. several steps must be taken which include identification of HIV-positive subjects, screening to exclude active TB, drug adherence, and monitoring; 2. fear of isoniazid resistance consequent upon monotherapy; and 3. concerns about adverse effects, especially hepatotoxicity. The fears and concerns are largely unjustified. The use of IPT has not led to any documented increase in isoniazid resistance, although this could be a problem if the drug is used as monotherapy in cases where active TB has not been excluded. Isoniazid has also not been identified as a cause of significant drug-related side effects in studies of HIV-positive persons reported to date. The patient, then, could have been screened for active TB, and if there was no evidence of active disease, could have been started on IPT. The duration of treatment is 6–12 months. However, the optimal length of prophylactic treatment is not known and studies are currently ongoing to try and answer this important question.
DIAGNOSIS OF SMEAR-NEGATIVE PULMONARY TUBERCULOSIS About 6 months after the first illness, the patient develops a productive cough, night sweats, and weight loss. She goes several times to the hospital outpatient department and on each occasion is prescribed a course of antibiotics. These visits and the antibiotics result in an initial improvement of the cough, which always recurs a week or 2 after the treatment. After an illness of 8 weeks, she is asked to submit three sputum specimens for acid-fast bacilli (AFB). These are reported as negative. She is reassured by the clinic that she does not have TB and is given yet another course of antibiotics. One month later, she is seen again because of deteriorating health status and continuing weight loss, and is referred for a chest radiograph. This is performed, and she is found to have bilateral lower lobe infiltrations. The hospital clinician reviews the chest radiograph, and, in light of the history and her HIV-serostatus, diagnoses smear-negative pulmonary TB. She is referred to the district hospital TB officer, where she is registered and commenced on anti-TB treatment.
COMMENT The patient’s management is unfortunately typical for many patients living in resource-constrained countries in sub-Saharan Africa. Clear guidelines, from WHO and at country level, exist for suspecting and diagnosing pulmonary TB – a cough for 3 weeks, no response to antibiotics, three sputum smears for AFB, and, if these are negative, a chest radiograph. In many cases, these are ignored or not adhered to, resulting in long delays between the start of illness and the diagnosis of pulmonary TB. Patients with pulmonary TB may also have a coexistent bacterial infection, and a course of antibiotics may improve the respiratory symptoms temporarily leading to a mistaken impression that pneumonia was the cause of the illness. These delays and mistaken
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impressions have two important adverse consequences: they compromise the prognosis of the individual patient, who then presents with late stage TB, and they facilitate the transmission of MTB infection between the index patient and close household contacts. The diagnosis of smear-negative pulmonary TB was made after 3 months in this particular patient. However, the diagnosis of this condition is fraught with difficulties and there are many pitfalls involved in trying to make a correct diagnosis.10 First, the presentation is non-specific, and a number of HIV- and non HIV-related diseases can give a similar presentation (Table 98.2). All of these conditions will result in negative sputum smears for AFB and many will be associated with an abnormal chest radiograph. If the clinical assessment of the patient is cursory and rushed, then an erroneous diagnosis of smear-negative pulmonary TB can be made. Treatment of left ventricular failure with anti-TB medication is pointless and dangerous. An audit of patients being treated for smearnegative pulmonary TB in various Malawian hospitals found that 14% had a non-TB diagnosis and consequently were receiving the wrong treatment for their condition.11 Second, sputum smears can be falsely negative in patients who in fact have smear-positive pulmonary TB. The main causes of falsenegative sputum smears are shown in Table 98.3. A wrong sputum smear diagnosis has considerable disadvantages for the patient and the close family. Many TB programmes in resource-poor settings opt, usually for reasons of expense, to treat smear-negative pulmonary TB patients with a regimen inferior to that used for smearTable 98.2 Alternative non-pulmonary tuberculosis diagnoses in a patient with chronic cough suspected to have tuberculosis Diagnosis
Pointers to the correct diagnosis
Left ventricular failure
Dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, haemoptysis, signs of heart failure Intermittent symptoms, generalized wheezing, symptoms wake the patient at night Dyspnoea, generalized wheezing, signs of right heart failure (cor pulmonale), history of smoking Shorter history, pleuritic chest pain, high fever, response to antibiotics Dry, non-productive cough, dyspnoea, chest findings unremarkable Chronic history, large amounts of purulent sputum, finger clubbing Risk factors (smoking, working in asbestos mines), older age
Asthma Chronic obstructive airways disease Pneumonia Pneumocystis jiroveci pneumonia Bronchiectasis Bronchial carcinoma
Table 98.3 Main causes of false-negative sputum smears in patients with pulmonary tuberculosis Sputum collection Sputum processing Smear examination Laboratory
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Inadequate sample of sputum; sputum stored too long before smear preparation; incorrect labelling of sputum container Faulty sampling of specimen for smear preparation Faulty staining of smear Inadequate time spent examining smear; inadequate attention to smear examination Shortage of trained laboratory technicians; poorly functioning light microscopes; lack of quality control
positive pulmonary TB. National guidelines usually advise that close contacts of index smear-positive pulmonary TB patients are actively screened for TB, and that children aged 5 years and below are offered isoniazid preventive therapy provided that active TB disease is excluded. Such contact tracing guidelines do not apply to close contacts of index smear-negative pulmonary TB patients. Third, chest radiograph interpretation in HIV-positive patients, particularly those with marked degrees of immunosuppression, is difficult. The classical radiographic hallmarks of pulmonary TB are cavitation, apical distribution, bilateral distribution, pulmonary fibrosis, shrinkage, and calcification. HIV-positive patients, because of failure to mount a good inflammatory response to tubercle bacilli, often have atypical radiographic findings of TB, such as infiltrates with no cavitation, involvement of the lower lobes, hilar and paratracheal lymphadenopathy, and sometimes a completely normal chest radiograph.
TREATMENT OF SMEAR-NEGATIVE PULMONARY TUBERCULOSIS The patient is registered for anti-TB treatment with a 2-month intensive phase of isoniazid, rifampicin, and pyrazinamide (2RHZ), followed by a 6-month continuation phase of isoniazid and ethambutol (6HE), according to Malawi TB National Guidelines. The initial phase with rifampicin is to be directly observed therapy (DOT), by either a health worker or family guardian, and the continuation phase is to be given unsupervised with drugs collected on a monthly basis from the hospital TB office.
COMMENT The patient has been appropriately started on the standard smearnegative pulmonary TB regimen in current use in Malawi. However, there is a growing recognition that a 6-month regimen of rifampicin throughout (2RHZ(E)/4RH) is superior to an 8-month regimen where the continuation phase is isoniazid and ethambutol.12 The 6-month regimen has the advantage of being 2 months shorter, more powerful as a result of the broad-spectrum action of rifampicin against other bacterial infections, and associated with a reduced risk of relapse after treatment has been completed. The disadvantage is that anti-TB treatment must be given by DOT for the whole duration of therapy, and rifampicin must be placed in all health centres, thus increasing the potential risk of drug abuse in the community. Rifampicin is well known amongst African communities as a useful drug for skin, respiratory, gastrointestinal, and venereal diseases, and there are temptations for inappropriate use and theft. Rifampicin throughout anti-TB treatment also makes adjunctive treatment with antiretroviral drugs difficult (see below).
ADJUNCTIVE TREATMENT FOR HIV INFECTION The patient, known to be HIV-positive, starts anti-TB treatment with rifampicin, isoniazid, and pyrazinamide and a few days later is started on CPT, 480 mg twice a day, to be continued indefinitely. She is referred to the antiretroviral (ARV) clinic and assessed to be in WHO clinical stage 3. The hospital in which the clinic is based has no machine for measuring CD4 lymphocyte counts, but,
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Management of an HIV-positive patient with smear-negative pulmonary tuberculosis
on the basis of being in WHO clinical stage 3, the patient is judged eligible for ART. She receives a group counselling education session about ART, where the principles of treatment are explained using a standard ‘flip chart’ and advice is given about storage of medication, adherence, and side effects. She is told that she will start ART after the initial phase of anti-TB treatment is completed and she is on isoniazid and ethambutol (EH). She spends 2 weeks in hospital, returns home to complete the initial phase of anti-TB treatment, and comes back to the hospital when she is on EH to start Malawi’s first-line ART regimen of stavudine, lamivudine, and nevirapine. She is given 2 weeks of stavudine–lamivudine–nevirapine, 1 tablet in the morning, and stavudine–lamivudine, 1 tablet in the evening. This starter phase is used to minimize the risk of cutaneous reactions from nevirapine: thus, nevirapine is administered as half-dose for 2 weeks and then full dose after that. There are no problems with the starter phase, and she then commences stavudine–lamivudine–nevirapine, 1 tablet twice a day. She is asked to come to the ARV clinic at the hospital on a monthly basis to collect her ART drugs. This is synchronized with her visits to the TB office, where she also must report on a monthly basis to collect isoniazid/ethambutol and cotrimoxazole.
COMMENT The patient is receiving CPT along with anti-TB treatment, and this should reduce her risk of HIV-related morbidity and mortality. However, the biggest impact on the course of her HIV disease will come from ART. The patient has been correctly assessed as being in WHO clinical stage 3,4 and in the absence of any CD4 lymphocyte counting capacity, she is eligible on this basis for antiretroviral treatment.
Antiretroviral treatment HIV adversely affects the outcome of anti-TB treatment. First, case fatality rates are increased.13 In sub-Saharan Africa, up to 30% of smear-positive pulmonary TB patients coinfected with HIV die before the end of their anti-TB treatment, and the mortality amongst those with smear-negative pulmonary TB is even higher, presumably because such patients have more advanced immunodeficiency. The ‘excess deaths’ observed among HIV-positive TB cases are partly attributable to TB and partly to severe HIV-related problems such as septicaemia, anaemia, super-added pneumonia, Kaposi’s sarcoma, and cryptococcal meningitis. Second, rates of recurrent TB after successful completion of therapy are more common in HIV-positive than in HIV-negative patients.13 Some cases of recurrent TB are true relapses (i.e. due to reactivation of persisting tubercle bacilli that have not been killed by anti-TB drugs) while others are due to reinfection with a new organism. ART may improve anti-TB treatment outcomes by reducing mortality and the risk of recurrent TB. HIV-positive pulmonary TB is classified in WHO clinical stage 3 and extrapulmonary TB in WHO clinical stage 4. HIV-positive patients in stages 3 and 4 are all potentially eligible for ART. Many countries in Africa are scaling up ART using a first-line regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). The preferred option in nearly two-thirds of African countries is a triple combination of stavudine–lamivudine–nevirapine, the one used for the patient in Malawi, which is manufactured generically and relatively cheaply as a fixed-dose tablet, taken twice a day. Other options are substituting zidovudine for stavudine and efavirenz for nevirapine.
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The problem with treating TB patients and using the preferred ART option is that a proportion of HIV-positive TB patients have CD4 lymphocyte counts > 350 cells/mm3, and in these patients ART may be unnecessary and potentially dangerous if nevirapine-based treatment is used.14,15 Nevirapine-induced toxicity (including skin reactions and hepatic dysfunction) occurs at higher rates in women with CD4 counts > 250 cells/mm3 and men with CD4 counts > 400 cells/mm3. The introduction of ART during anti-TB treatment in patients in industrialized countries is associated with reduced mortality, but the evidence base for such an effect in resource-poor countries remains to be established. There is good evidence in Africa that ART reduces the risk of active TB in HIV-positive patients, and this risk declines the longer ART is continued provided there is good adherence and the patient is maintaining good CD4 lymphocyte counts.16 Thus, in principle ART should decrease the risk of recurrent TB, but again the evidence base for such an effect is lacking. Concomitant use of ART during anti-TB treatment is also not easy, and there are a number of issues which need to be considered in every case.
Additive adverse drug reaction ART and anti-TB drugs may result in overlapping toxicity (see Table 98.4). Particularly important is the peripheral neuropathy caused by both isoniazid and stavudine. This can be partly prevented by ensuring that the patient also takes pyridoxine, 12.5 mg daily. Drug–drug interactions The NNRTIs (and also protease inhibitors, which are being used in second-line regimens in resource-poor countries) are metabolized mainly through cytochrome P450 (CYP450) enzymes. Rifampicin induces CYP450, leading to a reduction in the plasma concentration of nevirapine by 30–40% and efavirenz by 20–25%.14,15 There is concern that reduced nevirapine concentrations will lead to emerging drug resistance and treatment failure. Increasing the dose of nevirapine to compensate for this interaction may increase the risk of toxicity, and it also makes administration of therapy more complicated. The standard wisdom is therefore to avoid concomitant use of nevirapine and rifampicin. Clinicians in resource-poor countries are therefore faced with two choices. For TB programmes using rifampicin in the initial phase only, ART can be initiated in the continuation phase of anti-TB treatment as was done in the Malawian patient. The Table 98.4 Adverse drug reactions from ART and anti-TB drugs used together Adverse reaction
Main ART drug involved
Main anti-TB drug involved
Peripheral neuropathy Hepatitis
Stavudine Nevirapine
Gastrointestinal dysfunction (diarrhoea, abdominal pain) Skin rash
All drugs
Isoniazid Rifampicin, isoniazid, pyrazinamide All drugs
Central nervous system dysfunction
Nevirapine
Efavirenz
Rifampicin, isoniazid, pyrazinamide Isoniazid
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problem with this approach is that many HIV-related TB deaths occur during the first few months of anti-TB treatment, thus reducing the potential benefit of ART. For clinicians wanting to start ART during the initial phase of anti-TB treatment or for TB programmes using rifampicin throughout, efavirenz can be substituted for nevirapine. Efavirenz is generally well tolerated, although patients commonly experience transient central nervous system symptoms that can be ameliorated by taking the drug before going to bed at night. The problems with efavirenz are that the drug is teratogenic (and at least half of treated patients are women), there is still debate about whether the dose should be 600 or 800 mg daily,14 there is currently no fixed dose generic combination with stavudine and lamivudine, and the drug regimen is more expensive than the fixed-dose combination of stavudine–lamivudine–nevirapine. Data from Thailand and Brazil suggest that the standard 600-mg dose of efavirenz is sufficient in patients whose mean body weight is below 60 kg, and the general consensus is that 600 mg efavirenz should be used until further data are accumulated to support alternative dosing. Other options such as substituting rifabutin for rifampicin (rifabutin is a less potent inducer of CYP450) or using triple NRTIs (e.g. zidovudine–lamivudine–abacavir) are not currently feasible because of cost. There is some evidence that while nevirapine levels are reduced by rifampicin, they are still in the effective range. Further studies on safety, pharmacokinetics, and efficacy of concomitant nevirapine and rifampicin are urgently needed to resolve this issue.
recommend that patients with a CD4 count < 200 cells/mm3 should initiate ART as soon as anti-TB treatment is tolerated, i.e. within 2–4 weeks.4 For patients with CD4 counts > 200 cells/ mm3, ART should be started after the initial 2 months of antiTB treatment have been completed. In patients for whom CD4 counts are not available, ART should be initiated after the first 2 months of anti-TB treatment.
Immune reconstitution disease (IRD) The initiation of ART during anti-TB treatment can lead to IRD, manifested as worsening of symptoms and signs or the appearance of new TB lesions. This problem occurs more frequently if ART is started early in the course of anti-TB treatment and if the patient has an initial low CD4 lymphocyte count.17 The majority of cases have been reported to occur within the first 2 months of ART, with a median duration of ART of 4 weeks. The illness is generally managed with anti-inflammatory drugs, including corticosteroids in severe cases.
The patient is stabilized on anti-TB treatment with isoniazid and ethambutol, cotrimoxazole, and the generic combination of stavudine–lamivudine–nevirapine. She begins to experience symptoms of peripheral neuropathy. This is initially managed with pyridoxine (vitamin B6) 50 mg daily, adding amitriptyline in increasing doses up to 50 mg at night and adding ibuprofen 400 mg twice a day. Unfortunately, the burning sensation becomes intolerable and she develops some weakness of the lower extremities. After 4 months, the stavudine is substituted with zidovudine. The peripheral neuropathy begins to resolve, and she completes antiTB treatment without any further problems.
When to start ART The optimal time to start ART in HIV-positive TB patients is not known, and there are arguments for early as well as delayed antiretroviral therapy (Table 98.5). Current WHO guidelines
Table 98.5 When to start ART in HIV-positive tuberculosis patients Early ART start
Delayed ART start
2–4 weeks after start of anti-TB treatment (during initial phase of anti-TB treatment) Advantages May reduce early TB–HIV mortality
8 weeks after start of anti-TB treatment (during continuation phase of anti-TB treatment)
Disadvantages Increased pill burden Additive drug-related toxicities Rifampicin–nevirapine interaction Increased risk of IRD IRD, immune reconstitution disease.
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Patient more stable; pill burden less; continuation phase may not have rifampicin; less risk of IRD May have reduced impact on case fatality
Where to provide ART In most of sub-Saharan Africa, ART is delivered in hospital clinics while anti-TB treatment is delivered in the continuation phase from health centres as a result of decentralized management over the past 5–10 years. Expecting TB patients on a monthly basis to collect their anti-TB drugs from health centres and then come from remote parts of the district to collect ART drugs from the hospital is unrealistic and will result in few deserving patients actually receiving treatment for AIDS. Patients coming to the same facility will also usually have to queue in one office for anti-TB drugs and queue in another office for ART. Innovative solutions to this conundrum must be found if HIV-positive TB patients are to be properly served.18
PROGRESS ON ANTITUBERCULOSIS TREATMENT AND ART
COMMENT One of the important side effects of stavudine is peripheral neuropathy. Management is symptomatic and has been carried out appropriately in this patient. However, in a proportion of patients the symptoms deteriorate and the drug must be substituted with another NRTI, which is usually AZT. Zidovudine does not cause peripheral neuropathy, but it may lead to anaemia and patients need to have their haemoglobin measured at regular intervals.
POST-TUBERCULOSIS TREATMENT Following anti-TB treatment the patient is kept on the generic combination of zidovudine–lamivudine–nevirapine and cotrimoxazole, and when last seen she is well and back to work.
COMMENT The patient will now be followed up in the ARV clinic. She is to be maintained indefinitely on cotrimoxazole. Whether this is appropriate is unknown. In developed countries, where cotrimoxazole is mainly used as a prophylactic against P. jiroveci pneumonia,
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the antibiotic is usually stopped when the CD4 count is > 200 cells/mm3. In sub-Saharan Africa, where P. jiroveci pneumonia is an uncommon opportunistic infection in HIV-positive adults, cotrimoxazole is thought to have its main benefit in preventing falciparum malaria and bacterial infections. Plasmodium falciparum malaria increases viral load in HIV-positive adults, and may therefore be an important cause of enhanced HIV transmission and accelerated disease progression. Preventing malaria may therefore benefit the long-term prognosis of the HIV-positive patient on ART. A study from Uganda showed that a combination of cotrimoxazole, antiretroviral therapy, and insecticide-treated bed nets substantially reduces the frequency of malaria in HIV-positive adults.19 In 2004, WHO recommended that, in resource-poor settings, if a CD4 count is available, then CPT can be discontinued if the CD4 count rises above the threshold for starting CPT, provided patients have been adhering to ART for at least 1 year and provided the count is above the threshold on two occasions 3 months apart. The other issue is whether isoniazid preventive therapy is needed in addition to ART to reduce the risk of recurrent TB. ART reduces the risk of TB, but not back to the levels seen in HIV-negative persons.16 Studies in Haiti and South Africa found that post-treatment isoniazid significantly reduces the rate of recurrent TB in HIV-positive patients.13 However, this intervention has yet to find a place in the routine management of TB, mainly because the structures for administering IPT after TB treatment has been completed do not exist. If the main mechanism of recurrence is
REFERENCES 8. 1. UNAIDS and WHO. AIDS epidemic update, December 2005 (UNAIDS/05.19E). [online]. Available at URL:http://www.unaids.org 2. World Health Organization. Global Tuberculosis Control: Surveillance, Planning and Financing (WHO/HTM/TB/2005.349). Geneva: World Health Organization, 2005. 3. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis. Global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009–1021. 4. World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resourcelimited Settings: Towards Universal Access. Recommendations for a Public Health Approach. Geneva: World Health Organization, 2006. 5. Wiktor SZ, Morokro MS, Grant AD, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a randomised controlled trial. Lancet 1999;353:1469–1474. 6. Zachariah R, Massaquoi M. Cotrimoxazole prophylaxis for HIV-positive tuberculosis patients in developing countries. Trop Doct 2006;36:79–82. 7. Sonnenberg P, Glynn JR, Fielding K, et al. How soon after infection with HIV does the risk of
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reinfection, which appears to be the case in HIV-positive individuals who develop recurrent TB several months after completing treatment, then isoniazid may need to be given for life. ART delivered regularly to patients in an ARV clinic would provide the structure needed for delivery of isoniazid chemoprophylaxis. An important research question is whether it is needed, and whether long-term isoniazid can safely be given with stavudine, given that both drugs may cause peripheral neuropathy.
CONCLUSION Despite an interim international policy on the integrated management of HIV and TB,9 little in the way of HIV diagnosis or care has been offered to patients with TB in the high-burden arena of sub-Saharan Africa. National TB programmes have continued to traditionally focus on case finding and anti-TB treatment for the increasing numbers of TB patients presenting to health facilities. Fewer than 10% of African patients with TB were tested for HIV in 2005, and even fewer were offered the chance of ART.2,20 This is beginning to, and must, change, and the rapid scale-up of ART in sub-Saharan Africa must begin to take TB into account. The conclusive statement in a review by Corbett and colleagues20 is very pertinent: ‘The advent of ART in Africa is the most important event for TB patients since the introduction of anti-TB drugs, and HIV/AIDS and TB programmes will have to change greatly to benefit as much as possible from this development.’
tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis 2005;191:150–158. Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004(1): CD0000171. World Health Organization. Interim Policy on Collaborative TB/HIV Activities (WHO/HTM/TB/ 2004. 330. WHO/HTM/HIV/2004.1). Geneva: World Health Organization, 2004. Siddiqui K, Lambert M-L, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence. Lancet Infect Dis 2003;3:288–296. Harries AD, Hargreaves NJ, Kwanjana JH, et al. Clinical diagnosis of smear-negative pulmonary tuberculosis: an audit of diagnostic practice in hospitals in Malawi. Int J Tuberc Lung Dis 2001;5:1143–1147. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004;364: 1244–1251. Harries AD, Dye C. Tuberculosis. Ann Trop Med Parasitol 2006;100:415–431. Kwara A, Flanigan TP, Carter EJ. Highly active antiretroviral therapy (HAART) in adults with tuberculosis: current status. Int J Tuberc Lung Dis 2005;9:248–257.
15. Harries AD, Chimzizi R, Zachariah R. Safety, effectiveness, and outcomes of concomitant use of highly active antiretroviral therapy with drugs for tuberculosis in resource-poor settings. Lancet 2006;367:944–945. 16. Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS 2005;19:2109–2116. 17. Lawn SD, Gail-Bekker L, Miller R. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;5:361–373. 18. Zachariah R, Teck R, Ascurra O, et al. Can we get more HIV-positive tuberculosis patients on antiretroviral treatment in a rural district of Malawi? Int J Tuberc Lung Dis 2005;9:238–247. 19. Mermin J, Ekwaru JP, Liechty CA, et al. Effect of cotrimoxazole prophylaxis, antiretroviral therapy, and insecticide-treated bed nets on the frequency of malaria in HIV-1-infected adults in Uganda: a prospective cohort study. Lancet 2006;367:1256– 1261. 20. Corbett EL, Marston B, Churchyard GJ, et al. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet 2006;367:926–937.
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Gender issues in tuberculosis Anna Thorson and Claudia Garcia-Moreno
SEX AND GENDER IN TUBERCULOSIS: WHY DO THEY MATTER? Tuberculosis – like many other diseases and health-related conditions – shows marked differences between males and females in terms of detection and notification, progression to disease after infection and disease outcome, as well as the social consequences of the disease. Male–female differences can be due either to biological sex differences or to gender conditions; namely, how women and men, and girls and boys, are socialized, what roles are ascribed to them in a given society, the prevailing norms about masculinity and femininity, and the status and power accorded to each, which in most societies tends to favour men. Both biological sex and socially constructed gender differences are important determinants of health and interact to produce differences in risks and vulnerability, in health-seeking behaviour and in the ability of people to protect their own health. Furthermore, these factors interact with other social determinants of health outcomes such as, among others, social class, ethnicity and urban or rural location. Despite this, health research has not, until recently, addressed these issues systematically.1 Gender dynamics are thus key factors affecting the risk of a person becoming infected and developing TB as well as his or her access to health information, health-seeking behaviour and treatment outcome. In addition, gender norms and gender inequality influence coping capacities and the social consequences of having TB. Accordingly, gender dynamics need to be considered at all stages of the disease – from initial awareness of symptoms, through the processes of seeking help and being diagnosed, initiation of treatment and adherence to it, to the eventual health outcome, as well as the social and economic consequences of the disease.2,3 Gender interacts with other societal factors, including ethnicity and poverty, which lead to inequities in the risk of becoming infected with Mycobacterium tuberculosis, developing active disease and achieving successful treatment.4–7 Among those living in absolute poverty, women are less in control than men of the very limited healthcare resources available to them. The social structure of many societies in low-income countries today relies on women having a double or triple workload, including household, agricultural and/or waged work.8 As women are also the primary carers in the family, the impact of TB is severe for individuals, families and for society in general. Gender-based inequities are thus key determinants in respect to many aspects of TB control programmes in low- and middle income countries.1,6,9–11 The relationship between TB and poverty has been demonstrated in several contexts.12–14
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SEX-ASSOCIATED PATTERNS IN TUBERCULOSIS EPIDEMIOLOGY Based on case notification figures, more men than women are diagnosed with active TB, although in some countries, Afghanistan and Islamic Republic of Iran for example, this pattern is not found.1,14 This pattern may be an accurate reflection of a higher incidence of TB among men or it may, in some contexts, reflect gender barriers to accessing TB programmes and healthcare.6,10 In countries with a high prevalence of TB at the beginning and middle of the twentieth century, notification of TB cases showed a sex and age distribution that differs from the 2:1 male to female ratio reported today.14,15 In Denmark (1939–41), Norway (1937), England and Wales (1952–4), notification rates were similar for both sexes below the age of 15 years, but higher among women until their mid-twenties or early thirties. After the age of 40 years, notification rates among men were higher in most of these countries.15 These findings are intriguing in light of consistent contemporary reports of a higher proportion of male cases globally.
GENDER DISPARITIES, HIV INFECTION AND REGIONAL VARIATIONS Disaggregated notification rates show regional variations of sex distribution of cases. The spread of the human immunodeficiency virus (HIV) pandemic has had a profound impact on the epidemiology of TB, which has become the most important cause of death among those infected with HIV in sub-Saharan Africa. In this region, where HIV rates among young women can be three to six times higher than among men of the same age group,16 the corresponding high rate of coinfection with HIV and M. tuberculosis is having a significant impact on the epidemiology of TB. In Malawi, for example, women in the reproductive age range make up a major proportion of those who are coinfected, and TB notification rates among this group of women are increasing rapidly and exceeding those of men.17 In addition, the stigma associated with TB is particularly evident in regions with a high prevalence of HIV infection. To date, little research has been done on the sex and gender-related factors affecting risks of HIV-TB coinfection. By contrast, sex differences in reported cases of TB in many of the Eastern European countries are greater than expected, with most cases occurring in men. Thus the percentage of females notified with the disease ranges from about 33% in Uzbekistan to only 12% in Belarus. The sex differences are most evident in the age
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group of 15–45 years old. The Russian Federation faces the heaviest TB burden in the region and significant sex disparities are reported in all age groups.18 The reported gender disparities in TB in some Eastern European and former Soviet Union countries still require validation. There are, however, gender-related discrepancies in risk behaviours associated with TB. While there is a steep increase in women engaging in risk behaviours such as alcohol, substance and tobacco abuse these are predominantly male behaviours, and this could partly explain the high numbers of reported cases among males in these settings.19,20 Another contributing factor is the extremely high incidence of TB among male prisoners in the countries of the former Soviet Union.21 The TB epidemic also heavily affects women in this region as, apart from being a major cause of disease and death among them, families of women with the disease experience severe negative social consequences. Women are especially exposed to TB-related stigma and resource constraints, which create gender-based inequities in access to care and treatment. Although the reported impact of TB is clearly higher in men of adult age in most countries in Eastern Europe, the observed sex differences remain to be verified in population-based surveys. While an increasing number of women experience social marginalization, these women are not yet visible in the national TB statistics. Another knowledge gap results from the lack of reports from prisons for women. Furthermore, in some countries of the former Soviet Union, discrimination against ethnic or religious minorities is common and sometimes legal. There is only scattered information on how gender and being a member of an ethnic minority group negatively influences access to care.22 These interacting factors require further exploration.
ACTIVE VERSUS PASSIVE CASE DETECTION AND GENDER Significantly more men than women access TB diagnostic and screening services,23 although there are few published reports of studies on passive versus active case finding that address sex differences.7 A study carried out in Eastern Nepal in the early 1980s showed that when cases were actively sought by household visits 46% of the detected cases were females, compared to only 28% in the self-referral group. The male-to-female ratio was 1.2:1 in the active case-finding group compared to 2.6:1 in the self-referral group, but data on the age and sex distribution of the population were not given.24 Factors such as stigma and discrimination may play a role in these differences in case-finding. In a
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more recent study of the population-based prevalence of sputum smear-positive TB in a rural district in Viet Nam, a male-to-female ratio of 0.7:1 was found.25 The reported male-to-female ratio in the study district was 2.7:1. In addition the percentage of cases detected was estimated at 12% for women and 39% for men, both being lower than the overall percentage of cases detected in Viet Nam – at the time 80% – and significantly so for women.15 The results of published screening studies that included a male-tofemale ratio of cases are listed in Table 99.1. These are comparisons of crude, non-age adjusted, rates. In many of the studies mass radiography was used to identify potential cases, and those with radiological changes were often asked to provide on-the-spot sputum samples. In the studies based on household screening, various symptom combinations were used to identify suspected cases, who were then asked to provide sputum samples. It is noteworthy that several of the published studies listed in Table 99.1 were performed in India and apart from the Nepal and the Viet Nam studies, the male-tofemale ratios are relatively similar to those being currently reported. In an attempt to assess the extent of under-detection, a retrospective analysis of age- and sex-specific TB prevalence rates of smear-positive TB compared to age- and sex-specific notification rates in 14 countries was performed.26 A patient detection ratio was calculated by comparison of prevalence rates determined by active case-finding, and notification data resulting from passive case-finding. No evidence for male–female differences in detection rates was found by this method, and sex differences in notification rates were thus interpreted as reflecting actual differences in the incidence of TB.26 Some of these prevalence studies had, however, been carried out many years before the notification rates were reported, and in some the sample sizes had been small.26 The typical activities of women and men, and their involvement in society and in the family, have changed rapidly over the past 50 years and these changes are likely to have had an effect on the relative infection rates and probably also on disease progression.
TUBERCULOSIS INFECTION, DISEASE AND GENDER In HIV-uninfected populations only about 10% of those infected with M. tuberculosis ever develop TB and there is often a long period of latency before active disease develops. Transmission dynamics are complicated and the risk of infection does not correlate with the actual incidence of disease.27 Tuberculin surveys
Table 99.1 Results from studies on mass screening of smear-or culture-positive pulmonary tuberculosis, including a male-to-female ratio of cases Country
Screening method–diagnostic method
Population screened
Male-to-female ratio
India: Tumkur, Mysore 1961 India: Tumkur, Mysore 1973 India: Madras 1970 India: Tamil Nadu 1981–3 India: Bangalore 1984–6 Czechoslovakia 1961 Nepal 1980 Viet Nam 2000
X-ray–sputum X-ray–sputum X-ray–sputum Household survey–sputum Tuberculin test–sputum X-ray–sputum Household survey–sputum Household survey–sputum
21,021 24,785 206,609 18,688 29,400 10,0418 67,068 35,832
2.2:1 2.7:1 4.2:1 2.6:1 2.8:1 1.7:1 1.2:1 0.7:1
Table taken from Thorson A. Equity and Equality - Case detection of tuberculosis among women and men in Viet Nam. PhD thesis, Karolinska Institute University Press, 2003.
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carried out during the 1950s and early 1960s show a rather uniform pattern, with an equal prevalence of infection among boys and girls until the age of 15 years, after which the prevalence in males begins to exceed that in female.28 As with active case-finding studies, the magnitude of the male–female difference varies from region to region. Thus, for example, a study from India showed the prevalence of TB infection to be 1.8 times higher in men than in women in those aged 25 years, whereas a Danish study showed a lesser peak difference of about 1.2 times at the age of 20 years.27 It is difficult to extrapolate the extent of under-detection of TB from data on infection rates. In addition, there is evidence of differences in tuberculin reactivity between men and women with active TB, related to differences in immune responses to the disease process.29 Men appear to progress faster from infection to disease, and this is to some extent attributable to smoking. The male-to-female ratio in disease progression in a study population in south India dropped from 2.7 to 1.2 after exclusion of men who were smokers and alcoholics.30 An ecological study indicated that one-third of the sex/gender difference in TB is explained by male smoking.31 There have been a few longitudinal studies on the risk of tuberculin-positive individuals progressing to active TB and these show a higher risk of progression among women of reproductive age compared to men in the same age range.16,27 This may be related to pregnancy but might also reflect better detection in women as they use health services more frequently during this period.2
DIAGNOSTIC METHODS AND GENDER In studies from Bangladesh and Malawi, proportionally more men than women among those who submitted a sputum specimen were found to be positive for acid-fast bacilli on microscopical examination.23,32 To what extent these findings reflect a true sex-related difference in the incidence in pulmonary TB rather than differences in the diagnostic sensitivity of the method of investigation is not known. Differences in sensitivity may be due to both sexspecific differences in physiological characteristics of TB lesions and gender-related differences in seeking diagnosis. The latter include sociocultural restrictions for women against coughing and spitting, making it less likely that women will produce a good sputum sampling. The use of DNA fingerprinting techniques to study clustering of pulmonary TB cases in the Netherlands led to the conclusion that women with pulmonary TB generated fewer new incident cases than men.26 This study also indicated that men with pulmonary TB were positive on sputum smear examination more often than women. These findings imply that, in this setting, sputum smear microscopy for diagnosing pulmonary TB has a lower sensitivity among women than among men. In India, the rate of sputum-positive cases was significantly higher among men than among women and increased with age, whereas for women it decreased with age.30 It has been suggested that chest radiology findings differ between men and women with TB due to sex differences in their immune responses to the disease.29 In a study in Turkey, female TB patients had a higher frequency of lower lung field involvement, a finding usually regarded as quite uncommon in postprimary disease.33 In Viet Nam, on the other hand, there were no differences in lung field involvement, but significantly more men than women had pleurisy and miliary patterns of disease on chest radiology.34
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TUBERCULOSIS SYMPTOMS AND GENDER The diagnostic methods recommended in the directly observed treatment, short-course (DOTS) strategy of the World Health Organization (WHO) focus on identifying sputum smear-positive cases of pulmonary TB. The WHO and the International Union against Tuberculosis and Lung Disease recommend that all individuals presenting with a cough lasting for more than 3 weeks to healthcare facilities in settings with a high TB prevalence should be investigated for this disease by means of a sputum smear examination.35 Thus, long-term cough together with sputum production are key features for suspecting TB. A study on symptoms among 757 men and 270 women with smear-positive pulmonary TB in Viet Nam showed that, at the time of diagnosis, fewer women reported any of the symptoms of cough, sputum production and haemoptysis.36 At follow-up after 1 month of treatment, more women than men had recovered from their symptoms of cough and sputum production. In general, about 80% of all TB cases involve the lung,37 but in populations with a high prevalence of HIV infection extrapulmonary TB is relatively more frequent.27,38 Several studies have revealed a higher proportion of extrapulmonary TB among women than men,27,29 but the reason for this is unknown. In a WHO study in Bangladesh, Columbia, India and Malawi,11 it was found that women presented to the clinic with a greater diversity of nonspecific physical symptoms, and it was concluded that ‘health care professionals should be trained to consider the possibility of tuberculosis in females patients presenting with more atypical symptoms.’
HEALTH-SEEKING BEHAVIOUR AND GENDER From the perspective of patients, the health-seeking process has been described as having various components. These include symptom recognition (to recognize a symptom as a health problem), sick role (the patients consider themselves as ‘sick’ and ready to take an action), lay referral (discussions and guidance by people within their own social networks) and treatment action.39 Several gender and health studies in high-income countries have shown that women use healthcare facilities more often than men.40,41 This has been accredited to various factors including a higher actual morbidity among women, those of reproductive age having closer contact with the healthcare system through antenatal and mother and child care, and the female gender role allowing women to acknowledge ill health to a higher degree than the male gender role which considers that men should be strong and resist feelings of weakness.4,40,41 The situation is quite different in low-income settings where women may face more barriers to adequate healthcare since they have less access to financial resources and less decision-making power of their own, as well as their workload often being heavier than that of men. Being responsible for the health of the family, women often must put their own needs in the background, with resources being spent first on the children or husband. Access to adequate healthcare cannot be taken for granted for either men or women, and access is also closely related to socioeconomic status.8,42 In India, women are found to under-report morbidity and are said to practice a ‘culture of silence’ regarding their illnesses.43,44 A study of TB in Bangladesh showed that more men than women sought public healthcare for respiratory complaints, which was interpreted as representing a possible barrier in access to healthcare for these women.31 A study in urban Viet Nam showed that
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female TB patients had more often used a private provider in their health-seeking process,45 and in a population-based study of subjects with cough significantly more women than men had used low-quality providers of care such as drug sellers or private practitioners, whereas men were more likely to have used the national healthcare system with direct access to hospital care.46 In India also women were more likely than men to first consult a private provider, but the median patient delay was similar among male and women TB patients.30 In Viet Nam, despite poverty alleviation programmes which should enable those identified as poor to obtain exemption from some of the user fees in the national healthcare system, the poorest strata of the population spend a proportionally greater part of their income on healthcare. A major share of this spending is on relatively inexpensive but frequent healthcare actions that escape political attention, such as visits to unregulated healthcare providers within the private sector.47 The findings from Viet Nam and India mentioned above strongly suggest that the choice of healthcare provider is determined not only by financial status, but also by gender. In the WHO study in Bangladesh, Columbia, India and Malawi referred to earlier,11 fewer women than men were identified as TB suspects in India and Bangladesh, an equal number in Malawi and more women than men in Columbia. In a qualitative study of TB patients in Viet Nam, stigma and fear of social consequences were found to influence healthcare seeking by women to a greater extent than by men.48 These factors were considered to potentially lead to symptom denial and to a preference for private or other non-public providers.48 Similar findings emerged from a study based on in-depth interviews with TB patients in Pakistan where women found it more difficult than men to obtain adequate treatment because of restriction of their movements and a general unwillingness on the part of the household decision-makers to pay for their treatment.49 Tuberculosis-related stigma was also reported as being greater for women than for men and unmarried women were afraid to announce that they had the disease for fear of not being able to get married. In India a significantly higher proportion of women than men faced social stigmatization or rejection because of their illness, with 21% of women and 14% of men feeling inhibited to discuss their illness with friends or family.30 Women were also more likely to need someone to accompany them to DOT than men.30 In another study in Viet Nam, women with cough were shown to have less knowledge than men about the medical characteristics of TB, and this in turn resulted in them seeking care from less well-qualified providers.50 Traditional beliefs about TB seem to be related strongly to stigma,51 and a lack of knowledge about the characteristics of the disease could thus be related to experiences of stigma and lead to disempowerment regarding the perceived available choices for seeking healthcare. In Zambia there is conflicting evidence regarding factors associated with long patient delay in seeking healthcare among patients with cough: old age and severe disease were linked to a long delay, whereas gender, stigma or less knowledge in TB characteristics were not associated.52 This opposes earlier findings from the same country where being female and of low educational level were factors linked to longer delay among TB patients.53 In general evidence in relation to patient delay is conflicting from different parts of the world, whereas a longer provider delay for women has been suggested in several studies.11,38,53–55 The greater tendency for women to contact initially a traditional healer explained the longer delay among women in Nepal, whereas in the other settings delays occurred after contact with the national healthcare system. The patient delay was not significantly different
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between women and men in these studies. In Sarawak, Malaysia, being female was significantly associated with patient delay, whereas no association was found with provider delay.56 It should, however, be remembered that none of these studies were population-based; they were all retrospective studies of the health-seeking behaviour of those diagnosed with TB within the national healthcare systems. In Bangladesh, women who present with respiratory symptoms are less likely to undergo sputum smear examination.31 In the previously mentioned Malawi study, more men than women submitted sputum specimens for diagnosis of TB, although there were no data on the relative number of those seeking healthcare who had symptoms suggestive of this disease.23 In the population-based study from Viet Nam it was also shown that, among those with cough, women had been asked to provide a sputum sample at the hospital significantly less often than men, a difference which persisted when corrections were made for the presence and duration of symptoms.45 In the WHO study in Bangladesh, Columbia, India and Malawi mentioned earlier,11 it was shown that consistently more women than men dropped out during the process of diagnosis. Little is known about the actual mechanisms involved in creating a longer provider delay, including reasons for a lower access to diagnostic investigations for female TB suspects. The patient–doctor encounter is likely to be of importance not only for patient satisfaction and adherence, but also for a successful health outcome – affected, for example, by delay on the part of the doctor. In an interview study with healthcare providers in Viet Nam, male doctors expressed the opinion that female TB patients are more difficult to diagnose due to communication problems, whereas female doctors did not perceive any gender-related problems in this respect.57 The preference of patients with symptoms suggestive of TB, principally women but also men, to opt for care within the private sector should not be neglected. The use of unregulated providers needs to be recognized as a gender issue, as has been shown in several low-income countries.3,43,44,46 Special attention to genderrelated issues is thus needed in order to improve healthcare seeking and case detection of TB, especially among women. In the WHO study in Bangladesh, Columbia, India and Malawi, experiences with semi-active case-finding in Bangladesh provided good results in terms of reducing patient delay to TB diagnosis although it had no effects on provider delay.11 Evidence from different countries therefore suggest that women must negotiate their healthcare seeking to a higher extent than men, often because of a combination of sociocultural factors, such as responsibility for the household and the children and more limited access to resources, whereas the concerns of men are more straightforward, with interference with livelihood activities being the prime cause of unnecessary delays.7,11 While women are disadvantaged in terms of access in several settings, men also may face difficulties accessing diagnosis and treatment for TB and a better understanding of the barriers they face is also needed.
TREATMENT ADHERENCE AND SOCIAL CONSEQUENCES OF TUBERCULOSIS The stigma associated with TB related, for example, to the fear of contagion (despite adequate treatment), appears to be both substantial and universal and is described in various cultural contexts, although the form that it takes may vary from region to region, such as associations with HIV disease where this is prevalent.
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The social consequences of stigma often persist even when TB has been successfully cured: accounts from India, Bangladesh and Malawi show that, despite their disease being cured, women experience problems getting married. Women and men seem to experience the impact of stigma differently, though the psychological and social consequences are harsh for both women and men.11,58 In the WHO four-country study, psychological and emotional symptoms of distress were reported by a large majority of TB patients and these were related to stigma, discrimination and rejection by the family.11 It is essential that health information and education draws a distinction between reasonable precautions to minimize contagion and the creation of unnecessary fears of TB, thereby endeavouring to reduce the stigma associated with the disease.11 Treatment adherence in the WHO four-country study showed a higher dropout rate among men in all four countries and the same was found in the south India study. As men are the usual source of income in the family, the financial impact of illness and hospitalization may be the prime cause of their lower adherence rates, as well as difficulties in reaching clinics during opening times.11,30 More research is needed in order to understand the various gender-related and other factors affecting adherence for both men and women. Fear of being associated with TB may also lead to reluctance to receive directly observed therapy, as it becomes more or less obvious to anyone in the neighbourhood that the patient is being treated for this disease, and this may in turn lead to delays in following the referral chain. These factors seem particularly important for female TB patients as they may face specific constraints to daily healthcare contacts, such as lack of access to child care, to transport or to money for transport (even when treatment may be free) or requiring permission from their husbands to access healthcare.48 Men, on the other hand, also may not benefit from DOT as they could and eliminating barriers to compliance among men is also needed.
GAPS IN RESEARCH Although the reported prevalence of TB is clearly higher in adult men than in women in most countries, these observed sex differences still need to be confirmed in population-based surveys, and the role biology, gender and other social variables play in them understood. Similarly, the interaction with HIV/acquired immunodeficiency syndrome (AIDS) and the effects of the high incidence of HIV among young women on the epidemiology of TB in countries where the former is prevalent merits further investigations as to effects on healthcare access and treatment outcomes. A lack of reports from prisons for women, particularly in the Eastern Europe and central Asian region, is another knowledge gap. More information is needed on male–female differences in access to diagnosis and to treatment and the role of gender-based barriers in explaining this in different contexts and regions. Gender issues reflect local and regional social and cultural realities and it is therefore important that data are both analysed and used locally to inform programmes. Documenting the social and economic consequences of the disease, such as abandonment, divorce, stigma, and discrimination, for both women and men, is also important in order to mitigate its impact.
POLICY AND PROGRAMME CONSIDERATIONS Data disaggregated for sex and age need to be examined continuously at national and district levels in order to reveal dynamic
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processes such as the interaction with HIV/AIDS, to understand male–females differences and to assess the role of gender-related factors at all stages: from exposure and vulnerability to developing the disease, to access healthcare and treatment, and to the eventual outcome of treatment. Protocols are needed to facilitate the assessment of the way in which gender has an impact on the course of TB patients – from the number of women and men seeking healthcare with disease-related symptoms, those examined and diagnosed with TB, those returning for results and initiating treatment and those completing treatment. Sex-specific monitoring should be incorporated in all aspects of TB programmes.1,11 Strategies to reduce the stigma associated with the disease need to be developed and assessed in different contexts. Raising awareness among health providers is a key requirement to avoid inadvertent discrimination due to lack of attention to gender issues in the patient–provider encounter. All patients with suspected TB, whether male or female, should have equal right to diagnosis and treatment, and the provision of care should likewise be equitable, being based solely on need. In practice, this means that the patient–provider encounter needs to be individualized and to lead to the empowerment of the patient. For a disease associated with stigma and traditional beliefs, patient empowerment is of utmost importance for successful case detection and treatment.7,57 In order to provide TB treatment in an equitable manner, it is necessary to increase the awareness of possible sources of gender bias and other forms of disempowerment among those responsible for the care of TB patients. Treatment guidelines must therefore be sensitive to male–female differences in symptoms and also address the psychological and emotional aspects of the disease.11 This applies to both private and state healthcare providers. Targeted education to increase gender sensitivity among providers has yet to be tried. The ‘one-size-fits-all’ structure of the global WHO DOTS policy needs to be discussed further from an equity perspective. Apart from the practical concerns associated with daily healthcare contacts, there are, in the case of a stigmatizing disease such as TB, additional aspects to be considered when analysing the DOTS strategy. Services should aim to minimize disruption to daily livelihood and other activities by ensuring local accessibility, convenient timing and minimizing the number of contacts required. Individual treatment must be complemented with community-based interventions, which are crucial to increase awareness of the symptoms of the disease and the importance of early diagnosis, and to address stigma and discrimination. Contextualized gender-sensitive interventions such as semiactive case-finding and local models for supplying TB treatment, based on strategies for increasing empowerment of the patients, need to be developed and evaluated urgently. Although gender considerations should form an integral part of high-quality care, in practice these are often omitted or ignored.1,59 Addressing gender dimensions in strategies for TB control, and in the design of programmes and services, has the potential to improve quality of care, coverage and completion rates, thereby contributing to the overall effectiveness of strategies to achieve global control of TB.
ACKNOWLEDGEMENTS The authors thank Mukund Uplekar of the StopTB Department in WHO for his input.
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Gender issues in tuberculosis
REFERENCES 1. World Health Organization. Gender in Tuberculosis Research. Gender and Health Research Series. Geneva: World Health Organization, 2005. 2. Long NH. Gender specific epidemiology of tuberculosis in Viet Nam. PhD thesis, Karolinska Institutet, Stockholm, 2000. 3. Uplekar MW, Rangan S, Weiss MG, et al. Attention to gender issues in tuberculosis control. Int J Tuberc Lung Dis 2001;5:220–224. 4. Doyal L. In sickness and in health. In: Doyal L, ed. What Makes Women Sick: Gender and the Political Economy of Health. London: Macmillan, 1995. 5. Farmer P. Social scientists and the new tuberculosis. Soc Sci Med 1997;44:347–358. 6. Diwan VK, Thorson A. Sex, gender and tuberculosis. Lancet 1999;353:1000–1001. 7. Thorson A. Equity and equality—case detection of tuberculosis among women and men in Viet Nam. PhD thesis, Karolinska Institute University, 2003. 8. Vlassoff C, Bonilla E. Gender-related differences in the impact of tropical diseases on women: what do we know? J Biosoc Sci 1994;26:37–53. 9. Diwan V, Thorson A, Winkvist A, eds. Gender and Tuberculosis. Go¨teborg: School of Public Health, 1998. 10. Thorson A, Diwan VK. Gender inequalities in tuberculosis: aspects of infection, notification rates, and compliance. Curr Opin Pulm Med 2001;7: 165–169. 11. World Health Organization. Gender and Tuberculosis: Cross-Site Analysis and Implications of a Multi-country Study in Bangladesh, India, Malawi and Colombia. Report Series No. 3, Special Programme for Research and Training in Tropical Diseases (TDR). Geneva: World Health Organization, 2006. 12. Spence DP, Hotchkiss J, Williams CS, et al. Tuberculosis and poverty. BMJ 1993;307:759–761. 13. Zumla A, Grange J. Tuberculosis and the povertydisease cycle. J R Soc Med 1999;92:105–107. 14. World Health Organization. Global Tuberculosis Report. Geneva: World Health Organization, 2007. 15. Holmes CB, Hausler H, Nunn P. A review of sex differences in the epidemiology of tuberculosis. Int J Tuberc Lung Dis 1988;2:96–104. 16. UNAIDS. AIDS Epidemic Update 2007. Available at URL:http://www.unaids.org. 17. Glynn JR, Crampin AC, Ngwira BM, et al. Trends in tuberculosis and the influence of HIV in northern Malawi, 1988–2001. AIDS 2004;18:1459–1463. 18. World Health Organization. Global Tuberculosis Report. Geneva: World Health Organization, 2005. 19. McKee M, Shkolnikov V. Understanding the toll of premature death among men in eastern Europe. BMJ 2001;323:1051–1055. 20. Whiteside A. Reform in Eastern Europe: Assessing its impact on parallel HIV, TB and STD epidemics. Paper presented at the Third International Conference on Healthcare Resource Allocation for HIV/AIDS and Other Life threatening Illnesses, Vienna, 11–13 October 1999. 21. Vinokur A. The TB and HIV/AIDS Epidemics in the Russian Federation. World Bank Technical Paper. Washington, DC: World Bank, 2001. 22. Festenstein F, Grange JM. Tuberculosis in ethnic minority groups in industrialised countries. In Porter JDH, Grange JM, eds. Tuberculosis—An Interdisciplinary Perspective. London: Imperial College Press, 1999:313–338. 23. Boeree MJ, Harries AD, Godschalk D, et al. Gender differences in relation to sputum submission and
24.
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smear-positive pulmonary tuberculosis in Malawi. Int J Tuberc Lung Dis 2000;4:882–884. Cassels A, Heineman E, LeClerq S. Tuberculosis case-finding in Eastern Nepal. Tubercle 1982;63: 175–185. Thorson A, Hoa NP, Long NH, et al. Do women with tuberculosis have a lower likelihood of getting diagnosed? Prevalence and case detection of sputum smear positive pulmonary TB, a population based study from Viet Nam. J Clin Epidemiol 2004; 57:398–402. Borgdorff MW, Nagelkerke NJD, Dye C, et al. Gender and tuberculosis: a comparison of prevalence surveys with notification data to explore sex differences in case detection. Int J Tuberc Lung Dis 2000;4:123–132. Rieder HL. Epidemiological Basis of Tuberculosis Control. Paris: International Union against Tuberculosis and Lung Disease, 1999. Dolin P. Tuberculosis epidemiology from a gender perspective. In: DiwanVK, Thorson A, Winkvist A, eds. Gender and Tuberculosis. Go¨teborg: Nordic School of Public Health, 1998: 29–40. Bothamley G. Sex and gender in the pathogenesis of infectious tuberculosis: A perspective from immunology, microbiology and human genetics. In: Diwan VK, Thorson A, Winkvist A, eds. Gender and Tuberculosis. Go¨teborg: Nordic School of Public Health, 1998: 41–53. Balasubramanian R, Garg R, Santha T, et al. Gender disparities in tuberculosis: report from a rural DOTS programme in south India. Int J Tuberc Lung Dis 2004;8(3):323–332. Watkins RE, Plant AJ. Does smoking explain sex differences in the global tuberculosis epidemic? Epidemiol Infect 2006;134:333–339. Begum V, de Colombani P, Das Gupta S, et al. Tuberculosis and patient gender in Bangladesh: sex differences in diagnosis and treatment outcome. Int J Tuberc Lung Dis 2001;5:604–610. Bacakoglu F, Basoglu OK, Cok G, et al. Pulmonary tuberculosis in patients with diabetes mellitus. Respiration 2001;68:595–600. Thorson A, Long NH, Larsson LO. Chest X-ray findings in relation to gender and symptoms: a study of patients with smear positive tuberculosis in Viet Nam. Scand J Infect Dis 2007;39:33–37. Crofton J, Horne N, Miller F. Clinical Tuberculosis. London: MacMillan, 1992. Long NH, Diwan VK, Winkvist A. Difference in symptoms suggesting pulmonary tuberculosis among men and women. J Clin Epidemiol 2002;55:115–120. Lobue PA, Perry S, Catanzaro A. Diagnosis of tuberculosis. In: Reichman LB, Hershfield ES, eds. Tuberculosis—A Comprehensive International Approach. New York: Marcel Dekker, 2000: 341–375. Haas D. Mycobacterium tuberculosis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th edn. Philadelphia: Churchill Livingstone, 2000: 2576–2607. Ngamvithayapong J, Yanai H, Winkvist A, et al. Health seeking behaviour and diagnosis for pulmonary tuberculosis in an HIV-epidemic mountainous area of Thailand. Int J Tuberc Lung Dis 2001;5:1013–1020. Verbrugge LM. The twain meet: empirical explanations of sex differences in health and mortality. J Health Soc Behav 1989;30:282–304. Kandrack MA, Grant KR, Segall A. Gender differences in health related behaviour: some unanswered questions. Soc Sci Med 1991;32: 579–590.
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42. AbouZahr C, Vlassoff C, Kumar A. Quality health care for women: a global challenge. Health Care Women Int 1996;17:449–467. 43. Rangan S, Uplekar M. Gender perspectives of access to health and tuberculosis care. In: Diwan VK, Thorson A, Winkvist A, eds. Gender and Tuberculosis. Go¨teborg: Nordic School of Public Health, 1998: 107–125. 44. Fochsen G, Deshpande K, Thorson A. Power imbalance and consumerism in the doctor-patient relationship: health care providers’ experiences of patient encounters in a rural district in India. Qual Health Res 2006;16:1236–1251. 45. Lonnroth K. Thuong LM, Linh PD, et al. Utilization of private and public health-care providers for tuberculosis symptoms in Ho Chi Minh City, Viet Nam. Health Policy Plan 2001;16:47–54. 46. Thorson A. Hoa NP, Long NH. Health-seeking behaviour of individuals with a cough of more than 3 weeks. Lancet 2000;356:1823–1824. 47. Segall M, Tipping G, Lucas H, et al. Health care seeking by the poor in transitional economies: the case of Viet Nam. IDS Research Report 43. Brighton, Sussex: Institute of Development Studies, 2000. 48. Johansson E, Long NH, Diwan VK, et al. Gender and tuberculosis control: perspectives on health seeking behaviour among men and women in Viet Nam. Health Policy 2000;52:33–51. 49. Khan A, Walley J, Newell J, et al. Tuberculosis in Pakistan: socio-cultural constraints and opportunities in treatment. Soc Sci Med 2000;50:247–254. 50. Hoa NP, Thorson A, Long NH, et al. Knowledge of tuberculosis and health-seeking behaviour among men and women with a cough for more than three weeks in a rural district in Viet Nam. Scand J Publ Health Suppl 2003;62:59–65. 51. Long NH, Johansson E, Diwan K, et al. Fear and social isolation as consequences of tuberculosis in Viet Nam: a gender analysis. Health Policy 2001;58:69–81. 52. Godfrey-Fausett P, Kaunda H, Kamanga J, et al. Why do patients with a cough delay seeking care at Lusaka urban health centres? A health systems research approach. Int J Tuberc Lung Dis 2002;6:796–805. 53. Needham DM, Foster SD, Tomlinson G, et al. Socioeconomic, gender and health services factors affecting diagnostic delay for tuberculosis patients in urban Zambia. Trop Med Int Health 2001;6:256–259. 54. Pronyk RM, Makhubele MB, Hargreaves JR, et al. Assessing health seeking behaviour among tuberculosis patients in rural South Africa. Int J Tuberc Lung Dis 2001;5:619–627. 55. Yamasaki-Nakagawa M, Ozasa K, Yamada N, et al. Gender difference in delays to diagnosis and health care seeking behaviour in a rural area of Nepal. Int J Tuberc Lung Dis 2001;5:24–31. 56. Chang CT, Esterman A. Diagnostic delay among pulmonary tuberculosis patients in Sarawak, Malaysia: a cross-sectional study. Rural Remote Health 2007;7:667. 57. Thorson A, Johansson E. Equality or equity in health care access: a qualitative study of doctors’ explanations to a longer doctor’s delay among female TB patients in Viet Nam. Health Policy 2004;68:37–46. 58. Johansson E, Winkvist A. Trust and transparency in human encounters in tuberculosis control: Lessons learned from Viet Nam. Qual Health Res 2002; 12:473–491. 59. Vlassof C, Garcia-Moreno C. Placing gender at the centre of health programming: challenges and limitations. Soc Sci Med 2002;54:1713–1723.
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Tuberculosis and migration Deliana Garcia, Fraser Wares, Edward Zuroweste, and Phillipe Guerin
INTRODUCTION The global spread of disease has as a consistent point of reference human population movement. From the advent of measles in the New World to the more recent spread of human immunodeficiency virus (HIV) disease, the movement of people, or even a single person, has been central. Understanding the complexities of human population movement and its role in the spread of disease is critical for the development of effective international TB control strategies.
HUMAN MIGRATION Most of human history is based on the movement of people from one place of residence to another, since it has been through this continued movement of populations that every part of the planet has been settled. Termed ‘the great adventure of human life’,1 migration is the 60 million Europeans leaving their homes from the sixteenth to twentieth centuries and the 15 million Hindus, Sikhs, and Muslims swept up in the tumultuous shuffle of citizens between India and Pakistan after the partition of the subcontinent in 1947. The lure of land, a ‘better life’, and a safer habitat is perpetual – the so-called push and pull factors are enduring facts of human history. Migration has shaped our societies, and with all its entwined economic and political aspects has been called ‘one of the greatest challenges of the coming century’ (see Fig. 100.1).1,2 Through improved transportation and communications, a growing world economy, and increasing social inequality, human migration has reached unprecedented levels.3 The ease of movement and the rapid dissemination of information concerning opportunities to improve personal well-being mean that increasing numbers of countries are now points of origin, destination, or transit for migrants. Migration involves increasingly diverse populations moving rapidly between the sending and receiving locations, often with unequal social and physical environments that affect the health and well-being of those migrating.4 Migration is not a minor influence on societies. In 1990 some 120 million people, two in every 100 people lived outside of the country of their birth.5,6 In 2006, there were 191 million international migrants in the world, representing 3% of the world population. In the USA, Hispanics comprise the vast majority of migrating workers, and in 2003 became the largest minority group in the country.7 Figure 100.2 illustrates the increase over the past 40 years in the number of foreignborn people residing outside their country of birth.8
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Migration continues to be the result of social, political, and economic factors, as well as discrete environmental and political events such as natural disasters and humanitarian crises. The process of population mobility is regularly termed ‘human migration’ with a focus on the legal and administrative aspects of individual and group movement. Human migration is often perceived to be a slow and unidirectional process resulting in permanent resettlement.4 However, human migration is a dynamic process and efforts to describe the phenomena and its impact often falter by focusing on discrete episodes.9 Migration is a long-term process dotted with vital events and changing health status. Integrated international policy development and attention to the health status and the healthcare needs of migrants is often complicated by the fact that migration is linked to other politically charged issues such as international security, trade, economic development, labour needs, demography, poverty relief, integration and citizenship, social networks, gender, human rights, public health, organized crime, and remittances in an intricate web of competing forces.4 The interconnectedness of these issues precludes consensus on their rank order of importance. Each has far reaching effects beyond the individual migrant and the community of residence or origin. Remittances for example play an increasingly important role in the world economy. It is presumed that a large percentage of migrant remittances are delivered through unofficial channels, with total remittances believed to amount to more than US$100 billion. In 2004, India received some US$21 billion, the greatest amount of migrant remittances, followed by Mexico with US$18 billion (Fig. 100.3).10 Even as health issues are being raised more often in foreign policy discussions, focus continues to be on the legal or regulatory aspects of migration for those persons crossing international borders.11 Considerable attention is given to migration from lowincome countries into high-income countries, with a notable emphasis on the overburdening of healthcare systems. Until recently there has been little concern about the health of persons emigrating from countries like the USA despite their capacity to spread disease. The impact of migrants returning to low-income countries with a communicable disease is starting to receive greater attention as sending countries study the epidemiology of disease within their own countries. For example, Mexico reports that the greatest risk factor for HIV infection among rural Mexicans is migration to the USA. Return visits to the country of origin are also an important consideration. A study in the United Kingdom
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Elevation (metres) 100 250 500 1000 2000 3000 4000 5000
Population (thousands) < 500 5001000 > 1000
Copyright United Nations 1997
Fig. 100.1 Global population distribution.2
anticipatory – the orderly plan to leave the point of origin with resources intact and destination clearly chosen; and acute – the escaping from a major crisis with few resources, arriving in the state of shock and depending on the receiving community aid agencies for assistance.16
Anticipatory migration can include students and travellers, as well as workers. Even as these migrants may plan for the move to a new location, the receiving site may be unprepared for the influx and unable to absorb the demand created by their arrival. Acute migration includes those forced to move in response to political crisis or natural disaster. Among this group are early stage refugees and IDPs, as well as victims of human trafficking. In the case of refugees, they often spend long periods in cramped, poorly located, and poorly equipped resettlement camps. The rise in human trafficking reported internationally means that migrants are being brought to another location not only under cover but also to work in illegal industries such as prostitution. Female
Estimated number of international migrants
200 180 160 140 Millions
demonstrated that children who were second-generation migrants of South Asian ethnic origin had a higher risk of TB than their Caucasian counterparts. One risk factor explaining this was frequent visits to their countries of out-migration, i.e. Bangladesh, India, and Pakistan.12 Box 100.1 lists what travels with humans as they travel into new regions.13 While human migration is fuelled by the desire to improve one’s circumstances, it does not always mean that the movement is voluntary nor across international boundaries. Large groups of migrants move regularly between intracountry regions for a variety of reasons and varying periods of time. Some are looking for seasonal work; others migrate temporarily because of the nature of their work, e.g. truck drivers, transport workers, and fishermen. Others migrate for educational purposes, for health care, to escape environmental degradation, or to seek a safe habitat, e.g. internally displaced persons (IDPs). We should not underestimate the size of this seasonal ‘migration’ in volume (millions in the USA and Europe; Fig. 100.4), or the problems related to poor access to health services of this population.14,15 While it is important to understand the motivations for and effects of migration, it can be more useful to consider that migration is ‘a social process that links networks of people in a set of intimate relationships’.9 These relationships allow for both the transfer of disease and the provision of services to interrupt disease transmission. A principal distinction that can be made for all forms of human migration is whether the travel is planned or initiated with limited or no planning. The two categories of population movement identified by Peters et al. are:
120 100 80 60 40 20 0
1960
1965
1970
1975
1980 1985 Year
1990
1995
2000
2005
Fig. 100.2 Estimated number of international migrants courtesy of Economic and Social Research Council Society Today, International Fact Sheets. http://www/esrcsocietytoday.ac.uk/ESRCInfoCentre/facts/ international/migration.aspx?ComponentId¼15051&SourcePageId¼14912.
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4
$0.
Japan
N. Korea
9 0
6
$1.
$3.
Turkey
Poland Rights were not granted to include this content in electronicGermany media. Please refer to the printed book. Saudi Arabia 3 $2. Spain Portugal
India
Lesotho
1
$0.
Dominican Republic
United States .6
$10
2
Cape Verde
8
$1.
1
$0.
Nepal
$4.
S. Africa
9
$1.
Brazil
$0.
.6
$10
Mexico
Ecuador 4
$3.
El Salvador
8 $1.
Billions of US dollars (2001)
Source country Recipient country Source/recipient
Fig. 100.3 Selected annual flows of remittances. McHale, J and Kapur, D. Migration’s New Payoff, Foreign Policy 139:49–57.
Box 100.1 What travels with humans as they travel into new regions? 1. 2. 3. 4. 5. 6. 7. 8.
Pathogens in or on the body. Microbiological flora. Vectors on the body. Immunological sequelae of past infections. Vulnerability to infections. Genetic makeup. Cultural preferences, customs, behavioural patterns, technology. Luggage and whatever it contains.
Taken from Wilson.13
migrants are rapidly outnumbering male migrants, and are more likely to be trafficked.4 In the initial stage of a refugee crisis, the immediate needs are shelter, food, water, sanitation, and security. The main health problems seen in this initial stage are measles, malnutrition, respiratory infections, malaria (in many tropical countries), and diarrhoeal diseases. Once the emergency stage is over, the healthcare needs change. Services required now are much wider and the needs tend to mirror those of the host nation, although more exaggerated due to worse living conditions. At this stage, the provision of treatment for TB often becomes a major health priority.
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As for general migrants, linguistic and cultural barriers may exist for refugee communities in accessing healthcare. However, in many refugee situations, outside agencies, such as the United Nations High Commission for Refugees (UNHCR) or international non-governmental organizations (INGOs), come in to assist in the care of refugees, and services may be set up outside of the host nation’s health services to provide healthcare for the refugees. Paradoxically in some ‘stable’ refugee situations, due to an influx of healthcare services from UNHCR and INGOs, services and indicators may actually be better inside the refugee community than in the host country’s population. For example, in the Bhutanese refugee camps situated in eastern Nepal served by the INGO Save the Children (UK), antenatal care coverage was almost 100% (compared with Nepal figure of 44%), with 85% of deliveries attended by a trained health worker (cf. 33%), infant mortality rate (IMR) 62 per 1000 live births (cf. 98), and expanded programme on immunization (EPI) coverage of 95% (cf. 78%).17,18 In the more acute stages of refugee situations or where the situation remains ever unstable such as in recent times in the Darfur region of Sudan, morbidity and mortality rates are and may remain phenomenally high.19 International migration is the category of human migration most often considered when the topic is discussed. Within the category of international migration, two additional distinctions are made: regular and unofficial. Regular migrants are those who arrive after
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Rights were not granted to include this content in electronic media. Please refer to the printed book.
Rights were not granted to include this content in electronic media. Please refer to the printed book.
Fig. 100.5 Cambodian berry picker. Photograph by Alan Poe.
Fig. 100.4 Unrelated men sharing a one-room house in Immokalee, Florida, USA. Photograph by Alan Poe.
an application process that results in a recognized entry based on a valid passport or visa. Additionally there are those individuals whose movement is regulated by international convention that recognizes refugees or asylum seekers. Along with unofficial international migrants, these individuals generate the largest amount of political controversy because of their documentation status and questions concerning their legal rights to services in the receiving location. In evidence are increasingly restrictive immigration policies and public hostility towards immigrants arriving in new locations as a result of resettlement programs. International social inequality and health disparity are significant policy challenges.4 While all the population mobility described previously constitutes some form of human migration, the term migrant is most often connected to a labourer who moves in pursuit of employment (Fig. 100.5). The working definition for ‘migrant’ used here is drawn from several sources and includes elements from the UN Convention on the Rights of Migrants,20 and from the American Heritage Dictionary:21 ‘A migrant is a person who crosses a prescribed geographic boundary by chance, instinct, or plan and stays away from their normal residences to engage in remunerated activity.’ Migration affects the numerator and the denominator of the population of interest. Because migrant workers are a mobile population with a shifting composition, the actual numbers are not reliably known. There is a common understanding that most
migrants participate in multiple industries, particularly low-wage unskilled labour such as agriculture. They usually work in the sectors known as the ‘3D’ jobs – dirty, dangerous, and demanding,22 or as SALEPs – jobs that are shunned by all except the very poor.23 Migrants in different industries are affected by similar health access factors, such as unfamiliarity with local health resources, inability to communicate in the local language, and ineligibility for publicly or privately funded health services. Their health status is also affected by environmental and occupational exposure to hazardous chemicals, dangerous and repetitive work activities, and unsanitary housing and working conditions. Migrant workers are a mobile, working, poor population that struggles with problems of healthcare access similar to those of other underserved populations, with the additional burden of having to search for new care options as they move. In addition, the desire by some to avoid contact with governmental agencies makes the access to healthcare even more complicated. Their mobility results in poor continuity of care, as they are often unable to complete medical treatments, keep track of their medical records, and obtain routine or preventive care. Mobility is both the reason for and one of the larger barriers to continuity of care. Migrant workers have other barriers to healthcare services, such as poverty, low literacy, limited transportation, limited local language proficiency, and cultural differences. In addition, most low-wage jobs are hourly and do not provide sick leave or other benefits such as insurance.24 Many employers may prefer migrant or even illegal workers, who they perceive as more ‘obedient’, willing to do more work for less pay, and having little or no recourse to the law.25 Economic pressures make them reluctant to miss work and afraid of losing their jobs if they take time off to get medical care. Migrants can face psychological stresses. They are often dislocated from their families, on their own, and with no support. The family at home may be reliant on the migrant to remit part or all of their income. What part stress may play in the development of diseases in migrants is unknown, though it is well recognized that rates of TB increase in stressed populations, e.g. in times of war.26,27
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IMPACT OF MIGRATION ON THE DISSEMINATION OF DISEASE
Box 100.2 Case study
Migration has played an historic role in the spread of disease. Genetic comparisons of Mycobacterium tuberculosis suggest a common ancestor existed an estimated 3 million years ago with the spread of complex strains that resemble M. tuberculosis, perhaps coinciding with waves of human migration out of Africa.28 The appearance of TB in ancient peoples speaks to the importance of human migration in the movement of disease.29,30 Recent discussions of the role of human migration in the movement of disease have been strongly focused on HIV, and more recently on severe acute respiratory syndrome (SARS).31,32 Countries often attempt to control the spread of disease by controlling immigration.9 For many countries, TB is a reason to deny entry to potential immigrants, or even for deportation.11 This legal stance towards TB in migrants, not only violates human rights, but also is counterproductive to disease control. It has been shown that if migrants fear that going to a physician might lead to trouble with immigration authorities, then they are significantly more likely to delay seeking care for over 2 months, leading to disease progression in the individual migrant and an increased risk of continued transmission of TB infection to others.33 An additional assumption is that migrants will not complete their treatment because of their ‘migrating’ status. Again blame for lack of services and/or adherence to treatment is placed on the migrants themselves and not the authorities.
MIGRANTS AND TUBERCULOSIS DISEASE IN LOW-BURDEN COUNTRIES For countries like the USA where migration has been a large part of population growth, concern that immigrants would bring disease into the country resulted in the development of public health screening systems and border control health policies.4 This approach came out of the focus on the recognition, identification, and management of specific diseases, illnesses, or health concerns in mobile populations either pre-departure from their country of residence or at the time and place of their arrival.34 The specific Table 100.1 Treatment outcomes of TST positive contacts presented in Box 100.2 Category
No.
Per cent of total TST positives (%), n ¼ 182
Per cent of positives started on treatment (%), n ¼ 137
Completed treatment Lost after starting treatment Stopped treatment because of side effects Never started on treatment because of previous treatment Treatment ongoing Moved or lost before starting on treatment Refused treatment Pregnant
109 13
59.9 7.1
79.6 9.5
6
3.3
4.4
1
0.5
0.7
1 19
0.5 10.4
NA NA
26 7
14.3 3.8
NA NA
896
In August 2004, a 24-year-old Guatemalan immigrant was referred to one of the authors (ELZ) after presenting to a rural Pennsylvania community health centre with a 4-week history of cough, night sweats, fever, decreased appetite, and 7 lb weight loss (from 106 to 99 lb). He had been living in the USA for 10 months while working at a factory and living with six unrelated individuals. The patient had an unremarkable past medical history and denied any substance abuse or medication use. His family history was notable in that his father, an alcoholic, had died in Guatemala in 2002 of active pulmonary TB while being treated. According to the patient, his father had been noncompliant with his treatment for TB. The estimated burden of TB in Guatemala was 77 per 100,000 in 2002 (cf. five in the USA).38 Chest radiograph showed infiltrates in both lungs with a predominance in the left upper lung field. Marked pleural thickening was noted in the left apex. Cavities were seen in the right upper lobe with associated volume loss. The patient was employed in a local factory in which the main workplace was a very large open warehouse. The work created a great deal of dust so that all employees wore masks and goggles while working. The employees took all breaks and ate all meals in a common break room. The small break room had no windows and the doors were closed at all times to minimize the dust entering the room. Because of his respiratory distress and overall debilitated condition, the patient was hospitalized and treated initially with ceftriaxone and azithromycin. Sputum smear microscopy results were reported as ‘loaded AFB’, at which time the initial antibiotics were discontinued and treatment was begun with rifampin, isoniazid, ethambutol, and pyrazinamide. He was discharged from the hospital on day three to be isolated at home. Nurses from the Department of Health visited the patient in the hospital and initiated directly observed therapy immediately after his discharge. Within one week of beginning antituberculous treatment, the patient was asymptomatic. A DNA probe for Mycobacterium tuberculosis was positive on day eight and sputum culture was positive at 4 weeks. Sputum culture revealed the sample to be susceptible to all first-line TB medications. Sputum smears remained positive (‘numerous AFB’) on day 60 after treatment was initiated, and his culture remained positive at 8 weeks of therapy, finally becoming negative at week nine. Because of the cavitation on his chest radiograph and his positive culture at 8 weeks of therapy, the continuation phase of therapy was extended to 7 months for a total of 9 months of treatment. Within days, Pennsylvania Department of Health nurses initiated testing of contacts beginning with household contacts and frequent visitors, proceeding to co-workers at the index case’s place of employment and contacts in the hospital and community health centre. In March 2005, the nurses initiated a second round of testing for those contacts that had previously tested negative. Three additional people were tested shortly afterwards. The results of contact testing produced a higher than expected rate of infection, implying a highly infectious case. Of the 307 individuals tested, 182 were TST positive (Table 100.1), 117 were negative and eight did not have the test read. All six household contacts and 80 of all other close contacts had a positive TST. Seventy per cent of co-workers from the same shift and 51% of workers from different shifts were also positive. None of the healthcare workers who provided testing and treatment were TST-positive.
activities of immigration medical screening and border control practices, which derive from the historical practices of quarantine, intend to reduce threats to the public health and/or to mitigate potential impacts on the receiving country’s healthcare services.35 The quarantine-associated historical basis of migration health practices in high-income country settings has ensured that much of the interest in health and migration has been directed towards communicable diseases,36 commonly on those diseases differentially prevalent between the migrant and host population, TB being one such disease.37 The case study in Box 100.2 highlights the
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Tuberculosis and migration
Table 100.2 Estimated total cost of treatment for case and contacts presented in Box 100.2 Item
Quantity
Cost
Nursing Physician Interpreters Clerical TB Reps HIV Reps Volunteers Medication Chest X-ray CT scan chest Total:
1,800 hr 156 hr 285 hr 250 hr 600 hr 150 hr 50 hr 480 mo/Rif 182 exams 3 exams
$55,800 $7,020 $3,420 $1,950 $18,000 $3,900 $0 $34,323 $44,226 $1,511 $170,150
challenges and issues raised by TB in a migrant community in a high-income, low-TB-burden setting, in this case, the USA. The demographics of this migrant population emphasize the need for culturally competent outreach and nursing staff in communities experiencing a marked change in population migration. While gateway locales – cities that are the traditional ports of entry for most migrants – continue to receive the largest number of Hispanic and Asian immigrants, domestic migrants are increasingly moving to new areas for economic opportunity in the labour market.39 The mobility of this population is also significant, as a highly infectious case within a mobile population requires rapid deployment of contact investigators to review all potential contacts before they move to a new work setting or return to the country of origin. Without a concentrated rapid response to this highly infectious case, a wider spread of infection throughout the community could have occurred, resulting in a larger number of active cases. The impact of a single case on a low-incidence area is challenging in terms of both material costs and human resources. The case described in Box 100.2 occurred in a small, rural community in Pennsylvania (USA) with a very low incidence of TB. In addition to the public health impact of this case, the County Health Department had to gear up to handle the wider implications of treating this case and the many contacts. Table 100.2 shows the estimated total cost of treating this case and contacts – at US$170,000, the estimated expenditure was a sizeable one. Ramping up of the TB control system can be hampered by the absence of categorical TB funding or funding for emergency public health actions. In addition, as TB cases become less common in high-income country settings, healthcare workers become less experienced in identifying and managing cases, which can lead to delay in diagnosis and poor case management.40
MIGRANTS AND TUBERCULOSIS DISEASE IN HIGH-BURDEN COUNTRIES For a number of decades attention has been focused on the problem of TB in migrant populations moving from low- to highincome countries.41–44 However, little attention has been paid to the problem of TB linked with migration in low-income country settings, both internal and international. Compared to the difference in TB prevalence and incidence rates between low- and high-income countries, the difference between low-income
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countries is often less dramatic. For example, the estimated new smear-positive pulmonary TB incidence rates for Bangladesh, India, and Nepal at 102, 75, and 81 per 100,000, respectively, show little difference.45 However, in the urban areas of lowincome countries, where most migrants live, the risk of TB transmission and infection is higher than the estimated national averages. A recently conducted survey of risk of TB infection in India found that infection rates in urban areas were consistently 1.5–2 times higher than in rural areas in all four zones of the country.46 Therefore, the issues relating to migration between and within low-income, high-TB-burden countries are significantly different than those related to migration from low- to high-income countries. In contrast to the lack of TB disease differential between many low-income countries, there is a huge variety of migration patterns in the developing world, both across international borders and internally. Many international borders are in fact ‘open’ borders, either officially, e.g. India–Nepal, or unofficially, e.g. Bangladesh–India. Internal migration in low-income country settings is mainly for work. For example, across large parts of India, millions of its poorest citizens have on average only 130 days of work available locally. Eighty-five per cent of the Indian poor are either landless agricultural workers or marginal farmers.47 They must migrate for survival, with the vast majority moving internally within India. According to official Government of India figures, over 98 million people migrated from one place to another within the country in the 1990s, the vast majority for employment.48 Possibly the true migrant population in India is almost double this figure at around 180 million.49 A similar pattern may be true for China where the migrant population in the country was estimated to be 140 million in 2000.50 Within Nepal, from the 1991 Census data, almost 10% of the native population was estimated to migrate between districts.51 It is also a little acknowledged reality that the majority (approximately 70%) of the world’s refugees and IDPs are hosted in lowincome countries.52 Unfortunately, apart from a number of studies in refugee situations, there is little research around the problem of TB in migrant populations in low-income country settings.53–55 Liberalization of population movement and the economy in China have resulted in large numbers of people leaving the rural areas for the urban municipalities and rapid urbanization. The number of migrants in Beijing, China, increased rapidly from 2.8 million in 1994 to about 4 million in 2005. The majority of migrants are young and engage in unskilled manual labour. From 1993 to 2005, the proportion of TB cases who were migrants steadily rose from around one in 10 to just over one in three.56 Two-thirds of the migrant patients were under 30 years of age compared to less than 30% of permanent residents. Cure rates were significantly worse amongst the migrants at only 37% compared to over 90% in permanent residents. Thus, migrants with TB pose a major challenge to the TB services, and to TB control, in Beijing. A similar picture is seen in Vietnam with rapid urbanization and population movement, especially of men of working age, since the economic liberalization of the late 1980s.57,58 In a number of studies in the country, it has been observed that TB notification rates among the young, especially males, in urban settings increased, most notably in industrialized districts during the period 1990–2003.59,60 It is hypothesized by the authors that this is mainly due to poor living and working conditions and internal migration, although increasing HIV coinfection rates play a role. This limited impact of directly observed treatment, short course (DOTS), control measures is seen despite the National
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Tuberculosis Programme in Viet Nam having achieved the WHO targets of 70% of case detection and 85% cure from 1997 onwards – achievements predicted to reduce TB incidence rates by 11% per year in the absence of high HIV prevalence.60,61 A little considered form of migration in low-income, high-TB country settings is migration in order to seek healthcare, mainly in urban areas. Towns and cities in low-income countries, where the number of healthcare facilities is greatest and also where referral centres may exist, have a large ‘pull’ factor on people seeking healthcare. In a study in Kathmandu, Nepal, amongst a group of migrants who had TB, almost 40% had specifically moved there, seeking a diagnosis of their disease and medical care. They tended to delay longer in seeking healthcare than locals.62 This pull factor is strongly seen at those medical colleges involved in the Government of India’s Revised National TB Control Programme (RNTCP). A large number of patients are diagnosed at these medical colleges, but few actually receive their DOTS treatment from the medical college itself (Fig. 100.6).63 Rather they are formally ‘referred back’ to receive their treatment at a health facility closer to their residence. Referral can be within the same district where the medical college is located, an adjacent district, a further district within the same state, or even a district in another state. Patients will migrate large distances to places where they perceive they will receive high-quality care, e.g. at medical colleges. The process of ‘referral for treatment’ across large distances presents major challenges to TB control programmes in order for them to provide seamless care for such patients. The risk of such patients defaulting post-diagnosis and prior to treatment is high unless a mechanism for referring them for treatment is being implemented by the TB control programme. In 2005, the RNTCP piloted such a referral for treatment in two states of India and demonstrated that it was possible to implement such a mechanism under programme field
conditions in a low-income setting and provide seamless care to patients. The programme is now in the process of scaling the mechanism across the country and piloting an electronic referral for treatment information system. A similar system for referral of migrant patients undergoing treatment for active TB disease (TBNet) while migrating throughout the United States or from the USA to another country has been functioning since 1996.64
CONCLUSIONS Migrants from low-income high-TB-burden countries account for a growing proportion, and in many regions the majority, of TB cases in high-income low-TB-burden countries.65 To date, activities in relation to migration and TB have been designed for national application and to protect host populations in high-income low-TB-burden countries from the risk of infection transmission and to mitigate the impact on their healthcare systems. However, as long as global health disparities and prevalence differentials exist, the health systems and policies in the migrant-receiving nations will continue to be challenged. Meeting health challenges through international cooperation and collaboration has become an important foreign policy component in many countries, as well as for the World Health Organization. It would appear that the time is right for a more multilateral and integrated approach to addressing the issue of TB in migrants. Enshrined in Article 2 of the United Nation’s Universal Declaration of Human Rights is the fundamental right of access to healthcare for all, despite residence status.66 Any suggested exclusion of refugees or undocumented migrants from medical care is not only unethical, but also could represent a danger of contamination to the local population.67,68
Health sector contribution in 14 urban areas, 2005 100%
N = 362,330
N = 48,056
N = 25,105
N = 73,202
TB suspects referred
All smear + cases diagnosed
New smear + cases detected
Number of patients provided DOT
90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
State government
Other government
Fig. 100.6 Health sector contribution in 14 urban areas, 2005.
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Corporate sector
Private practitioners
NGOs
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Tuberculosis and migration
Greater international recognition that the impact of migration and TB is of a much greater magnitude within the low-income high-TB-burden countries themselves via internal migration is also needed. While it is important that high-income low-TBburden countries try to protect their own citizens against the importation of TB, their respective national control and regulatory systems alone will be unable to extend their immediate mandate or authority to the source of the problem. In addition, the usefulness of screening for TB among immigrants and the rationale for investing large amounts of money in a low-prevalence country have been questioned.69 To be effective, the management of health issues resulting from population mobility will require a much closer integration of national and global health initiatives for both infectious and non-infectious disease conditions.70 Certainly the advent of a TB vaccine, new medications with a shorter treatment period, and better diagnostic tools will find immediate application for use with international and intranational migrants. It has been proposed that the optimal strategy for TB control amongst migrants in the long term would be for high-income countries to dramatically increase their investment in TB control efforts in the low-income high-TB-burden country settings. This
REFERENCES 1. Parfit M. Human migration. National Geographic 1998; No. 4(Oct):Supplement. 2. United Nations. Global population distribution, 1997. Available at URL:http://www.reliefweb.int/ mapc/world/globcity.html 3. Department of Economic and Social Affairs. World Economic and Social Survey 2004. New York: United Nations, 2004. 4. MacPherson DW, Gushulak BD, Macdonald L. Health and foreign policy; influences of migration and population mobility. Bull World Health Organ 2007; 85:200–206. 5. Stalker P. The Work of Strangers. Geneva: International Labour Organisation, 1994. 6. National Geographic. Population. National Geographic 1998;No. 4(Oct):Supplement. 7. Census Bureau, US Department of Commerce News, 13 June 2003. 8. Economic and Social Research Council. Society Today, Global migration. [online]. Available at URL: http://www.esrcsocietytoday.ac.uk/ ESRCInfoCentre/facts/international/migration.aspx? ComponentId=15051&SourcePageId=14912 9. Evans, J. Migration and health. Int Migration Rev 1987;21(3):v–xiv. 10. McHale J, Kapur D. Migration’s new payoff. Foreign Policy Nov/Dec 2003. 11. Crawley, H. Forced migration and the politics of asylum: the missing pieces of the international migration puzzle? Int Migration 2006;44(1):21–26. 12. McCarthy OR. Asian immigrant tuberculosis—the effect of visiting Asia. Br J Dis Chest 1984;78(3): 248–53. 13. Wilson ME. Travel and the emergence of infectious diseases. Emerg Infect Dis 1995;1(2):39–46. 14. Rust GS. Health status of migrant farmworkers: a literature review and commentary. Am J Public Health 1990;80(10):1213–1217. 15. Dobson J, Salt J. Review of migration statistics. Political Economy of Migration in an Integrating Europe (PEMINT), Working paper 7/2002. London: Migration Research Unit, Department of Geography, University College London, 2002. 16. Peters D, Hershfield ES, Fish D, et al. Tuberculosis status and social adaptation of Indochinese refugees. Int Migration Rev 1987;21(3):845–856.
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would address the problem of TB amongst migrants at the source. In their 2005 paper, Schwartzman et al. concluded: the U.S. government’s underwriting of the expansion of the DOTS strategy in Mexico, the Dominican Republic, and Haiti is the most effective long-term approach to reducing tuberculosis morbidity and mortality among migrants from those countries and would produce net savings in the United States. These projected domestic benefits should encourage the governments of developed countries to provide substantial and sustained funding for the control of tuberculosis abroad.71
In a subsequent paper, the same group show that a modest investment of $4.2 million for DOTS expansion in Haiti would result in 63,080 fewer TB cases, 53,120 fewer TB deaths, and net societal savings of $131 million over 20 years.72 The Haitian government is unlikely to be able to make even this modest investment into TB control activities, leading the authors to state ‘Given this, and the substantial potential humanitarian, economic, and public health benefits, we conclude that foreign donors should strongly consider investing in DOTS expansion in Haiti.’72 This would seem to be an example par excellence where all partners would win and a prime case of ‘prevention being the cure’.
17. Wares F, MPH. Personal communication with Mr UR Poudyal, Kathmandu, November 1998. 18. Nepal South Asia Centre. Nepal Human Development Report 1998. Kathmandu: Nepal South Asia Centre, 1998: 104–105. 19. Depoortere E, Checchi F, Broillet F, et al. Violence and mortality in West Darfur, Sudan (2003–04): epidemiological evidence from four surveys. Lancet 2004;364(9442):1315–1320. 20. United Nations. International convention on the protection of the rights of all migrant workers and members of their families. Adopted by General Assembly resolution 451158 of 18 December 1990. In force since 1 July 2003. New York: UN General Assembly, 1990. [online]. Available at URL:http:// www.smc.org.ph/rights/UNconven.htm 21. American Heritage Dictionary of the English Language, 4th edn. Boston: Houghton Mifflin, 2000. 22. Even dirty-dangerous-difficult jobs become hard to get. Korea Economic Weekly, 9 February 1998. 23. Bo¨hning WR, Stryk R. The impact of the Asian crisis on Filipino employment prospects abroad. SEAPAT Working Paper, International Labour Office, 2000. 24. Guerin PJ, Vold L, Aavitsland P. Communicable disease control in a migrant seasonal workers population: a case study in Norway. Euro Surveill 2005;10(3):48–50. 25. International Labour Organisation. Going home, but not willingly. World of Work 1998;25. 26. GEFONT. Paper presented to the National Workers education seminar on the Trade Union response to migrant workers, Kathmandu, 4–6 August 1996. 27. Styblo K. Epidemiology of tuberculosis. In: Selected Papers, vol. 2. The Hague: Royal Netherlands Tuberculosis Association, 1991. 28. Anonymous. Ancient disease. Nature 2005;437:7055. 29. Morse D, Brothwell DR, Ucko PJ. Tuberculosis in ancient Egypt. Am Rev Resp Dis 1964;90(4):526–541. 30. Mays S, Taylor GM, Legge AJ, et al. Paleopathological and biomolecular study of tuberculosis in a medieval skeletal collection from England. Am J Phys Anthropol 2001;114:298–311. 31. Sharp PM, Bailes E, Chaudhuri RR, et al: The origins of acquired immune deficiency syndrome viruses: where and when? Philos Trans R Soc Lond B Biol Sci 2001;356:867–876. 32. Morens DM, Folkers GK, Fauci AS. The challenge of emerging and re-emerging infectious diseases. Nature 2004;430:242–249.
33. Asch S, Leake B, Gelberg L. Does fear of immigration authorities deter tuberculosis patients from seeking care? West J Med 1994;161(6):373–376. 34. International Organisation for Migration (IOM) and World Health Organization (WHO). Migration medicine: First International Conference on the Health Needs of Refugees, Migrant Workers, other Uprooted People and Long Term Travellers. In: Seminar Report. Geneva: IOM, 1990. 35. Centers for Disease Control and Prevention (CDC). Technical instructions for the medical examination of aliens, revised 2002. Atlanta, GA. [online]. Accessed 27 May 2007. Available at URL:http://www.cdc. gov/ncidod/dq/panel.htm 36. Markel H, Stern AM. The foreigness of germs: the persistent association of immigrants and disease in American society. Millbank Q 2002;80:757–788. 37. Centers for Disease Control and Prevention (CDC). Recommendations for prevention and control of tuberculosis among foreign-born persons. Report of the Working Group on Tuberculosis among Foreign-Born Persons. MMWR Recomm Rep 1998, 47(RR-16):1–29. 38. World Health Organization (WHO). Global Tuberculosis Control. Surveillance, Planning, Financing (WHO/HTM/TB2004.331). Geneva: World Health Organization, 2004. 39. Frey, WH. Zooming in on diversity. American Demographics, July/August 2004. 40. Horne NW. Problems of tuberculosis in decline. Br Med J 1984;288:1249–1251. 41. Watkins RE, Plant AJ, Gushulak BD. Tuberculosis rates among migrants in Australia and Canada. Int J Tuberc Lung Dis 2002;6(7):641–644. 42. McKenna MT, McCray E, Onorato I. The epidemiology of tuberculosis among foreign-born persons in the United States, 1986–1993. N Engl J Med 1995;332:1071–1076. 43. Keizer ST, Annee JACM, Van Deutekom H, et al. Screening for tuberculosis among immigrants and asylum-seekers in the Netherlands: methods and results. Tuber Lung Dis 1994;75(Suppl):30. 44. Research Committee of the British Thoracic Society and Tuberculosis Association. Tuberculosis among immigrants related to length of residence in England and Wales. Br Med J 1975;2:698–699. 45. World Health Organization. Global Tuberculosis Control. Surveillance, Planning, Financing (WHO/ HTM/TB2007.376). Geneva: World Health Organization, 2007.
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46. Government of India (GoI). Annual Risk of Tuberculous Infection in Different Zones of India. A National Sample Survey, 2000-2003. Bangalore: GoI, 2005. 47. Sainath P. Everybody Loves a Good Drought. New Delhi: Penguin Books India, 1996. 48. Office of the Registrar General, Government of India. Census of India, 2001. [online]. Accessed 27 2007. May Available at URL:http://www. censusindia.gov.in/ 49. Hansen H. HIV/AIDS in India. Update (UNDP) Regional Project. HIV & Development Asia and the Pacific 1998;1(4):9. 50. Department of Population, Social Science and Technology Statistics, National Bureau of Statistics of China. Status and characteristic of migration and floating labor force. Beijing: China Statistics Press 2004:310–315. 51. Niroula BP. Internal migration. In: Population Monograph of Nepal. Kathmandu: Central Bureau of Statistics, 1995:131–165. 52. United Nations High Commissioner for Refugees (UNHCR). Statistical Yearbook 2005. Trends in displacement, protection and solutions. Geneva: UNHCR, 2007. 53. Mastro TD, Connix R. The management of tuberculosis in refugees along the Thai-Kampuchean border. Tubercle 1988;68:95–103. 54. Bhatia S, Dranyi T, Rowley D. Tuberculosis among Tibetan refugees in India. Soc Sci Med 2002;54(3): 423–432.
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55. Biot M, Chandramohan D, Porter JDH. Tuberculosis treatment in complex emergencies: are risks outweighing benefits? Trop Med Int Health 2003; 8(3):211–218. 56. Zhang LX, Tu DH, An YS, et al. The impact of migrants on the epidemiology of tuberculosis in Beijing, China. Int J Tuberc Lung Dis 2006; 10(9):959–962. 57. Completed Census Results. Vietnam Population Census, 1989, vol. I. Hanoi: General Statistical Office, 1991. 58. Completed Census Results. Population and Housing Census Vietnam, 1999. Hanoi: General Statistical Office, 2001. 59. Duc LV, Vree M, Sy DN, et al. Steep increases in tuberculosis notification among young men in the industrialized districts of Danang, Vietnam. Int J Tuberc Lung Dis 2007;11(5):567–570. 60. Huong NT, Duong BD, Co NV, et al. Tuberculosis epidemiology in six provinces of Vietnam after the introduction of the DOTS strategy. Int J Tuberc Lung Dis 2006;10(9):963–969. 61. Dye C, Gamett GP, Sleeman K, et al. Prospects for worldwide tuberculosis control under the WHO DOTS strategy. Lancet 1998;352:1886–1891. 62. Wares DF. Migration and tuberculosis in South Asia. A briefing paper. Kathmandu: WHO SEARO, 1998. 63. Salhotra V. Patients migrating for health care: experiences with a referral for treatment mechanism for TB patients in India, 2005. Presentation made at the 37th Union World Conference on Lung Health 31 Oct–4 Nov 2006, Paris, France.
64. Migrant Clinicians Network. The Monograph Series, The TBNet System. 2000. 65. EuroTB and the national coordinators for TB surveillance in the WHO European Region. Surveillance of tuberculosis in Europe. Report on tuberculosis cases notified 2002. Saint Maurice, France: Institut de Veille Sanitaire, 2004. Available at URL:http://www.eurotb.org 66. United Nations (UN). Universal Declaration of Human Rights, (1948).G.A. Res 217A (III), UN GAOR Res 71, UN doc. A/810 (1948). 67. Iseman MD, Starke J. Immigrants and tuberculosis control. N Engl J Med 1995;332:1094–1095. 68. Small PM. Towards an understanding of the global migration of Mycobacterium tuberculosis. J Infect Dis 1995;171:1593–1594. 69. Menzies D. Controlling tuberculosis among foreign born within industrialized countries. Expensive band-aids. Am J Respir Crit Care Med 2001;164(9): 914–915. 70. Gushulak BD, MacPherson DW. The basic principles of migration health: population mobility and gaps in disease prevalence. Emerg Themes Epidemiol 2006;3:3. 71. Schwartzman K, Oxade O, Barr RG, et al. Domestic returns from investment in the control of tuberculosis in other countries. N Engl J Med 2005;353:1008–1020. 72. Jacquet V, Morose W, Schwartzman K, et al. Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti. BMC Public Health 2006;6:209.
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Tuberculosis control in the workplace Franc¸ois GE Bonnici, Nani Nair, and Shaloo P Kamble
INTRODUCTION For individuals, employers and nations, TB has significant social and economic consequences. Out of the estimated nine million people to develop active TB every year, over half are in the most economically productive time of their lives (between 15 and 54 years of age), working and contributing to their families, communities and national economies.1 In general, the risk of developing TB at the workplace is related to the risk of developing TB in the surrounding community, however, healthcare workers and people in particular work environments (e.g. in mines) are at an increased risk of being infected whereas those exposed to certain elements while working (such as silica) are at an increased risk of developing active disease, once infected. The resurgence of TB in the last decade of the twentieth century and the emergence of multidrug-resistant disease demonstrate that TB remains a threat that employers and nations cannot afford to ignore. Effective TB control measures in the workplace are therefore key elements of broader national and global strategies to reach the Millennium Development Goal of halving and beginning to reverse the incidence of TB by 2015 (MDG Goal 6, Target 8).2
THE WORKPLACE AND EMPLOYMENT SECTOR The workplace refers to the physical work site of an employee, such as a factory, an office, a hospital, a mine, a farm or even a prison. This definition is not merely limited to the main place of work, but cafeterias, restrooms, training sessions, business travel, conferences and other work-related venues are also included. The employment sector denotes public, para-statal or private sector organizations (organized or informal) with expertise in providing services and products to the community. Examples of such organizations include everything from state-run railways and hospitals to private business enterprises in almost any sector from heavy industries (e.g. steel plants or cement plants) to light manufacturing (e.g. IT and electronic consumables) to retail (e.g. hotel chains or banks).
ECONOMIC AND SOCIAL IMPLICATIONS OF TUBERCULOSIS IN THE WORKPLACE Globally, it is estimated that TB leads to a decline in worker productivity on the order of US$13 billion annually, although new research yet unpublished by the World Bank suggests that the global economic
burden of TB mortality might be several times this figure.3 Recognizing the consequences the disease has on a country burdened by TB, the Government of India has estimated the impacts of TB on their national economy, on individuals and their families (see Box 101.1). Businesses worldwide are also recognizing that the TB epidemic can do tremendous damage to their operations. According to the World Economic Forum’s Global Business Survey in 2005 of 10,993 business leaders of which 1,487 (13.5%) are from Africa, 81% of African business leaders expressed some concern over the impact of TB on their business in the next 5 years, with 31% seriously concerned.4 The costs of TB to employers can be significant, particularly in high-burden countries and in regions with high HIV prevalence. Tuberculosis in the workplace can disrupt workflow, reduce productivity and increase both direct costs related to care and treatment and indirect costs such as the replacement and retraining of workers. Certain employers have measured the direct costs of TB to their operations (see Box 101.2). A diagnosis of TB has a serious impact on the individual worker. Employees suffering from TB are absent for months from work, losing skills, experience and proportionate income, incurring additional costs for themselves and for their employers. It implies prolonged illness, frequent periods of absenteeism, loss of wages, sometimes even loss of job entirely and other forms of discrimination and suffering. Family members of workers with TB are affected as well. Apart from being at a higher risk of getting infected due to close
Box 101.1 Socioeconomic impact of tuberculosis in India
41,42
Tuberculosis kills more adults than any other infectious disease, almost 400,000 deaths annually. Tuberculosis predominantly affects those in economically productive years (15–54). Loss of 3–4 months on average of working time, translating to roughly 20–30% of the household’s annual income. Estimated annual direct cost of TB to the Indian healthcare system is approximately US$300 million while the annual indirect costs are estimated to be US$3 billion. Estimated average total cost of TB to an individual with the disease is US$171.
Based on data from TB in India: Annual Status Report, 2005. Frontline TB Care Providers working towards freedom from TB. Central TB Division, Ministry of Health and Family Welfare, Government of India and Int J Tuberc Lung Dis. 1999 Oct;3(10):869–77, Socio-economic impact of tuberculosis on patients and family in India. Rajeswari R, Balasubramanian R, Muniyandi M, et al.
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Box 101.2 Case study – Cost-effective workplace management at 1,3 AngloGold (South Africa)
Box 101.4 Industries associated with increased risk of occupational lung disease with increased predisposition to active tuberculosis
AngloGold, South Africa, estimated that each case of TB in its operations in the Vaal River and West Vilts regions cost $410 per case in lost shifts among unskilled employees. AngloGold runs a comprehensive TB management programne for the workplace. They have found that an effective TB detection and management programme can lead to net cost savings. AngloGold spends about US$90 per employee per year and accrues a benefit of US $105 through the prevention of active TB among HIV-infected employees.
Guidelines for Workplace TB control activities: the contribution of workplace TB control activities to TB control in the community World Health Organization, Geneva (WHO.CDS.TB.2003.323) and Anglo Gold Case Study, Global Health Initiative Case Study Library, World Economic Forum. http://www.weforum.org/en/initiatives/globalhealth/Case%20Study% 20Library/index.htm
contact with the infected case at home, a reduction in household income adversely affects the health and well-being of the family. For example, children in TB-affected families were shown to be withdrawn from school to supplement household incomes in India, with a fifth of schoolchildren discontinuing their studies.5 When TB affects women workers, the impact on the individual and the family is even greater.5 Women generally have poorer accessibility to health services, face greater discrimination and get less family support in times of illness, especially when they suffer from diseases like TB and human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS), which still continue to carry stigma in many societies.
OCCUPATIONAL RISK OF TUBERCULOSIS HIGH-RISK WORKPLACES People working in settings that entail exposure to hazardous chemicals or dusts are at a higher risk of developing occupational lung disease, which in turn predisposes workers to a higher risk of developing active TB (see Box 101.3). Occupational settings with an increased proclivity to TB are mining, work in foundries, blasting operations, glass and ceramic manufacture and stone cutting.5,6 Box 101.4 lists industries associated with an increased incidence of occupational lung disease and TB. All pneumoconioses and occupational lung diseases pose a marginal increase in the risk of developing active TB; however, cumulative exposure to silica dust that emerges from the mining of hard rock (such as granite or gold-bearing quartz) dramatically increases the risk of mine workers developing active TB.7–9 The incidence of TB in mines has been found to be up to 15 times higher than in the general population. Miners with advanced
Mining Especially silica dust exposure from mining of hard rock (granite or gold bearing quartz) All pneumoconioses from mining other minerals. Metalwork in foundries. Blasting operations. Glass and ceramic manufacturing. Stone cutting. Textile industry.
silicosis have an increased incidence of active TB; however, studies in South Africa have confirmed that exposure to silica dust increases the risk of developing TB even in the absence of radiologically detectable silicosis.10 Further studies have also confirmed that silico-TB is associated with increased and premature mortality compared with uncomplicated TB alone.11 In addition silicosis is often mistaken for TB and vice versa, on both clinical presentation and radiological findings, making the diagnosis and management of patients more complicated and occasionally flawed. Both illnesses present clinically with chronic cough, fever and weight loss and with fibrotic changes on chest radiograph. Protection of workers from occupational exposure to silica, dust and chemicals requires adequate ventilation of mines and closed environments. Environmental interventions range from the expensive installation of directional air flow ventilation systems and air disinfection devices to more affordable measures such as air filters within existing heating or air-conditioning units to more simple measures such as opening windows and doors to facilitate air circulation. Standard measures to protect workers should also include regular monitoring for dust exposure and screening for TB in high-risk workplaces and adequate personal protection (such as face masks).12 Although the exposure to chemicals, silica and dust increases the risk of developing occupational lung disease and consequently active TB, other factors, such as overcrowded living conditions, poverty, poor sanitation and high HIV/AIDS prevalence (see later) in the community, may also contribute, particularly in those industries
Box 101.3 Pneumoconiosis and silicosis Pneumoconiosis: The general term for lung disease caused by inhalation of mineral dust. Silicosis: A fibronodular lung disease caused by inhalation of dust containing crystalline silica (alpha-quartz or silicon dioxide), or its polymorphs (tridymite or cristobalite). Risk factors for silicosis include any work that includes exposure to silica dust. Quartz, the most common form of crystalline silica, is abundantly present in granite, slate and sandstone. Mining, stone cutting, quarrying, road and building construction, work with abrasives manufacturing, sand blasting and many other occupations and hobbies involving exposure to silica.
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Fig. 101.1 Advanced pulmonary TB. This chest radiograph reveals the presence of bilateral pulmonary infiltrate, and ‘caving formation’ present in the right apical region. Source/Credit: Public Health Image Library (PHIL), Centers for Disease Control and Prevention. Public domain, free of any copyright restrictions.
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Box 101.5 Workplace environments with occupational risk of exposure to tuberculosis
Rights were not granted to include this content in electronic media. Please refer to the printed book.
Fig. 101.2 Mining hard rock quartz in South Africa. Source/Credit: Awaiting copyright permission from New Jersey Medical School.
with large, migrant workforces, e.g. in mining, oil and gas, chemical and manufacturing (Figs 101.1 and 101.2). There is anecdotal, but insufficient evidence of the risk of TB transmission in workplaces with a high density of close contact such as restaurants, shops and shopping malls, pubs and nightclubs and open-plan offices.13,14
TUBERCULOSIS AND HEALTHCARE WORKERS The risk of transmission of TB mycobacteria from individuals with TB to healthcare workers has been known for decades.15 The risk is greatest when a large number of patients with infectious (smearpositive) TB are managed within a healthcare facility and when drug-resistant forms of the disease are present in patients cared for by healthcare workers.16 However, these risks can be mitigated with effective infection-control practices.17 In high-income countries, the burden of TB among healthcare workers has declined dramatically over several decades, due to the reduction in TB incidence in the general population and the implementation of comprehensive recommendations of infectioncontrol practices to protect healthcare workers by reducing nosocomial transmission.18 A recent review of healthcare workers in high-income countries showed the overall incidence of TB disease in the general population and native healthcare workers was less than 10 and 25 per 100,000 per year, respectively.19 However, healthcare workers in low- and middle-income countries that carry more than 90% of the global TB burden face much higher risks. In a recent systematic review of 51 studies, the annual incidence of TB disease in healthcare workers in lowand middle-income countries ranged from 69 to 5,780 per 100,000 (with the attributable risk for TB disease compared to
Increased occupational risk of nosocomial transmission to TB in: Healthcare facilities with standard infection-control practices to reduce nosocomial transmission: In-patient TB facilities Bronchoscopy suites Intensive care units Autopsy suites Microbiology laboratories. Healthcare facilities with few or poor infection-control practices to reduce nosocomial transmission:21 Internal medicine wards Surgical suites Emergency facilities Certain medical occupational categories in particular at higher risk in these settings (radiology technicians, laboratory technicians, patient and ward attendants, nurses, ward attendants paramedics, clinical officers). Insufficient evidence of occupational risk in: Facilities that serve people at increased risk of active tuberculosis: Correctional settings (e.g. prisons) Long-term care facilities Home care services Specialist outpatient clinics (e.g. HIV/AIDS clinics) Homeless shelters.
the risk in the general population ranging from 25 to 5,361 per 100,000 per year).20 These countries often have limited resources and even low-cost strategies to decrease nosocomial TB transmission are infrequently used.21,22 The large variation in the risk to healthcare workers is explained by the wide differences in healthcare facilities and the populations that they serve. This variation is determined by several factors: the socioeconomic environment, the organizational structure of healthcare facilities, climate and population density. A number of additional factors may also contribute to nosocomial transmission of TB in resource-limited countries. These include delays in seeking care, the health system’s ability to provide timely and appropriate diagnosis and treatment and an underestimation of the risks of transmission by healthcare workers. Box 101.5 shows specific work locations and occupational categories associated with acquiring TB disease. Several studies have also shown that medical and nursing students have a higher incidence of TB infection and disease.23–25 Tuberculosis among health workers constituted among an average 3% of all TB cases in various settings.26 In countries with limited resources control of the environmental factors in healthcare settings is especially important, as these centres are often settings of a high degree of transmission. Faulty sputum collection, laboratory testing procedures, and unnecessary and prolonged institutional care, generally in overcrowded conditions further aggravate the risks of transmission. To institute infection-control measures at healthcare facilities is therefore imperative.
INFECTION-CONTROL STRATEGIES IN HEALTHCARE FACILITIES TO REDUCE RISK TO HEALTHCARE WORKERS There are three levels of infection-control measures to reduce the risk of transmission of TB bacilli in healthcare facilities: (i) administrative, (ii) environmental/engineering and (iii) personal
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protection.27 The administrative measures are the most important since any environmental controls and personal respiratory protection are often difficult to implement. Valuable administrative measures include early diagnosis of potentially infectious TB patients, prompt separation or isolation of infectious TB patients and the prompt initiation of appropriate antituberculous treatment. Other important measures include an assessment of the risk of transmission in the facility, an infectioncontrol plan that outlines the measures that should be taken and adequate training of healthcare workers to implement the plan. Since the exposure to infectious droplet nuclei cannot be completely eliminated, various environmental control methods including UV lighting, laminar air flow systems and HEPA filters can be used in high-risk areas to reduce the concentration and thereby the risk of inhalation of droplet nuclei containing TB bacilli. Many of these environmental control measures require resources not available in most provincial, district and health centre level facilities in developing countries where the burden is highest. However, many simple, cheap and effective steps such as opening windows to allow in sunlight and increase natural ventilation, using fans to control the direction of air flow, can be easily be implemented in resource-limited settings.22,26 A third control mechanism is personal protection for healthcare workers themselves. Some guidelines recommend regular screening of healthcare workers during employment and offering Bacillus Calmette-Gue´rin (BCG) immunization should they not have been previously vaccinated.27 Personal respiratory protective devices for healthcare workers, such as tight-fitting masks over the mouth and nose capable of adequately filtering out infectious particles, are more expensive than surgical masks. Surgical masks (cloth, paper) commonly used by healthcare workers do not filter out infectious droplet nuclei, although they may be of some use for patients to promote ‘cough hygiene’. These are the least effective of the three infectioncontrol measures, and cannot therefore be recommended to supplant the more effective, less expensive infection-control measures described under administrative and environmental controls.
SPECIAL CONSIDERATIONS IN HIGH-RISK WORKPLACES In a number of workplace settings, protecting a workforce from TB requires measures beyond those described so far. These include settings with high HIV incidence and high rates of drug resistance. In countries with high HIV prevalence, employer healthcare programmes should include HIV/AIDS activities. Opportunities exist to link HIV and TB activities as part of such employer-based programmes. Intensive TB control strategies including prompt investigation of TB symptoms may be an effective way of controlling prevalent TB in high-HIV-prevalent populations.29 In addition, HIV-infected TB patients should be offered extended care, with cotrimoxazole to reduce morbidity and mortality from opportunistic infections. HIV-infected patients at risk of TB exposure at work should receive isoniazid prophylaxis to decrease the risk of both first episodes and recurrences of TB once active disease has been ruled out.30 In particular, emphasis should be placed on patient counselling and confidentiality. Concerns among employees regarding confidentiality at work appear to be major barriers to accessing care. Prompt recognition of multidrug-resistant (MDR) TB and extensive drug-resistant (XDR) TB requires access to specialist laboratories with drug sensitivity and testing capabilities.
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Unfortunately, MDR- and XDR-TB are transmitted in the same manner as drug-susceptible mycobacteria. There is some evidence to show comparable infection rates; hence there is the importance for early identification and employer awareness about drug-resistant TB, in order to protect both workers and community from its transmission.31 The management of drug-resistant cases is complicated and requires specialized technical guidance with referral.
MANAGEMENT OF TUBERCULOSIS CONTROL IN THE WORKPLACE THE EMPLOYMENT SECTOR’S ROLE IN TUBERCULOSIS CONTROL The role that employers can play in TB control is often underestimated. There are two major ways in which the employment sector can contribute to TB control in complementing public sector and civil society activities. The employment sector can provide: 1. significant resources, both core business competencies and financial resources; and 2. significant reach to patients not easily reached through the public healthcare system. Private sector organizations have expertise in management, communication and country-specific knowledge which they could use to complement national TB programme activities. This includes the ability to manage projects including the supply and distribution of products; and to communicate, market and create innovative social mobilization techniques, using their experience at global, regional and country levels. Often the employment sector is ideally placed to identify and treat TB cases in employees, their immediate families and the communities that surround large business operations in rural or remote environments. Employees and their families tend to use health services provided by the employer and may not be aware or be able to easily access those provided by the public sector. Some employees have higher incomes and may be more likely to seek private sector treatment. Some potential patients are difficult to reach for national TB programmes; however, for some employers, the same people are easy to reach. Employers can raise employees’ awareness of TB, educate them to identify common symptoms, encourage people with symptoms to seek care and ensure they receive treatment under directly observed treatment, short course (DOTS), at, or through, the workplace. In addition, business operations like plantations, cement works and mines are often based in remote and hard-to-reach locations, often situated far away from public health clinics, making it very difficult and certainly much more expensive, for people to access healthcare. Large employers located in these areas are ideally placed to establish health services which include TB control activities. The services of these workplace clinics can then be extended to the adjacent community, increasing access to health and TB control services to benefit both public health and the business sector. Programme managers of national TB programmes have a mandate to work with potential partners, including business and industry, to implement TB management programmes. Both the Guidelines for Workplace TB Control Activities (2003 WHO/ILO) and the Global Plan to Stop TB 2006–2015 encourage national TB programmes to form partnerships with employers and develop workplace interventions for TB.3,32
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Tuberculosis control in the workplace
STEPS TO ESTABLISH TUBERCULOSIS SERVICES IN THE WORKPLACE Undertake a situational analysis A situational analysis is the first step in implementing a workplace programme for TB. This provides management with the necessary information to plan by assessing the extent of the TB problem in the workplace, the existing services, availability of trained health staff and opportunities to collaborate with the national TB control programme. Advocate with stakeholders As with any new initiative, extensive advocacy efforts are needed to garner support of stakeholders – management at various levels, health staff, workers and unions – of the benefits of a TB control programme. This could involve dissemination of informational and educational materials, explaining the dangers of undiagnosed and untreated TB and how the proposed interventions will benefit both employees and employers. Formulate policy and implement an action plan A policy on TB control in the workplace should be formulated in line with the national policy if such policy exists in consultation with different stakeholders, while the implementation plan should be developed with workplace health staff and the appropriate TB control centre, based on the situational analysis and the resources available to implement it. GUIDING PRINCIPLES TO INTRODUCE TUBERCULOSIS CONTROL IN THE WORKPLACE Outlined below are the key guiding principles for the introduction of TB services in the workplace, based on the experiences emerging from a number of workplace initiatives around the world.33–35
Building broad commitment and dedication to tuberculosis control Commitment should emanate from top management through workers’ unions and even from the standard employee. It should be reflected adequately, not only in budget allocations, but also in the endorsement of publicizing, disseminating and underwriting policies relating to TB amongst their workers. Developing a tuberculosis workplace policy A workplace policy on TB should be based on existing national policy. The policy should be developed and formalized in consultation with all stakeholders including the national TB programme, corporate management, departments of trade and labour, occupational health professionals, workers’ unions and communities. It should be based on the principle that workers have a right to work in environments that do not pose undue hazards to health and that employers have the responsibility towards employees who suffer on account of any workplace or occupation-related risks, including TB. The policy should guarantee that no employee is dismissed on account of having TB, ensure non-discrimination, confidentiality, equal opportunities for employment and ready access to treatment. Providing a safe workplace environment Airborne transmission of TB is enhanced when workers are confined to small, enclosed spaces that lack sufficient ventilation to clear the air through dilution or removal of infectious droplet nuclei. A healthy workplace should guarantee a healthy work
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environment that will minimize the transmission of TB. Those working in mines, for example, should be provided special environmental protection such as systems that will allow a rapid inflow of fresh air into mine shafts.
Implementation of the Stop TB Strategy as an integral part of ongoing workplace health services The introduction of the Stop TB Strategy and DOTS services into the various workplace settings should as much as possible utilize or build on existing facilities or arrangements already in place to provide healthcare to employees.36 Many large businesses already have medical infrastructure, staff and budgets in place. The only additional investments required may be training of the existing health staff, provision of extra supplies such as antituberculous drugs, or facilitating laboratory diagnosis. Many of these are already made available free of cost to collaborating businesses by governments in high-TB-burden countries. Establishing collaborations Collaborations with committed partners from different sectors including employees’ associations and community-based NGOs are most useful for getting the needed support for a workplace programme and feedback on implementation. As most workplaces may not have well-established medical services on site, collaborations with nearby government, NGO or private health facilities should be sought and formalized. Collaborations are more likely to succeed when the benefits of such partnerships are shared equally between the partners, giving each partner a sense of shared ownership of the programme. Respecting the rights of employees and patients Employees and patients have the right to demand that their reports, records and status are kept confidential by the health staff and not disclosed to the management or others. Treatment compliance is much more likely to succeed if this is respected. Providing social welfare benefits to patients and their families Even if medication is provided free of cost, there are often other expenses incurred such as transportation costs and money spent on nutritional supplements, in the face of lost wages due to absenteeism. These are often deterrents to compliance with treatment regimens. Social welfare benefits like free treatment, retaining sick workers on the payroll during treatment, free transportation to health facilities and food support are important incentives to help workers complete their treatment. Strengthening health promotion and education Workers should have easy access to user-friendly informational material in the language commonly spoken at the workplace. Interactive health education sessions to demystify TB, remove the stigma attached to the disease, explain signs and symptoms and persuade employees to come forward for diagnosis if they have any symptoms should be held on a regular basis. Monitoring and reviewing progress The programme should be closely monitored for quality and compliance in order that quick remedial action can be taken if problems arise during implementation. The progress of each patient should be reviewed on a regular basis and defaulters traced promptly. Regular reports must be sent in standardized formats to the national TB programme on individual patient progress as well as to corporate management on progress with the workplace interventions.
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Recognizing and rewarding success Workers who have successfully completed their treatment and have been declared cured should be acknowledged, either privately or publicly, depending on whether the worker wishes to make his or her identity known. Public recognition provides the opportunity to further educate employees on TB, on the importance of seeking diagnosis without shame or fear of stigma. National TB programmes must also publicly acknowledge the commitment and initiative taken by businesses or industries in addressing the problem of TB (Box 101.6). PILLARS OF TUBERCULOSIS CONTROL IN THE WORKPLACE (FIG. 101.3) Detecting tuberculosis cases in the workplace Detecting TB cases first requires the identification of those suspected of having TB, typically through symptoms or through regular screening, followed by confirmatory tests. The diagnosis of pulmonary TB is confirmed by smear microscopy and mycobacterial culture to detect the presence of TB bacilli. While a chest radiograph may indicate TB, diagnosis primarily relies on sputum microscopy and culture particularly in the workplace setting, since the radiological findings of a number of occupational lung diseases closely resemble the radiological findings of TB.37 Early and accurate detection of infectious cases is vital to prevent the further spread of TB, particularly in closed and overcrowded work environments. It will also prevent prolonged illness, treatment failure and/or the development of MDR-TB. If diagnostic facilities are 35
Box 101.6 Case study – India Business Alliance to Stop TB
The India Business Alliance to Stop TB (IBA) was developed by the Global Health Initiative (GHI) of the World Economic Forum to stimulate and facilitate business sector engagement in TB control in India through catalyzing partnerships, advocacy, technical support for developing policies and programmes and delivering TB preventive and treatment services through partnerships. The IBA was launched on World TB Day, 24 March 2004, to educate, test, treat and support company employees and to raise public awareness of thistogrowing health threat – a first Rights were not granted include public this content in electronic media. Pleaseapproximately refer to the printed book.people, for India and the world. By 2006, four million including the workforce, their dependents and community, were estimated to be covered by the 32 member companies of the India Business Alliance through different interventions towards TB care and control in partnership with the Revised National TB Control Programme (RNTCP), Confederation of India Industry (CII), World Health Organization and Stop TB Partnership. It serves as a model for similar initiatives, currently being replicated in China through the China Health Alliance. S Puri Kamble, F Boldrini, F Bonnici. The India Business Alliance to Stop TB: An innovative partnership in TB Control. Poster PS-61723–04, 37th Union World Conference on Lung Health, Paris, 2006.
Management support and employment buy-in Detect TB cases
Provide treatment
Report cases and track outcomes
Uninterrupted TB drug supply
Fig. 101.3 Key elements of a successful TB workplace programme.
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Box 101.7 The Youngone Industries tuberculosis programme, 1 Bangladesh Youngone Sports Shoe Industries Ltd was established in 1988 in the Republic of Korea. It is the largest employer in the Chittagong Export Processing Zone in Bangladesh with about 22,000 employees, 85% of whom are women between 18 and 30 years. In 1996 TB was recognized as a serious problem and, in partnership with the national TB programme of Bangladesh, a workplace TB control programme was designed. Company policy was formulated to state that no employee would be dismissed from service on account of TB, that employees could return to work when well and that treatment under DOTS would be provided at the company’s medical centre. A team of 10 doctors, 15 nurses and 40 health counsellors received training in the detection and management of TB. Counsellors encouraged workers with symptoms to come forward for TB screening. They were then referred to the local government hospital for diagnosis. A workplace laboratory for sputum collection and microscopy was also established. Health education programmes addressed the issues of fear, stigmatization and discrimination in addition to other aspects of TB. In the year 2002 alone, 100 TB cases were diagnosed among the 22,000 workers. Through home visits, counsellors motivated patients to continue their treatment, recording an impressive treatment success rate of 88%. The sustained high-level management and company commitment has resulted in a successful plan for prevention and control of TB among employees. DOTS at the Workplace. Guidelines for TB Control Activities at the Workplace. New Delhi, Regional Office for South-East Asia, World Health Organization 2003.
not available at the workplace, suspect cases should be referred to the nearest health facility for these tests.
Treating all detected cases and ensuring treatment adherence It is most important that the entire course of therapy is given according to the standard TB regimens recommended by the national TB programme and that the drugs given are of good quality.38 Non-adherence to treatment is likely to lead to treatment failure and possibly drug resistance as well. A responsible person who facilitates adherence to treatment by supporting the patient and supervising treatment is often referred to as a ‘DOT provider’.39 A healthcare professional, supervisor at the workplace, community health worker or a trusted colleague of the patient can all provide such support at the workplace. Employees should have the option of identifying the most convenient provider in their case. The possible side effects the drugs may produce must also be mentioned with the assurance that this problem, if reported to the health staff in time, can be dealt with appropriately. When services and drugs are given free of charge, TB services are easily accessible and convenient to attend and the worker continues to receive a salary and other benefits, adherence to treatment is much more likely to succeed (Box 101.7). Guaranteeing an uninterrupted supply of good quality antituberculous drugs Should drug treatment be given at the workplace, drug requirements should be realistically ascertained and their procurement planned well in advance to ensure an uninterrupted drug supply. Close collaboration with the national TB programme is essential to procure good quality drugs.
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Tuberculosis control in the workplace
Recording and reporting A TB treatment record comprises either a digital or card record of patient treatment, with basic patient information and additional details related to the daily monitoring of drug administration. This record is also used to declare the outcome of treatment. It is important for a workplace programme to maintain such records, in order to register patients on local and national TB registers for quarterly and annual reports. The World Health Organization standard reporting system includes laboratory and treatment registers, quarterly reports on case-finding and a quarterly report on treatment outcomes.40 Regular review and monitoring The management should closely review and monitor progress together with the national TB programme staff of the country in order to ensure both the quality and cost-effectiveness of services being provided and to take quick remedial action when required.
REFERENCES 1. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO/ HTM/TB/2006.362. Geneva: World Health Organization, 2006. 2. Health in the Millennium Development Goals, Implementation of the United Nations Millennium Declaration, Report of the Secretary-General (A/57/ 270). New York: UNSG, 2002. 3. World Health Organization. Guidelines for Workplace TB Control Activities: The Contribution of Workplace TB Control Activities to TB Control in the Community. WHO.CDS.TB.2003.323. Geneva: World Health Organization, 2003. 4. Global Business Survey, 2005. Geneva: World Economic Forum, 2005. 5. Davies JC. Silicosis and tuberculosis among South African gold miners—an overview of recent studies and current issues. S Afr Med J 2001;91:562–566. 6. Rosenman KD, Hall N. Occupational risk factors for developing tuberculosis. Am J Ind Med 1996;30:148–154. 7. Corbett EL, Churchyard GJ, Clayton T, et al. Risk factors for pulmonary mycobacterial disease in South African gold miners. A case-control study. Am J Respir Crit Care Med 1999;159(1):94–99. 8. van Sprundel MP. Pneumoconioses: the situation in developing countries. Exp Lung Res 1990;16(1):5–13. 9. Sherson D, Lander F. Morbidity of pulmonary tuberculosis among silicotic and nonsilicotic foundry workers in Denmark. J Occup Med 1990;32(2):110–113. 10. Hnizdo E, Murray J. Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners. Occup Environ Med 1998; 55(7):496–502. Erratum in: Occup Environ Med 1999; 56(3):215–216. 11. Churchyard GJ, Kleinschmidt I, Corbett EL, et al. Factors associated with an increased case-fatality rate in HIV-infected and non-infected South African gold miners with pulmonary tuberculosis. Int J Tuberc Lung Dis 2000;4(8):705–712. 12. Guild RH, Ehrlich RI, Johnson JR, et al., eds. Handbook of Occupational Health Practice in the South African Mining Industry. Johannesburg: Safety in Mines Research Advisory Committee, 2001. 13. Pettit S, Black A, Stenton C, Black N. Outbreak of tuberculosis at a Newcastle public house: the role and effectiveness of contact screening. Commun Dis Public Health 2002;5(1):48–53. 14. Gronauer W. [Employees and regular customers of restaurants and discos as transmitters of tuberculosis.] Gesundheitswesen. 1994;56(1):33–36. [In German.]
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CONCLUSION The workplace is one of the most appropriate settings to implement TB control, since people most affected by TB are between the ages of 15 and 54 years of age. These men and women, whether working in healthcare facilities, offices, factories or small-scale industries can be easily cared for through workplace interventions, thus saving lives, improving productivity and benefiting both workers and employers. The employment sector has a significant stake and role in controlling TB, from the responsibility for the health of employees on its premises through to saving the costs due to disruption of work schedules and the need to replace and retrain workers lost to the disease. Reducing transmission, protecting workers and providing TB services in the workplace is both feasible and costeffective in most high-risk settings, and can often be integrated with health services already being provided to workers and sustained through supervision by a well-informed management.
15. Fennelly KP, Iseman MD. Health care workers and tuberculosis: the battle of a century. Int J Tuberc Lung Dis 1999;3:363–364. 16. Pearson ML, Jereb JA, Frieden TR, et al. Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis. A risk to patients and health care workers. Ann Intern Med 1992;117:191–196. 17. Jensen PA, Lambert LA, Iademarco MF, et al. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR Recomm Rep 2005;54:1–141. 18. Fella P, Rivera P, Hale M, et al. Dramatic decrease in tuberculin skin test conversion rate among employees at a hospital in New York City. Am J Infect Control 1995;23:352–356. 19. Seidler A, Nienhaus A, Diel R. Review of epidemiological studies on the occupational risk of tuberculosis in low-incidence areas. Respiration 2005;2:431–446. 20. Joshi R, Reingold AL, Menzies D, et al. Tuberculosis among health-care workers in low- and middleincome countries: a systematic review. PLoS Med 2006;3(12):e494. 21. Harries AD, Maher D, Nunn P. Practical and affordable measures for the protection of health care workers from tuberculosis in low-income countries. Bull World Health Organ 1997;75:477–489. 22. Pai M, Kalantri SP, Aggarwal AN, et al. Nosocomial tuberculosis in India. Emerg Infect Dis 2006;12:1311–1318. 23. Harries AD, Karnenya A, Namarika D, et al. Delays in diagnosis and treatment of smear-positive tuberculosis and the incidence of tuberculosis in hospital nurses in Blantyre, Malawi. Trans R Soc Trop Med Hyg 1997;91:15–17. 24. Sidibe K, Zuber P, Wiktor SZ, et al. Tuberculin skin testing reactivity among health care workers and level of exposure to tuberculosis patients in Abidjan, Cote d’ Ivoire. Int J Tuberc Lung Dis 1997:1(Suppl):S103. 25. Dq AN, Limpakarnjarat W, Uthaivoravit PLF, et al. Increase risk of Mycobacterium tuberculosis infection related to the occupational exposure of health care workers in Chiang Rai, Thailand. Int J Tuberc Lung Dis 1999;3:377–381. 26. World Health Organization. Guidelines for Prevention of Tuberculosis in Health Care Facilities in Resource Limited Settings. WHO/CDS/TB/1999.269. Geneva: World Health Organization, 1999. 27. Centres for Disease Control and Prevention. Guidelines for preventing the transmission of mycobacterium tuberculosis in health care facilities. MMWR Morb Moratl Wkly Rep 1994;43(RR13):1–132. 28. National Institute for Health and Clinical Excellence. Tuberculosis: Clinical Diagnosis and Management of Tuberculosis, and Measures for Its Prevention and Control.
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Clinical Guideline 33. London: NICE, 2006. Available at URL:http://www.nice.org.uk/page. aspx?o=CG033NICEguideline Corbett EL, Bandason T, Cheung YB, et al. Epidemiology of tuberculosis in a high HIV prevalence population provided with enhanced diagnosis of symptomatic disease. PLoS Med 2007; 4(1):e22. Corbett EL, Marston B, Churchyard GJ, et al. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet 2006;367(9514):926–937. Doyle AJ. Tuberculosis: preventing occupational transmission to health care workers. AAOHNJ 1995;43(9):475–481. Stop TB Partnership and World Health Organization. Global Plan to Stop TB 2006–2015. WHO/HTM/ STB/2006.35. Geneva: World Health Organization, 2006. Protecting Your Workforce from Tuberculosis: A Toolkit for an Integrated Approach to TB and HIV for Businesses in South Africa. Global Health Initiative, World Economic Forum. 2008. TB Management in the Workplace: An Introduction for Businesses in India. Global Health Initiative, World Economic Forum, 2004. Puri Kamble S, Boldrini F, Bonnici F. The India Business Alliance to Stop TB: an innovative partnership in TB control. Poster PS-61723-04, 37th Union World Conference on Lung Health, Paris, 2006. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952–955. Toman K. Tuberculosis Case-Finding and Chemotherapy: Question and Answers, 2nd edn. Geneva: World Health Organization, 2004. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. WHO/ CDS/TB/2003.313. Geneva: World Health Organization, 2003. World Health Organization. Adherence to Long-Term Therapies: Evidence for Action. Geneva: World Health Organization, 2003. World Health Organization. Revised TB Recording and Reporting Forms and Registers. Geneva: World Health Organization, 2006. Central TB Division. Frontline TB Care Providers Working towards Freedom from TB. TB in India: Annual Status Report, 2005. Ministry of Health and Family Welfare, Government of India. Rajeswari R, Balasubramanian R, Muniyandi M, et al. Socio-economic impact of tuberculosis on patients and family in India. Int J Tuberc Lung Dis 1999;3(10):869–877.
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Tuberculosis and poverty S Bertel Squire and Rachael Thomson
INTRODUCTION Tuberculosis generally affects the most vulnerable: those who live in poverty, are marginalized, or are economically and socially excluded. So what can be done to support vulnerable people to access proper TB services and cope when the disease affects them or their families? The association between poverty and TB is widely discussed. In a global analysis it is clear that the highest burden of TB is found in poor countries. Fifteen of the 22 countries that account for 80% of the world’s TB burden are classified as low income (GNI per capita of less than US$875), five as low-middle income, and only two as upper-middle income.1,2 Within-country analysis suggests that the prevalence of TB is higher among the poor and other vulnerable groups such as the homeless.3 Deprived areas tend to have higher rates of TB incidence.4,5 This chapter discusses why poor people are most affected by TB and particularly focuses on possible ways of overcoming the barriers they face in accessing services. These are key issues which have central implications for the manner in which TB control is delivered, and they correspond with Steps 1–3 of the six steps (see Box 102.1) laid out in the WHO guide ‘Addressing Poverty in TB Control: Options for National TB Control Programmes’.6 The chapter is, therefore, structured around selected examples and case studies which are presented in line with these three steps. The Global Plan to Stop TB uses these steps as a roadmap for the way in which the Global Stop TB Partnership will address poverty with the aim that all countries will:7 1. develop the capacity to monitor the extent to which TB control reaches and serves the poor and vulnerable; and 2. develop key strategies for improving access to TB control for the poor and vulnerable.
ESSENTIAL CONCEPTS The term ‘poor’ in this chapter refers throughout to a range of disadvantage (not just income poverty) including a lack of material well-being, of infrastructure, and of power and voice. Compared with the general population, poor and vulnerable groups are at greater biological risk both of infection with Mycobacterium tuberculosis (MTB) and breakdown of latent infection to disease.8 A variety of factors contribute to this risk including increased aerosol transmission in overcrowded and
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poorly ventilated living or working conditions,9 poor nutrition,10 and interaction with other diseases (such as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)). Although important, the biological risks of TB associated with poverty are not the main focus of this chapter. In recent years there has been a growing recognition not only that the risk of developing TB is greater among the poor but that the converse relationship is also important. Tuberculosis itself diminishes the livelihoods of affected individuals both through the lost productivity associated with chronic ill health and through the direct and indirect costs incurred by patients in their pathway to diagnosis, treatment, and cure. The concept of a pathway to TB cure is illustrated in Fig. 102.1 in an adaptation of a model used by Uplekar et al.11 This illustrates two concepts that underpin this chapter. First, the majority of TB cases arising in the community are poor. Second, that the poor face barriers that affect them more than they affect the non-poor as they proceed along the pathway to care. The result is that poorer patients tend to ‘drop out’ at all stages of the pathway to cure while non-poor patients tend to follow the pathway through to a successful conclusion. The extent of the drop-out illustrated for each stage of the pathway is hypothetical, and will differ according to local context. Although the pathway is illustrated as a smooth, linear process in order to convey the concept of differential poor/non-poor dropout, it is clear that the pathway followed by most patients is more complex. Most patient pathways are characterized by delays at each stage and by repeated visits to multiple care providers within each stage. These delays and repeated visits are costly to patients and can serve to increase the slope of the drop-out rate at each stage. Poverty, therefore, will tend to sharpen the angle of the slope of the drop-out rate while pro-poor measures in the delivery of TB control will tend to flatten the slope. Tuberculosis control that is delivered in a manner that takes account of the needs of the poor will, therefore, improve the effectiveness of TB control: more patients will be diagnosed and cured and taken out of the pool of infectious cases that drive transmission. In addition, pro-poor TB control, therefore, has the potential to reduce poverty by reducing the costs and delays experienced by patients as they move along the pathway to cure. Recognition of the importance of poverty in this relation with health is increasingly reflected in international policy on health and development. This is illustrated in the Report of the Commission for Macroeconomics and Health,12 the Poverty Reduction Strategy Papers,13 the Millennium Development Goals
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Step 1: Establish the profile of poor and vulnerable groups Government or other data. Locally done surveys. Step 2: Assess poverty-related barriers to the accessing of TB services Economic barriers. Geographical barriers. Social and cultural barriers. Health system barriers. Step 3: Take action to overcome barriers to access Economic barriers: integrate services within primary-care provision, encourage pro-poor public–private mix DOTS, promote TB control in workplaces, improve coverage of smear microscopy networks, avoid user fees, provide free smear microscopy and other diagnostic services. Geographical barriers: extend diagnostic and treatment services to remote regions, provide free transport to patients from such regions, promote community-based care. Social and cultural barriers: engage former patients and support groups to advocate for services and encourage community mobilization. Health system barriers: engage in health service decentralization to ensure capacity strengthening in less well-served areas and by establishing TB control as a district-level priority. Step 4: Work with groups that need special consideration Refugee communities, asylum seekers, economic migrants, displaced populations. Pockets of deprivation in wealthier countries; ethnic minorities, homeless people. Injecting drug users. Prison populations. Step 5: Harness resources for pro-poor services Global Fund to Fight AIDS, TB, and Malaria, poverty reduction strategies. Technologies to enhance efficiency and effectiveness of services. Step 6: Assess pro-poor performance of TB control Harness human and other resources through alliances with partners (such as universities). Include socioeconomic variables in routine data collection. Include TB-related questions in district health surveys. Undertake periodical studies of care-seeking, diagnostic delay, and use of DOTS. Do qualitative assessments among community members and patients about who benefits from TB services (including linked services for HIV) and who does not. “Addressing Poverty in TB Control. Options for National TB Control Programmes” WHO/HTM/TB/2005.352.
(MDG 2000),14 and the Global Fund to Fight AIDS, Tuberculosis, and Malaria.15 In 2002 the Stop-TB Partnership adopted ‘Stop TB, Fight Poverty’ as the World TB-Day theme. In 2004, there were an estimated 8.9 million new cases of TB, only 53% of which were notified by DOTS programmes.16 The global targets, adopted by the World Health Assembly, were to detect 70% of new pulmonary smear-positive cases annually by the end of 2005, and to cure 85% of detected cases. Despite impressive progress towards the cure-rate target (83% of 1.6 million patients were successfully treated under DOTS in the 2003
120 Non-poor people with TB
100 Nominal number of patients
Box 102.1 Addressing poverty in tuberculosis control: six practical steps
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Poor people with TB
80 60 40 20 0 Symptoms
Help seeking
Health services
Diagnosis Treatment Adherence
Positive outcome
Pathway to TB care (shown as a linear process)
Fig. 102.1 Transitions in TB.
cohort), the case-detection rate by DOTS programmes was less than 60% by the end of 2004, and we suggest that most of the undetected TB cases are likely to be found among the poor.17
STEP 1: ESTABLISHING THE PROFILE OF POOR AND VULNERABLE GROUPS UNDERSTANDING POVERTY Poverty is multidimensional; as a result there are several approaches in which poverty has been conceptualized: deprivation of income or basic needs, notions of material well-being, an absence of infrastructure, a lack of power and voice, and an unravelling of social structures.18 The material disadvantage concept of income or consumption poverty relies on measures of nutritional and other material requirements for a ‘minimum’ standard of living for individuals and households.19 This concept of poverty goes beyond the lack of private income, to include the need for basic health and education and other essential services. In terms of measurement, application of this concept may result in measures of income, possessions, or assets or receipt of welfare payments. Measures of material disadvantage can also be applied to geographical areas where people live using variables such as high unemployment, or overcrowding or composite indices such as a deprivation index. An advantage of measuring material disadvantage is that it allows measurement to change over time. However, it is difficult to calculate minimum standards because they vary from time to time and from setting to setting. Increasingly social disadvantage is applied to the concept of poverty and vulnerability.20,21 This is a relative concept that can be applied in different settings and encompasses social exclusion from normal life in society, for example ability to participate in work or social networks, to a lack of voice and basic rights. Social disadvantage is more difficult to capture through practical measurements. Analyses, such as a gender analysis, which critically examine power relationships in different settings and circumstances, can provide an important entry point to the analysis of social disadvantage.
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METHODS OF MEASURING POVERTY FROM THE TUBERCULOSIS LITERATURE Measures of poverty of individuals and households Several approaches for determining the socioeconomic status of individuals or households have been used. These range from poverty lines and selected indicators based on different concepts, i.e. consumption or notions of well-being, to gender analysis. Poverty lines and selected indicators Many studies have analysed poverty and TB based on individual characteristics as a proxy for socioeconomic disadvantage, and used poverty lines developed for the context of the country or place.22–24 These characteristics or indicators of poverty have been selected on the basis that they contribute significantly to the welfare level of the individuals or households. Among the indicators chosen are income level, occupation, education, and gender. Some authors use context-specific predictors of poverty, such as homelessness or lifestyle aspects of vulnerability, such as intravenous drug use.25,26 A few studies have used an established poverty line and a proxy measure of poverty, e.g. reported income, linked to this poverty line to determine the socioeconomic status of individual patients (Table 102.1).24,27 The major weakness of this approach is that when it comes to fieldwork it is very difficult to base a poverty estimate on a single reported variable. In response, a number of studies have used a ‘proxy means test’. This is a quantitative way of calculating welfare levels of households and individuals using existing national or regional measures of poverty, such as data from integrated household surveys or living standards surveys.28 In Malawi, for example, data from the 1998 Integrated Household survey were used to develop a proxy means test through regression analysis (see Table 102.2).27 The advantage of this approach is that several weighted Table 102.1 An example of a quantitative proxy measure of poverty Variables
Coefficients
P value
Variable description
Constant 3.622 < 0.001 -0.169 0.006 1 = yes; 0 = no Cooking using firewooda Car 0.306 < 0.001 1 = yes; 0 = no Light using 0.263 < 0.001 1 = yes; 0 = no electricityRights were not granted to include this content in -1.439 < refer 0.001 to the printedNumber Household electronic media. Please book. of people in the sizea household Occupation 0.175 0.001 1 = formal employment; 0 = informal Sex of head 0.135 0.12 1 = male; 0 = of household female Education of 0.127 0.35 Number of head of years in school household a Use of firewood and household size have negative coefficients because they are associated with lower welfare levels and deeper poverty. Nhlema-Simwaka B, Benson T, Kishindo P, et al. Developing socioeconomic measures to monitor access to tuberculosis services in urban Lilongwe, Malawi. Int J Tuberc Lung Dis 2007;11(1):65–71.
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individual or household characteristics are used to come up with a proxy poverty measure, avoiding reliance on a single variable such as reported income. The major disadvantage is that the proxy measure relies on the precision of inclusion and exclusion that it achieves. In general terms this depends on the number of variables used: the more variables, the greater the precision.
Gender analysis Some studies have applied a gender approach to analyse the poverty status of TB patients.29 Poverty affects both men and women, but gender differentiates the experience of poverty in terms of the kinds of claims and entitlements that men and women mobilize. Gender imbalances in accessing intra-household resources and responsibilities help to shape the ability of different household members to gain access to extra-household institutions, etc.29 In general women control fewer productive assets, work longer hours, and earn less income than men. A number of studies have used gender as the primary analysis factor for TB and access to care.29,30 These studies reveal significant differences in access to services and impact of the illness on patients, household, and communities. Selected indicators based on participatory poverty assessment Participatory poverty assessments (PPAs) have been used by few studies of TB.27 PPAs are pro-poor in that poor people themselves analyse poverty.31 One limitation of PPAs is that measures of well being are often relative and therefore cannot be compared with similar values/categories across populations. Another limitation is that the methods used in PPAs often, although not always, seek participants’ perceptions based on their lived experiences and opinions rather than observable behaviour or outcomes. Analysis of poverty based on areas Some analysts assess poverty and TB based on aggregate, area-based measures. Among the better known are the Jarman, Carstairs, and Townsend indices of poverty. These use area of residence as a proxy for poverty status and have been used in the analysis of TB incidence (by notification rates).9,32,33 The Townsend index comprises the following weighted variables for a residential area: the percentage of households with no car, the percentage of owneroccupied houses, and the percentage of households with more than one person per room. The Jarman index aggregates the following factors: number of old-age pensioners living alone, number of children aged 5 years, proportion of single parent families, number of the unemployed, number of unskilled workers, number of people living more than one to a room, and number of those of high mobility (such as the homeless). These indices are useful in analysing the proportion of TB cases from different residential areas, hence different social groups, at an aggregate area-level. However, these indices cannot capture the inter-household or intrahousehold differences within these areas in terms of material or social disadvantage. These composite indices are developed based on information for the particular context, such as census data, and as such are only relevant to the country or place for which they are developed. Some analysts have used other area-based variables such as population growth, immigration rate, and literacy levels to describe poor and non-poor geographical areas.5 Again, the area of residence is used as a proxy indicator of the poverty status of patients or small populations. Mapping of these indicators on geographical information systems can be helpful in identifying poor areas and in planning the prioritization and distribution of health services in general and TB services in particular (see Fig. 102.2).
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102
Table 102.2 An example of a qualitative indicators matrix: ranking criteria for poor and non-poor categorization Category
Assets
Livelihood activities
Poor
Use communal water Do not have electricity in the households Have a mat for sleeping
Have piped water Have electricity
Nonpoor
Housing
Food availability
Grass thatched Undertake daily wage labour Unskilled or semi-skilled house Iron roofed but Petty trading Rights were not granted to include this in fewercontent than two electronic media. Please refer to therooms printed book. Iron roofed house Medium- or large-scale Adequate rooms business Employed in private or public (two to three) organization
Do not eat sometimes due to lack of money or food
Eat at all times except when ill
Nhlema-Simwaka B, Benson T, Kishindo P, et al. Developing socio-economic measures to monitor access to tuberculosis services in urban Lilongwe, Malawi. Int J Tuberc Lung Dis 2007;11(1):65–71. Secondary education
Private piped water
Population % with secondary education
Percentage of households with private piped water
06
0 20
723
21 40
2530
41 60
3147 24
60
18 48
14 14 6 5
9
43
4
32
40 16
46
21
8 22
6 5
5
12
41 44
34 17
33 2
36
2 1
21
8 22
23
36
24
0
42 14 31 11 40 16 13 32
37
45
36
4
10
20
3
57 23
45
15
9
35
1 1
47
17
33
18
44
34
13
2
37
41
43
30
48
56
39
28
49
10 20 42 31 12
3
57
29
39 50
30
41
Source : 1998 National Census
28
49
46
81100
25
Source : 1998 National Census
29
56
61 80
Pop. < 100
24
38
Kilometres
0
5
38
Kilometres
Fig. 102.2 Poverty indicators by area, Lilongwe, Malawi.
CONCLUSION FOR STEP 1 The multiple approaches used by different analysts of poverty and TB support the notion of the multifaceted nature of poverty and the need for continued use of an inclusive definition of the kind adopted in this chapter. In many countries, notably several in Africa, ‘the poor’, as defined here, constitute 75% or more of
the population. When such a high proportion of the population is poor, it becomes important to scrutinize the whole health system for its ability to serve the needs of poor TB patients (see Step 3, below) as well as to provide specific services for situations and population groups requiring special consideration (see Step 4, Box 102.1).
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STEP 2: ASSESS POVERTY-RELATED BARRIERS TO THE ACCESSING OF TUBERCULOSIS SERVICES THE IMPOVERISHING EFFECTS OF THE PATHWAY TO CURE As with all chronic illness, it is well accepted that TB leads to the impoverishment of patients and their households through the inability to work due to illness. Less well recognized are the direct and indirect costs of accessing diagnosis and treatment. As already outlined, the pathway to TB cure is characterized by many, and repeated, visits to different care providers.29,34 Poor and vulnerable people have longer pathways to care than other social groups because of the difficulties they encounter in overcoming the barriers along the way. Certain groups such as women, the unemployed, and the homeless can have longer delays than others.29 Living in rural areas is also significantly associated with longer delay in developing country settings.35 The direct and indirect costs of accessing care are generally higher before rather than after diagnosis.36 Although aggregate real costs for poor people tend to be lower than other social groups, costs relative to income are higher. In addition, the poor have less disposable income and less income security due to the nature of their livelihood activities, such as daily wage labour and petty trading.37 A study from Thailand showed that patients with incomes below the poverty line spent 15.3% of their household income on the direct costs of an episode of TB. This compared with 8.6% of household income spent by patients with below average income and 1.8% of household income spent by patients with above average income.24 In Malawi (where consultations and diagnostic tests are provided free of charge) the poor were spending more than twice their total monthly income (and more than five times their disposable monthly income) in achieving a TB diagnosis.37 By comparison the less-poor were spending the equivalent of a month’s total income and just under twice their disposable monthly income.
CATEGORIZING BARRIERS TO CARE These aggregate costs are incurred by patients in order to overcome the barriers associated with the different stages along the pathway to cure. The costs are composed of a matrix of interlinked barriers determined by geography, sociocultural circumstance, and health systems (see Box 102.2). The most obvious example would be the higher costs required to pay for longer or more difficult journeys imposed by remote geography. A less explicit example would be the additional cost incurred by a woman who is impelled by the stigma associated with a TB diagnosis to seek a diagnosis or treatment a great distance from home in order to minimize disclosure despite the presence of a much closer service provider of equal quality. Although these barriers Box 102.2 Barriers to accessing tuberculosis care for poor people
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Financial barriers – e.g. user fees, payments for diagnostic tests. Geographical barriers – e.g. distance from services providing TB diagnosis. Sociocultural barriers – e.g. stigma and lack of knowledge about available services. Health system barriers – e.g. lack of health system responsiveness because of human resource constraints.
are therefore often defined as ‘geographical’, ‘sociocultural’, etc., distinguishing and characterizing each of them is complex. It is important, therefore, not to confuse the broad economic costs of the pathway to cure with specific financial barriers such as the need to pay fees for diagnostic tests or health service consultations. As illustrated in the following case studies most poor patients face a combination of barriers.
Case study 1: Malawi’s ‘lost’ cases of tuberculosis In Malawi, despite an established and well-run TB control programme, around 14% of patients with confirmed TB never start treatment and are so-called lost cases.38 This is an important issue for TB control, not only because these people suffer ill health and die, but they also continue to be infectious to the rest of the community. A study in Ntcheu District, rural Malawi, located these lost cases and used critical incidents narrative interviews to identify why they did not start treatment. Interviews with five lost patients and 14 carers of lost patients who had died revealed that it had taken a long time to receive a positive diagnosis of TB. The major reasons for this were cited as health system structural barriers. The unifying feature of all the lost cases was poverty. Families were poorly educated, subsistence farmers living in basic housing. Fourteen of the 19 missing cases died within 6 weeks of their positive TB status being established.
Patients generally consulted formal medical services before traditional healers, but they encountered barriers with these services. Health centre staff were considered by patients to be slow to order sputum microscopy tests even if they did recognize symptoms suggestive of TB. On the other hand staff voiced their frustration with the large number of symptomatic patients whose sputum smear results came back negative and were perceived to be false-negatives. There were substantial delays between being tested and receiving results. Some respondents claimed they received the result after the patient had died. Difficulties in transporting specimens and results between peripheral health centres and the district laboratory were probable explanations. Patients did not have enough money to pay for the expected and real costs of travel, providing family members as carers in hospital, food, and other daily necessities.
Case study 2: challenges to tuberculosis control in China In China, 5 million people have active TB, meaning China has the second highest TB burden in the world. The TB case-detection rate has only recently progressed towards the global target of 70% despite massive investment.39 Many people with TB symptoms face difficulties in accessing health services, and those who succeed experience delays in getting an accurate TB diagnosis. What are the barriers that exist to getting a quick tuberculosis diagnosis after first seeking care? Using a combination of qualitative and quantitative methods, this question was asked by researchers in a social assessment study in four provinces in China. Up to 60% of patients experienced a delay between first visiting a health centre and receiving a diagnosis. Most patients had to make more than one visit before receiving a diagnosis and between 17% and 30% made more than six visits.40
Lack of money was the main reason for delayed healthcare seeking. Costs included transport, accommodation, and lost working time. Tuberculosis patients in low-income brackets
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took 4 days longer to seek healthcare than wealthier patients. The social assessment found that perceived costs of TB diagnosis and treatment by communities were two to five times higher than the actual costs. This perception that TB care was very expensive prevented many from seeking help. Even within a system where the TB-specific elements of diagnosis and treatment were free, care was still found to be expensive for poor people. Repeated visits to health centres before diagnosis (often up to six times) and overprescription of additional, non-TB treatments resulted in high costs. Gender, age, and educational status were influential in where individuals sought care. Women took longer to seek care than men. Men were often prioritized within families for receiving healthcare as they were seen as the ‘backbone’ of the family. Women, young women especially, expressed concerns about being able to get married if it was known they had TB. A disjointed health system was another reason for the delay in seeking healthcare. Village healthcare providers had low knowledge and awareness of TB symptoms, and poor communication and diagnostic skills. Few clinics had the medical equipment or specially trained staff capable of identifying TB cases at an early stage.
CONCLUSION FOR STEP 2 The costs of complex and lengthy pathways to cure add to the economic burden of patients and households and lead to wider social impacts of the illness, such as children taking up their parents’ activities, and an inability to support school fees.36 In India 34% of patients reported that they could not afford to buy adequate food or clothing for their children due to loss of income and this impact was greater in urban than in rural settings.36
STEP 3: TAKE ACTION TO OVERCOME BARRIERS TO ACCESS A pro-poor focus, although important in itself, will only make a difference to the individual lives of the poor if practical steps are taken to address the obstacles that these people face in accessing good TB services,37 and if programme implementation takes account of the distribution of poverty within target communities as a whole. Several gains may be made through general health system reforms, but we focus here on two selected examples where refinement of the manner in which TB services are delivered could help to overcome barriers to access.
FOCUS ON LABORATORY SERVICES FOR SPUTUM SMEAR MICROSCOPY AS THE CORNERSTONE OF TUBERCULOSIS DIAGNOSIS Getting tested for TB can be a complicated process, even after patients have reached the formal healthcare system. Following WHO recommendations, patients must submit three samples of sputum over a number of days. They must wait for results that sometimes take weeks to arrive as local level healthcare services do not always have the equipment, consumables, or human resources required to turn around sputum results in a timely fashion.41–43 Patients either must travel long distances to submit sputum or village and district level centres must transport sputum to central testing laboratories, a time-consuming and expensive
499 suspects
Fig. 102.3 Audit of sputum submission over 6 months at one diagnostic centre, J Kemp, SB Squire, IK Nyirenda, FML Salaniponi “Is tuberculosis diagnosis a barrier to care?” Trans R Soc Trop Med Hyg 1996;90:472 (Abstract).
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37% of patients asked to submit sputum dropped out of the diagnostic process
466 on-spot 423 overnight 413 next day 404 result available 316 collected result
procedure.37 Many patients are lost in the system because they do not submit all the specimens, fail to collect results, or are not registered for treatment (see Fig. 102.3).53
Importance of on-spot delivery of results to patients One way of reducing these losses might be to provide sputum smear results on the same day as patients provide specimens. For example, ‘one-stop’ diagnosis could be achieved by basing the treatment decision on the first direct sputum smear. There is, however, great concern that the advantage gained in treating patients who would otherwise have been lost is outweighed by the reduction in sensitivity associated with losing the second and third smears. Until newer rapid, sensitive, and specific diagnostic tests become available for use at health centre level, modifications of sputum smear microscopy which may achieve one-stop diagnosis of TB with similar sensitivity and specificity to that achieved by the conventional 2- to 3-day approach are being appraised. One modification is bleach treatment of the first smear.45 An alternative is changing the sequence of specimen submission by asking patients to submit two sputum specimens half an hour apart at their first encounter with the health service (see Fig. 102.4).40,46 Economic modelling of the current three-smear approaches against the two one-stop algorithms suggest that the current approach is the least cost-effective from all perspectives, with a cost per patient starting treatment within 5 days of $177 for patients and $20 for the health system. Equivalent figures for the one-stop approaches were $57 and $10 (two-smear method) and $56 and $5 (bleach digestion). The one-stop methods resulted in savings for patients of up to 61% of monthly income, with the greatest benefits being experienced by the poor (SBS – work in progress).45 Although promising, there are a number of technical hurdles still to overcome before these one-stop diagnostic algorithms can be rolled out in developing countries.47 In addition there would need to be a shift in international policy. Conventional definitions of smear-positive or -negative TB require results from three sputum specimens. A one-stop diagnosis would require international consensus about the reliability, in terms of sensitivity and specificity, of diagnosis based on two smears, or even one smear.48 INVOLVE INFORMAL HEALTH PROVIDERS AND COMMUNITY STRUCTURES, INCLUDING PATIENTS, IN TUBERCULOSIS CONTROL Tuberculosis control, through the detection and cure of infectious cases, has traditionally been seen as the province of formal, publicly funded health services. More recently there has been a recognition
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Patient with cough for more than 3 weeks, visiting a formal health provider
Time Day 1
Bleach digested smear
Two smears 1 hour apart
Current WHO-recommended three-smear process
Patient provides on-spot sputum sample
Patient provides on-spot sputum sample Patient provides second sample 1 hour later
Patient provides on-spot sputum sample
Patient receives results if laboratory is on site*
Patient receives results if laboratory is on site*
Day 2
Patient returns to bring overnight/early morning sample Patient provides next day sample
Unspecified days later
Patient receives results
*Note: If no laboratory is on site then the delay resulting from transporting specimens to nearest laboratory is the same for all three diagnostic processes.
Fig. 102.4 TB diagnostic algorithms. Kemp JR, Mann G, Simwaka BN, et al. Can Malawi’s poor afford free tuberculosis services? Patient and household costs associated with a tuberculosis diagnosis in Lilongwe. Bull World Health Organ 2007 Aug;85(8):580–585.
that health systems vary considerably around the world and that private practitioners, both formal and informal, play a significant role in health service delivery. There has been a strong move towards active engagement of private practitioners in TB control through an initiative known as public–private mix (PPM),49 particularly for case detection. A recent review explored the published literature to assess the range of providers included in PPM pilots for their ability to provide case-detection services for the poor.50 From a case-detection perspective, the essential elements of a pro-poor PPM model were identified: cost-effectiveness from a patient perspective, accessibility, acceptability, and quality. The review revealed that a very large part of the total spectrum of potential PPM-participating partners has not yet been explored. Current models focus on private-for-profit healthcare providers and non-governmental organizations. It is important to think critically about the type of private providers who are best suited to meeting the needs of the poor, particularly informal providers closely embedded within communities.
Case study 3: storekeepers Storekeepers have been successfully engaged as community-based supervisors of TB treatment in a rural setting in South Africa.51 More recently there has been a realization that they might also play a role in case detection. Chronic coughs and other common health complaints are already self-treated at a community level through grocery stores which act as a first point of call for many poor people seeking care. A pilot project where storekeepers are trained in TB symptoms and referral has been implemented in three subdistricts in urban Lilongwe. It has gained strong support from the local community who feel better supported and informed about TB. This project grew from a study of care-seeking pathways amongst TB patients which identified storekeepers as the most important first contact on the care-seeking pathway. Key findings included the following:
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Storekeepers know about the symptoms of TB and want to refer their customers but are afraid they will be ignored without formal acknowledgement. Community awareness of the new health role of storekeepers is therefore essential. A broader health advisory role for additional health issues such as malaria might decrease the stigma surrounding TB and HIV/AIDS, allowing people to be more open in seeking advice. HIV and AIDS health education and home-based care groups exist and want to support the storekeepers and community leaders in a health role.
CONCLUSION It is often assumed that if TB patients (who tend to be poor) are accessing TB services, then these services will, by definition, be serving their needs. Some assert that there is, therefore, no need to invoke special measures in order to address the needs of the poor in TB control. Others agree that the needs of the poor are important, but are the remit of the general health system rather than TB control services specifically. We have presented arguments in this chapter demonstrating that poor TB patients face disproportionately large barriers on their pathway to cure. We agree that the manner in which the general health system is arranged and integrated with TB control activities is of major importance in meeting the needs of the poor. Nonetheless, there are specific measures that TB control programmes and their partners should consider as their responsibility in order to properly address poverty in the delivery of their services. Unless TB control programmes actively shoulder this responsibility, we predict that TB control will at best make sluggish progress towards its targets and at worst will ignore those with greatest need.52
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patients and family in India. Int J Tuberc Lung Dis 1999;3(10):869–877. Kemp JR, Mann G, Nhlema-Simwaka B, et al. Can Malawi’s poor afford free TB services? Patient and household costs associated with a TB diagnosis in Lilongwe. Bull World Health Organ 2007;85(8): 580–585. Squire SB, Belaye AK, Kashoti A, et al. ‘Lost’ smear positive pulmonary tuberculosis cases; where are they and why did we lose them? Int J Tuberc Lung Dis 2005;9(1):25–31. Wang L, Liu JJ, Chin DP. Progress in tuberculosis control and the evolving public-health system in China. Lancet 2007;369:691–696. Yan F, Thomson R, Tang S, et al. Multiple perspectives on tuberculosis diagnosis delay from community members to policy makers in poor rural counties of four provinces in China. Health Policy 2007;82(2):186–199. Mundy C, Ngwira M, Kadewele G, et al. Evaluation of microscope condition in Malawi. Trans R Soc Trop Med Hyg 2000;94:583–584. Mundy CJF, Bates I, Nkhoma W, et al. The operation, quality and costs of a district hospital laboratory service in Malawi. Trans R Soc Trop Med Hyg 2003;97:403–408. Mundy CJF; Harries AD; Banerjee A; et al. Quality assessment of sputum transportation, smear preparation and AFB microscopy in a rural district in Malawi. Int J Tuberc Lung Dis 2002;6:47–54. Cambanis A, Yassin M, Ramsay A, et al. Rural poverty and delayed presentation to tuberculosis services in Ethiopia. Trop Med Int Health 2005;10: 330–335. Yassin MA, Cuevas LE, Gebrexabher H, et al. Efficacy and safety of short-term bleach digestion of sputum in case-finding for pulmonary tuberculosis in Ethiopia. Int J Tuberc Lung Dis 2003;7:678–683. Cambanis A, Yassin M, Ramsay A, et al. A one day method for the diagnosis of pulmonary tuberculosis in rural Ethiopia. Int J Tuberc Lung Dis 2006;10:230–232. Ramsay A, Squire SB, Siddiqi K, et al. The bleach microscopy method and case detection for TB control. Int J Tuberc Lung Dis 2006;10:256–258. Mase SR, Ng V, Henry M, et al. Incremental yield of serial sputum smear examinations in the evaluation of suspected pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis 2007;11(5):485–495. World Health Organization. Public–private mix (PPM) for TB care and control. [online]. Accessed March 2007. Available at URL:http://www.who.int/ tb/dots/ppm/en/index.html Malmborg R, Mann G, Thomson R, et al. Can public-private collaboration promote TB case detection among the poor and vulnerable? Bull World Health Organ 2006;84:752–758. Wilkinson D. High-compliance tuberculosis treatment programme in a rural community. Lancet 1994;343(8898):647–648. Squire SB, Obasi A, Nhlema-Simwaka B. The Global Plan to STOP TB: a unique opportunity to address poverty and the Millennium Development Goals. Lancet 2006;367:955. Kemp J, Squire SB, Nyasulu I, et al. Is tuberculosis diagnosis a barrier to care? Trans R Soc Top Med Hyg 1996;90:472.
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Clinical trials in tuberculosis Jonathan Levin, Christian Lienhardt, and Andrew Nunn
INTRODUCTION Clinical trials involve the evaluation of a medical treatment (e.g. a drug or a vaccine or a new drug delivery system) in a group of human subjects. Randomized controlled trials (RCTs) provide the strongest evidence of the efficacy and safety of a medical treatment. Before studies can be carried out in human subjects, the drug will have to be tested in animals. The purpose of preclinical toxicology studies is to assess the safety of the drug and help to establish doses at which studies in human subjects can be carried out. Clinical trials are conventionally categorized into four phases: Phase I trials are usually single-dose studies in which low doses are tried first and then cautiously increased until a maximum tolerated dose can be established. In many indications, such studies are carried out on healthy volunteers, but for serious diseases which may require relatively toxic drugs patients will be used instead. In addition, pharmacokinetic (PK) studies are undertaken in order to measure the concentration–time profile of the drug in blood in order to establish the rate at which the drug is absorbed and eliminated. Phase II trials are carried out in order to find the best dosage and also the best route of administration. The aim is to get preliminary indications of efficacy, further evidence of safety and a firm recommendation for doses and dose schedules. Nowadays some researchers carry out further Phase II studies to obtain an early indication of efficacy in order to justify the expense of further drug development. Phase III trials are the pivotal trials carried out in order to provide the necessary information on the efficacy and safety of the drug before a dossier is submitted to the Regulatory Authorities applying for registration. In these trials, the investigation product is usually tested against the standard of care or a placebo. Phase IV trials are post-registration studies to monitor and evaluate long-term use of the drug and to discover more about the effect of the drug in special subpopulations (e.g. the elderly or subjects with impaired liver or renal function). This pharmacovigilance, or post-marketing surveillance, also aims to detect rare side effects which could not be detected in the earlier trials, since the drug will be used by far more persons – and a wider range of persons. Usually, Phase IV trials do not have the same restrictive inclusion and exclusion criteria as earlier Phase trials. The technicalities of RCTs are briefly dealt with in the next section, followed by a number of examples of clinical trials in TB research. The experimental procedures must be clearly specified for both ethical and scientific reasons, as described in the trial
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protocol section. The ways in which trials should be conducted, now codified through the establishment of good clinical practice (GCP) and good laboratory practice (GLP), as well as managed are described. How a number of committees may oversee the conduct of the trial in order to ensure adherence to GCP, and how data management and analysis of a clinical trial also must meet the most rigorous standards are also discussed in this chapter.
THE DESIGN OF CLINICAL TRIALS THE NEED FOR A CONTROL GROUP In the previous section we referred to clinical trials as randomized controlled trials – and central to the philosophy of clinical trials is the idea of a control group. The effect of a treatment for a given subject can be defined as the difference between what happened to the patient as a result of giving him/her the treatment, and what would have happened if an alternative or no treatment had been given. In order to say what ‘would have happened’ we use a control group which is studied at the same time as the experimental treatment group.
RANDOMIZATION AND BLINDING In a clinical trial, in order to evaluate the difference between the control and treatment groups on a given outcome measure, it is essential to avoid bias in treatment allocation. It is also important to ensure that the two groups are as similar as possible with regard to factors that might influence the outcome measure. Since some of these factors may be unknown, the best way to achieve this is to randomly allocate subjects to treatment groups. Unless the trial is very large, trialists may use stratified randomization if there is a well-known prognostic factor or well-defined subgroups (e.g. in a TB trial, we could decide to stratify on human immunodeficiency virus (HIV) status or on the presence or absence of cavitation on the chest radiograph). The randomization schedule should be prepared by a person who is independent of the trial. One of the most important features of RCTs is concealment of the allocation of treatment. It is essential that the treatment to be allocated is not known when a patient is being considered for inclusion. To avoid any possible problems whereby doctors may differentially manage patients on different regimens it may be possible to blind the regimen by the introduction of placebo-matches to drugs patients are not receiving, which is called double-blind as neither the investigators nor the patient are aware of which treatment the patient is receiving.
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Most clinical trials are designed to show the superiority of a new treatment over the current treatment. Because standard drug regimens for TB are highly effective under trial conditions it is almost impossible to demonstrate a new treatment to be more effective. Non-inferiority trials assess whether a new regimen can be regarded ‘as good as’ the existing treatment if it is no worse than the control by a predetermined amount. This might be, for instance, because it has a superior safety and tolerability profile or because it can be given for a shorter period of time, e.g. 4 months compared to 6 months. An example of a non-inferiority trial is given in the next section.
the MRC in East Africa, Hong Kong and Singapore to assess short-course regimens of chemotherapy for TB.4 The formation of the Global Alliance for Tuberculosis Drug Development (GATB) has heralded what promises to be an exciting new era; at the present time there are several promising drugs in the development pipeline offering the prospect of shortening chemotherapy to 4 months or less. There are currently some ongoing trials investigating whether the use of the quinolones, gatifloxacin and moxifloxacin could shorten the overall treatment duration from 6 to 4 months. These trials use a non-inferiority design, as discussed earlier.5 An important feature of TB drug trials is the need to assess effectiveness in patients with HIV infection. This has been further complicated by decisions about when to give antiretroviral treatment (ART) to those requiring both ART and antituberculous drugs. Initially, trials of new TB drugs are being conducted only in patients not requiring immediate ART. However, it is essential to determine what, if any, interactions may exist between the TB and HIV drugs when given concurrently.6
PARALLEL GROUP DESIGNS AND CLUSTER RANDOMIZED TRIALS
TRIALS TO ASSESS DRUG DELIVERY, ADHERENCE TO TREATMENT
The most commonly used study design for clinical trials is the parallel group design, in which (usually, but not necessarily, equal numbers of ) subjects are randomly allocated to one of two (or more) groups and the outcome measure is compared between the groups at the end of the study. In the above situation the unit of randomization is usually an individual patient. However, in some studies the unit of randomization will be a group or cluster of individuals, although the unit of observation remains an individual. This type of study is used when an intervention is more appropriately given to a community and in TB has been used to compare different models of supervision (some such studies are discussed in the review by Volmink and Garner1) or to investigate ways of improving adherence to TB treatment, as in Senegal.2
Although most trials assess the efficacy of drug regimens it is important not to overlook the trials which investigate the logistics of drug delivery, treatment supervision and interventions to prevent clinical disease. Particularly significant in the understanding of the delivery of TB regimens were the trials conducted at the TB Research Centre in Madras (Chennai) which established the effectiveness of treatment at home compared to treatment in sanatoria; these trials also demonstrated that contacts were at no greater risk when patients were given ambulatory treatment than when given treatment in sanatoria.7 The need for ensuring good adherence to treatment has long been recognized.8,9 A recent publication reviewed the evidence from randomized and quasi-randomized trials comparing directly observed therapy (DOT) with self-administration of treatment either in people receiving treatment for clinically active disease or in those receiving preventative treatment.1
Blinding is, however, not always practical, for example when intermittent treatment is being compared with daily treatment or when one treatment is given by injection. In some circumstances it may be necessary to break the blind for individual patients, especially following a severe adverse event that might possibly be drug-related.
SUPERIORITY AND NON-INFERIORITY TRIALS
TUBERCULOSIS CLINICAL TRIALS THE HISTORY OF TUBERCULOSIS CHEMOTHERAPY TRIALS Tuberculosis has a special place in the development of randomized clinical trials. The Medical Research Council (MRC) trial of streptomycin heralded the advent of effective chemotherapy for TB;3 it is also widely recognized as the first clinical trial conducted according to principles now universally accepted. The MRC had access to a small quantity of streptomycin and decided it could be used most effectively in a clinical trial. A total of 107 patients were assessable at 6 months and the death rate in those receiving streptomycin was significantly less than in those receiving bedrest alone. During the 20 years that followed the introduction of streptomycin, all the antituberculous drugs available today for first-line treatment of TB, and almost all those used in secondary regimens, were developed. Within 20 years (from about 1965 to 1985) the regimens in use today were introduced worldwide through clinical trials. A particularly important series of studies, made possible following the introduction of rifampicin, the last of the first-line TB drugs to be discovered, were those conducted by
TRIALS OF PREVENTATIVE THERAPY An important series of trials conducted in the USA demonstrated the effectiveness of isoniazid chemoprophylaxis in those with a relatively high risk of developing clinical disease.10 More recently, trials have been initiated in HIV-infected persons to assess the effectiveness of different regimens of chemoprophylaxis for the prevention of TB in this population known not only to be at high risk of developing clinical disease but also likely to need longer or repeated courses of treatment.11
THE TRIAL PROTOCOL An essential document to the conduct of any trial is the protocol, the main components of which are described below. Some specific methodological aspects, such as the choice of comparator, the determination of the trial population, the criteria for inclusion and exclusion and the methods of statistical analysis, which are all related to the choice of the interventional medical product (IMP) to be tested, are, however, not covered in this section.
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RATIONALE FOR THE STUDY In a trial protocol, this section sets out the reasons why the trial is needed and what question(s) it intends to answer. It is important to summarize succinctly what is already known about the subject area to be investigated. This needs an up-to-date and thorough literature review, and experts in the area might be consulted. It is important to discuss what is directly relevant to the overall aim of the proposed trial and to give thorough and valid arguments about how it will add to existing knowledge. The specific hypotheses to be tested must be clearly outlined.
OBJECTIVES This section must define clearly the primary objectives (preferably no more than one or two) as well as the secondary objectives, some of which may be exploratory.
DETAILED DESIGN OF THE TRIAL This is the heart of the proposal, in which the methods and the techniques to be used in the trial must be clearly and unambiguously described:
The trial population The trial population should be described, indicating its appropriateness for the study objectives and whether it is sufficiently representative to allow generalization of the findings. Background information on the population (epidemiological indicators, justification of why it is chosen) is useful. The sample size calculation The sample size calculation must be clearly presented, specifying the significance level to be used in comparing the primary outcome between the treatment and control arms, the minimum difference between treatment arms that we would like to be able to detect as being statistically significant and the power of the proposed study required to detect this difference if it exists. The intervention Full details of the intervention to be tested and the control arm must be given (drug(s), combined treatment, vaccine, or public health intervention) with details of the type and doses given and other relevant details where appropriate. Recruitment of patients This should start with a precise description of the inclusion and exclusion criteria. The content of the initial screening, as well as the recruitment procedures, must be specified. It should also be stated clearly how the IMP or intervention is to be delivered. Follow-up Follow-up of patients during and after treatment must be clearly defined, with an indication of the timing and content of visits and on the length and modalities of follow-up. Outcome measures As outcome measures will be used to estimate the likely efficacy and/or safety of the IMP, it is important that their choice be carefully made and well justified. Usually, a primary endpoint that would serve to give an estimate of the efficacy of the IMP is selected. Additional secondary endpoints may be required in order to explore specific aspects related to safety or efficacy. For all of these, measurement must be clearly stated.
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Data collection Case-report forms (CRFs) must be clearly designed, in order to collect all suitable information and get unequivocal responses. Piloting is generally useful. Handling of specimens (when, where, how), labelling and recording, transport, storage and processing (blind reading) must be clearly stated. A flowchart of data collection in the field is generally useful. Data collection and processing must also be clearly outlined, with the methods for data cleaning and validation. Proposed statistical analysis The way data will be analysed according to selected end points, indicating the main and secondary outcome analyses, as well as in any subgroup analyses, must be detailed before the start of the trial. The primary analyses in conventional superiority trials should be conducted by intention to treat (ITT), that is, according to randomization allocation. For non inferiority trials, it is more appropriate to conduct the primary analysis per protocol, that is, only including subjects who achieved a pre-specified level of adherence to treatment. It is important to indicate how patients who default or die either during treatment or in the follow-up phase, or who are withdrawn from the trial, will be classified. ADMINISTRATIVE ASPECTS AND LOGISTICS The site(s) where the trial will take place, including where and how patients will be recruited, the laboratory tests to be performed, the material and equipment needed and whether specific training will be delivered, need to be described. Storage places for data recording forms and specimens (e.g. serum) must be identified.
TRIAL MANAGEMENT The overall trial management procedures should be described as precisely as possible, with the identification of the main management persons (sponsor, principal investigator(s), investigators) and their respective links. The terms of references of the main managing committees (see Trial Management and Coordination below) should be indicated. If the trial is multicentre, the means of trial coordination, including the communication between collaborators, should be described.
REPORTING AND DISSEMINATION Mention should be made of the means of reporting and disseminating the results of the trial.
ETHICAL CONSIDERATIONS Attention should be drawn to the ethical aspects of the trial from the start. The patient information sheet and the informed consent forms should be drafted, translated into appropriate language and pilot-tested. Whether individual subjects or communities will be recruited and randomized should be considered here. Confidentiality must be considered as well, with anonymization of the CRFs and data storage. Specific aspects (such as establishing voluntary counselling and testing for HIV infection) should also be considered. The Institutional Review Boards or Independent Ethics Committees that will review the protocol should be specified.
DETAILED TIMELINE Trials are always delayed for a series of unexpected reasons, so it is important to be prepared for this and to give enough time for the
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Clinical trials in tuberculosis GCP
Full documentation
R&D submission Regular progress reports
Pharmacology
Sponsorship Research question
Protocol development
Final protocol
Registration (unique trial number)
Consent and recruitment
Final trial Checkdocuments list
Trial supply
Approval obtained
R&D results Checklist before seeking approval Peer review
Trial management & monitoring
Trial begins
Ethics submission (are you ready to start?)
End of trial
Data analysis
Audit Reports Protocol amendment Safety reports
Funding research Sponsor(s) Trial continues
IDMC (makes recommendations to TSC)
Dissemination of results
Trial terminated
Trial modified
Fig. 103.1 Timelines for a clinical trial.
preparatory and post-trial stages and to specify the envisaged timelines in the protocol (Fig. 103.1):
Preparation of the trial: Sufficient time should be allocated to prepare the trial (see below) and get permission from the appropriate institutional review boards/independent ethics committees (IRB/IECs) to carry out the trial. Conduct of the trial: The overall expected duration of the trial, including the intervention time and potential follow-up after treatment if needed, must be stated. Analysis and reporting: After the end of the ‘field work’, sufficient time should be allowed for data preparation, data cleaning, statistical analysis, write-up of reports and publication of results.
BUDGET The budget must be detailed, complete, with capital and recurrent costs, and fully justified.
GOOD CLINICAL PRACTICE AND GOOD LABORATORY PRACTICE The role of good clinical practice and good laboratory practice is to provide standards of operation and conduct in clinical research. GCP refers to work done in clinical practice or trials in humans, while GLP refers to work that is laboratory-based, including preclinical studies and the operation of laboratories where the work will be used for regulatory activities. Both stress key features: 1. resources (organization, personnel, facilities, equipment and training); 2. rules (protocols, SOPs, and other written procedures);
3. characterization (test systems and their proper use and maintenance); 4. documentation (raw data, final report and archiving); and 5. quality assurance, independent of the conduct of the study. Conducting clinical trials under GCP and GLP requirements is now a legal obligation made to the sponsors and the investigators, which ensures the protection of human subjects, helps the generation of credible quality data and increases the chances of regulatory success.
DEFINITION OF GCP The definition given by the International Conference on Harmonisation’s (ICH) Guideline for Good Clinical Practice states that: GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.12,13
MAIN ASPECTS OF GCP The GCP guidelines describe in detail the responsibilities of the IRB/IECs and the suitable characteristics and various responsibilities of the main persons conducting the research (the investigator(s) and the sponsor(s) of the trial),14 and give indications on the main documents to be produced for the conduct of the trial (such as trial protocol, investigator’s brochure, CRFs, informed consent) and on the way they should be archived for trail checking (Box 103.1). It also gives detailed guidance for the monitoring of the trial.
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Box 103.1 The Principles of the International Conference on Harmonisation’s Good Clinical Practice (GCP) 1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). 2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 3. The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. 4. The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. 5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol. 6. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion. 7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. 8. Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective task(s). 9. Freely given informed consent should be obtained from every subject prior to clinical trial participation. 10. All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification. 11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 12. Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. 13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
Institutional Review Boards/Independent Ethics Committee GCP guidelines describe the responsibilities of the IRB/IEC in safeguarding the rights, safety and well-being of trial subjects. They indicate its suitable composition, functions and operations, as well as the procedures for the assessment of protocols, production of advice and continuous evaluation of the ethical aspects of the research. The IRB/IEC should review the trial protocol prior to implementation, to ensure that the designed protocol is scientifically sound and justified and respects all rights of the participants. It is the role of the IRB/IEC to ensure that all information is gathered on the risks and benefits of the intervention, that appropriate information is provided to the patient prior to recruitment and that appropriate care and treatment are provided during the study. Informed consent Formally described in the Declaration of Helsinki, the informed consent (IC) is the process by which a participant voluntarily confirms his/her willingness to participate in the trial. Basic principles are that the participation of an individual in a clinical research must be voluntary, and that it is the right of the subject to refuse or withdraw from the trial without compromising his/her treatment. The IC must state clearly the purpose of the study and the type of intervention to be tested, explain the principle of random assignment, explain clearly the expected risks/benefits to the participants, the treatments available and how to deal with trial-related injuries or side effects. It should respect confidentiality of trial subjects. The IC should be approved by the IRB/IEC, and should be revised if important information becomes available which may be relevant to a subject’s consent. Before consent is obtained, the potential participant must be fully informed of the purpose and nature of the intervention, as well as all pertinent aspects of the trial. This is usually done through a Patient Information sheet, written in simple, non-technical language. Risks and benefits must be clearly explained in the language of the patient, who should be allowed ample time and opportunity for questions and decision making. The IC must be signed and dated before participation in the trial and kept in the patient’s file.
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If the subject is illiterate, an impartial witness should be present. It must be made clear that a subject may freely withdraw consent at any time.
The role of the investigator GCP guidelines give details on the suitable qualifications of the investigator and on his/her responsibilities pertaining to the following areas:
Personnel and facilities: Ensure adequate staffing for the conduct of the trial, and ensure access to all necessary facilities; Compliance with the protocol: Ensure that all trial operations are conducted in full compliance with the agreed protocol and potential amendments. Any deviation from the protocol should get written permission from the sponsor; Patient population: Ensure access to patients in adequate numbers so as to complete the requested sample size; Ethics requirements: Ensure submission of trial documents to the IRB/IEC, transmission of approval to the sponsor and submission of updates on safety issues or changes to the protocol; Study medication: Ensure adequate storage, inventory and delivery of the study medication; Adverse events (AE) and serious adverse events (SAE): Document all AEs and SAEs and ensure appropriate reporting to the sponsor, the IRB/IEC and where relevant the regulatory authorities; and Records and reports: Ensure accuracy, completeness, legibility and timeliness of the data reported to the sponsor in the CRFs and in all required reports.
The role of the sponsor The ICH GCP guidelines define very clearly the roles and responsibilities of the sponsor of the trial, who has overall responsibility for all activities conducted within the trial:
Trial design, quality control and quality assurance: Ensure that qualified individuals are engaged in the trial process, with production of a scientifically sound and detailed protocol; maintenance of quality assurance and quality control systems with written procedures to ensure that the trial is conducted and data are generated, recorded and reported in compliance with the
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protocol, GCP and the applicable regulatory requirements (if any); Trial management, data handling and record keeping: Ensure qualified individuals are engaged to supervise the overall conduct of the trial, handle and verify the data, conduct the statistical analyses and prepare the trial reports; Investigator selection: Ensure the investigator is carefully selected and agrees to: ○ Conduct the trial according to the agreed protocol, in compliance with GCP and, if appropriate, the applicable regulatory requirement(s); ○ Comply with procedures for data recording/reporting; ○ Permit monitoring, auditing and inspection; and ○ Retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed Compensation to subjects and investigators: Provide insurance or indemnification against claims arising from the trial, except for claims that arise from malpractice and/or negligence; Notification/submission to regulatory authority: Ensure submission of required applications to the appropriate authority for review, acceptance and/or permission to begin the trial; and Safety information: Ensure ongoing safety evaluation of the investigational product: Premature termination or suspension of a trial, if necessary; Link with appropriate committees (data monitoring committee, trial steering committee, etc.).
Trial monitoring The purpose of trial monitoring is to verify that: 1. the rights and well-being of human subjects are protected; 2. the reported trial data are accurate, complete and verifiable from source documents; and 3. the conduct of the trial is in compliance with the currently approved protocol and potential amendment(s), GCP and applicable regulatory requirements. It is the responsibility of the sponsor to ensure that the trial is adequately monitored. Monitoring should take place before, during and after the trial. It is the role of the monitor to prevent, detect, document and correct any error, mismanagement, neglect or protocol violation that might have occurred in the trial. Non-compliance with the protocol, standard operating procedures, GCP and/or applicable regulatory requirements by an investigator/institution should lead to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator or institution, the sponsor should terminate the investigator’s/institution’s participation in the trial and promptly notify the regulatory authority(ies).
Clinical trial protocol and Investigator’s Brochure ICH GCP guidelines give detailed information on the format and content of the trial protocol and on the methods for implementing and approving protocol amendments. It also gives a clear delineation of the contents of the Investigator’s Brochure. When planning trials, the sponsor should ensure that sufficient safety and efficacy data from non-clinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration and in the trial population to be studied. The sponsor should update the Investigator’s Brochure as significant new information becomes available.
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Standard Operating Procedures (SOPs) When planning a trial, it is essential to ensure that all activities are performed according to the same standard and with full compliance with GCP requirements. For that, all activities should be conducted according to precisely written SOPs which should cover all aspects of clinical research: inclusion/exclusion criteria, withdrawals from the study, specific diagnostic procedures, patient consent and ethics, data management, documentation and reporting of adverse events (AEs) and serious adverse events (SAEs). SOPs are extremely important for defining minimum standards and act as points of reference for any question or potential debate around a specific procedure. Audit The purpose of a sponsor’s audit, which is independent of and separate from routine monitoring or quality control functions, is to evaluate trial conduct and compliance with the protocol, SOPs, GCP and the applicable regulatory requirements. The sponsor should ensure that the auditing of clinical trials is conducted in accordance with the sponsor’s written procedures. GOOD LABORATORY PRACTICE Similarly to GCP, guidelines for good laboratory practice have been established. GLP is defined as ‘a quality system concerned with the organizational process and the conditions under which studies are planned, performed, monitored, recorded, archived and reported’. GLP has arisen from the need to apply quality standards in drug research, development and testing. Strict adherence to GLP helps in removing sources of errors and uncertainty. All work done in laboratories that may be used for regulatory purposes should be done to the standards of GLP, i.e. properly documented and quality controlled. This applies to laboratory work that analyses materials from human studies, whether standard clinical samples or pharmacokinetic analyses. It is necessary to ensure that all equipment is regularly serviced (and these services are recorded), that all reagents are of the proper standard for the task and have not passed their expiry date, that all equipment is regularly calibrated and the data on calibration are recorded. All work should be conducted to the manufacturer’s specifications and/or protocols for the work should exist. Output from machines should be retained and not just recorded in laboratory notebooks. Document trails are required to ensure that all the data can be verified and are of adequate quality. Overall, the GCP and GLP rules are designed to ensure that the best possible clinical research is practiced, and that the patient’s rights are protected while at the same time ensuring that highquality data are collected.
TRIAL MANAGEMENT AND COORDINATION Clinical trials should be seen as a complete experimentation process, from the start (research question) until the end (proof of safety and/or efficacy of the IMP). As for all experimentation, it is essential to ensure validity and reproducibility of results, but as trials deal with human subjects, it is essential to ensure safety and appropriate care of patients contributing to the trial. The aim of trial management and coordination is to ensure smooth and harmonized operations between the various personnel/institutions involved in the conduct of the trial at all stages, from the development of the protocol up to the analysis of data and report of findings, respecting GCP and GLP principles.
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BEFORE THE TRIAL One of the first priorities is to ensure the quality of the product to be tested (manufacturing according to good manufacturing practice requirements, production and availability), and ensure proper labelling, with expiry dates which fit with the duration of the trial. A clear and complete Investigator’s Brochure must be written. The required forms (such as the informed consent forms, the CRFs and the AE/SAE report forms) must be drafted and pilottested. The standard database and data management system must be developed and installed. Site(s) should be evaluated. It should be ensured that the investigator clearly understands the protocol and accepts the obligations pertaining to the conduct of the trial. SOPs must be developed for aspects of the trial that need standardization – such as the recruitment procedures, the conduct of tests/medical exams, withdrawals from the trial and the identification, declaration and treatment of AEs and SAEs. On the administrative side, all trial documents, including trial registration, submission to IRB/IECs and trial insurance certificates, must be assembled and stored in a safe place. If the trial is multicentre, it is important to formalize from the start the links between partners, so that each of them knows clearly what his/her role is in the trial operations.
DURING THE TRIAL Trial management and coordination requires good communication between the various researchers/institutions/committees involved in the trial at all stages. This is particularly important in multicentre trials. Trial management relies mainly on rigorous and ongoing monitoring of trial activities. The objective is to ensure that the trial is conducted, recorded and reported in accordance with GCP requirements, that the trial follows the SOPs as well as the applicable regulatory requirement(s) that have been set up and that the trial data are accurate, complete and verifiable from source documents. These activities are carried out through regular site visits (Box 103.2). These start at the preparation phase, through a pre-trial monitoring visit, to ensure the feasibility of the trial in the centre and the interest of the investigator. It is then followed by an initiation visit, the purpose of which is to ensure that the investigational team understands the protocol and GCP requirements and during which study materials, documents and products are delivered. Then, once the trial has started, clinical monitors conduct regular visits to check that the trial is conducted according to the protocol and to GCP standards and assess whether the investigational team needs help in solving problems. At the end of the trial, a close-out visit is carried out, to ensure that the investigator file is archived properly and that all data are being properly collected and reported. In addition to trial monitoring, regular supervision is needed to ensure proper process of operations at all levels. This supervision consists of regular site visits and regular meetings with collaborators (coordination meetings). This is particularly important for multicentre trials.
AT THE END OF THE TRIAL It is essential to ensure that accurate, complete and legible data have been collected and are available to the sponsor for statistical analysis and report writing. The remaining documents and trial supplies are disposed of in accordance with the sponsor’s instructions. Once data have been cleaned, the dataset is locked for data analysis. Report on findings will follow, together with the appropriate information to the trial committees, sponsor and patients.
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Box 103.2 Content of clinical monitoring visits Initiation visit Purpose To ensure that all necessary information and documents have been provided to the centre and have been reviewed and understood by the study staff; and To ensure also that all due material and products have been delivered to the site(s). Check that The entire study staff has fully understood the protocol, trial procedures, good clinical practice (GCP) and regulatory requirements in order to conduct the trial efficiently; All items required to commence the study at the study site are available and adequate; and If necessary, any other action needs to be taken. Monitoring visits during the trial Purpose To ensure that investigator’s obligations are being fulfilled; To ensure that data submitted in support of the safety and efficacy/ effectiveness are accurate and complete; and To review all individual subject records and other supporting documents and compare those records with the reports (e.g. SAE reports, CRFs) prepared by the investigator for submission to the sponsor. Check that The facilities used by the investigator continue to be appropriate and acceptable for the purposes of the study; The study protocol or investigational plan is being followed; Changes to the protocol have been approved by the IRB and/or reported to the sponsor and the IRB; Accurate, complete and legible records are being maintained; Accurate, complete and timely reports are being made to the sponsor and IRB; and The investigator is carrying out the agreed-upon activities and has not delegated them to other previously unspecified staff. Close-out visit Purpose To assure archiving of trial documents is in accordance with GCP and regulatory requirements. Check that Accurate, complete and legible records have been collected and are available to the sponsor; The remaining documents and trial supplies are disposed in accordance with sponsor instructions; and The investigator understands his/her ongoing responsibility.
ADMINISTRATION AND LOGISTICS In terms of trial management, the person responsible for the trial should ensure an appropriate supply and storage of investigational products, clinical material and equipment, laboratory material and equipment, consumables and forms (such as consent forms, CRFs and AE/SAE forms). He/she should also ensure that the budget is appropriate to the activities of the trial and that funds are being made available for use. In addition, an appropriate accounting and financial reporting system must be established. All administrative documents must be duly completed, filed and timeously reported. In conclusion, good trial management and coordination at all stages relies on regular trial monitoring, appropriate trial supervision and sustained communication. Management involves various committees, which are described below.
CHAPTER
Clinical trials in tuberculosis
COMMITTEES TO SUPERVISE A TRIAL This section describes the functioning of three committees, the trial steering committee (TSC), the independent data monitoring committee (IDMC) and the trial management committee, commonly used to oversee different aspects of a clinical trial (Box 103.3). The committees required for a trial of TB drugs would not differ in any particular way from a trial of any other type of treatment. An underlying basis for each of these committees would be to ensure that the trial is conducted to appropriate standards, patient safety is given the highest priority and every effort is made to deliver the trial within the planned time span. The role of the TSC is to monitor and supervise the progress of the trial towards its interim and final objectives. The TSC will be responsible for ensuring that the trial is conducted according to ICH GCP, particularly in relation to the safety of the trial participants. The chairman of the TSC should be independent of the investigators and if possible there should be a majority of independent members. Before the trial commences the TSC should agree and sign off the study protocol. The TSC is responsible to the trial sponsor and will need to monitor the enrolment and retention rates to ensure they are within the planned targets. The TSC will receive reports from the IDMC and will need to consider their response. In the unusual event that the TSC is unwilling to implement the recommendations of the IDMC, it may be necessary for the TSC, or selected members, to meet with the IDMC. The membership of the IDMC should include at least one clinician who is familiar with the disease area, a statistician and, where relevant, representatives of any other specialties involved in the trial. The minimum recommended membership is three persons. The IDMC should meet either before the trial starts or soon after recruitment starts to review the trial protocol and procedures including stopping rules and the analysis plan, to develop or approve their terms of reference and operating procedures. The usual practice is for the meetings of the IDMC to include both open and closed sessions. At open sessions the chief investigator or deputy together with other members of the trial team will be present to update the committee on general progress and to highlight any concerns they have that they wish the IDMC to address. During the closed session only the IDMC members and the trial statistician, or in some cases another designated statistician, should be present. During the closed session the trial statistician presents results from the trial which will usually have been circulated in advance. Box 103.3 Committees involved in a clinical trial Committee Trial steering committee
Independent data monitoring committee Trial management committee
Membership Chair: Independent clinician/trialist Additional independent members Chief investigator Principle investigators (selection) Trial statistician Observers, including remaining investigators, representative(s) from pharmaceutical company A minimum of three independent members, to include trialist, statistician and clinician Chair: investigator Members representative of all aspects of the trial, e.g. administration, clinical data, laboratory, monitors, data management and statistics
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The DAMOCLES project conducted a systematic review of the published literature on IDMCs for RCTs, and they summarized information and opinions on best practice.15 In contrast to the TSC and IDMC, the trial management committee (TMC) would be expected to meet at least monthly and possibly weekly, certainly in the early stages of the trial. The TMC would have as its membership persons representing every aspect of the trial’s activity and if possible would include investigators from the study sites who would usually be expected to participate by telephone. The TMC should have its finger on the pulse of the study so as to be aware at the earliest opportunity of any problems that might require an immediate response. Monitors would report back to the TMC on their site visits and the TMC would consider the appropriate response to issues raised at monitoring visits.
DATA MANAGEMENT AND ANALYSIS DATA ENTRY The data entry and data management systems for clinical trials should not only ensure that the data entered are correct and verified, but should also be able to demonstrate that this has been the case. Alternatives to manual data entry include electronic systems such as data-fax, hand-held electronic data recorders and Web-based entry systems.
DATA MANAGEMENT There are now a number of sophisticated database packages specifically developed for clinical trial applications, although particularly in developing countries (where many TB trials are carried out) sufficient rigour can be achieved through the use of standard database packages such as MS ACCESS. The purpose of data management procedures (which should be formalized through written SOPs) is to: 1. ensure a valid and verified database of trial data is locked before analysis and has demonstrable integrity through transparent predefined procedures; 2. derive the required outcome measures; and 3. test out analysis procedures so that data analysis can be correctly carried out when data lock has been performed. Generally, a clinical trial database will consist of a number of related files that together constitute all of the data in the CRF.
DATA ANALYSIS As we have seen earlier, the trial protocol will contain a description of the main statistical procedures that will be carried out in order to produce the final report. Before any analyses are performed a detailed statistical analysis plan must be produced and agreed upon by all the investigators.
CONCLUSION This chapter has given a brief introduction to clinical trials in TB research. In particular it is essential for all parties involved in carrying out a clinical trial to have recently attended training in GCP (say within the past 4 years). More detailed discussion on issues in clinical trials can be found in the books by Meinart, Piantadosi, Pocock and Senn among others, while Ellenberg et al. deals specifically with data monitoring committees.16–20
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REFERENCES 1. Volmink J, Garner P. Directly observed therapy for treating tuberculosis. Cochrane Database System Rev 2006, Issue 2. Art. No.: CD003343.pub2. 2. Thiam S, LeFevre AM, Hane F, et al. Improving adherence to tuberculosis treatment in a resourcepoor setting: A cluster randomised controlled trial. JAMA 2007;297(4):380–386. 3. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948;2:769–782. 4. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946– 1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;10(Suppl 2):S231–S279. 5. Nunn Andrew J, Phillips Patrick P, Gillespie Stephen H: Design Issues in Pivotal drug trials for Drug Sensitive Tuberculosis (TB). Tuberculosis 2008;88 (Suppl. 1):S85–S92. 6. Kwara A, Flanigan TP, Carter EJ. Highly active antiretroviral therapy (HAART) in adults with tuberculosis: current status. Int J Tuberc Lung Dis 2005;9(3):248–257.
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7. Dawson J J Y, Devadatta S, Fox W, Radhakrishna S, Ramakrishnan C V, Somasundaram P R, Stott H, Tripathy S P, Velu S. A 5-year study of patients with pulmonary tuberculosis in a concurrent comparison of home and sanatorium treatment for one year with isoniazid plus PAS. Bull World Health Organ 1966;34: 533–551. 8. Fox W. Compliance of patients and physicians: Experience and lessons from tuberculosis—I. BMJ 1983;287:33–35. 9. Fox W. Compliance of patients and physicians: Experience and lessons from tuberculosis–II. BMJ 1983;287:101–105. 10. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Bibl Tuberc 1970;26:28–106. 11. Quigley MA, Mwinga A, Hosp M, et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 2001;15(2):215–222. 12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guidelines. Guideline for Good Clinical Practice, E6. Geneva: ICH, 1996. Available at URL:http:// www.ich.org
13. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Edinburgh: World Medical Association, 2000. Available at URL:http://www. wma.net/e/policy/b3.htm 14. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: Council for International Organizations of Medical Sciences (CIOMS), 1993. 15. DAMOCLES Study Group, NHS Health Technology Assessment Programme: A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 2005; 365(9460):711–722. 16. Meinert CL. Clinical Trials: Design, Conduct and Analysis. Oxford: Oxford University Press, 1986. 17. Piantadosi S. Clinical Trials: A Methodological Perspective. London: Wiley, 1997. 18. Pocock SJ. Clinical Trials: A Practical Approach. London: Wiley, 1983. 19. Senn S. Statistical Issues in Drug Development. London: Wiley, 1997. 20. Ellenberg S, Fleming TR, Demets DL. Data Monitoring Committees in Clinical Trials: A Practical Perspective. London: Wiley, 2002.
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Tuberculosis and social justice A historical perspective Mathew Gandy
The understanding and control of TB is one of the most significant chapters in the history of humankind. In a detailed chronology of the disease from classical times until the twentieth century the Italian historian Arturo Castiglioni remarked on ‘the marvelous progress from demonism to bacteriology’.1 For Castiglioni, writing in 1933, the science of bacteriology marked a decisive advance in the progressive development of Western civilization. The decline of TB was a marker on a path towards a better future in which rational knowledge would prevail over the ignorance, superstition and neglect of the past. Yet Castiglioni’s faith in the centrality of science to the eradication of disease masks the full complexity of the epidemiology of TB, the rapid decline of the disease from the middle decades of the nineteenth century, before the disease was fully understood, and its more recent resurgence point to an array of social, economic and political developments beyond the confines of the laboratory.
CLASS, RACE AND DEATH IN THE TWENTIETH CENTURY The production of more accurate data on morbidity and mortality in the last decades of the nineteenth century began to reveal the disproportionate concentration of TB among specific social groups. The relationship between TB, race and social class became more evident not only because of the changing politics of public health but also because the partial retreat of the disease had highlighted its higher prevalence among the poor, non-white people and other marginalized groups.2 A parallel discourse of differential susceptibility to TB began to develop alongside the sanitarian emphasis on improved hygiene. Instead of new bacteriological insights dispelling the earlier hereditarian emphasis of the nineteenth century, the ‘constitutional’ dimensions to disease epidemiology became reformulated in terms of different degrees of racial resistance to TB. The recognition of differential mortality by race provoked a complex array of arguments which sought to use prevailing cultural and biological conceptions of human difference as a means to explain widening inequalities in human health. In the British colonies, for example, a theory of ‘virgin soil’ populations emerged which attributed high rates of TB mortality among non-white people to the lack of ‘tubercularization’ or disease resistance amongst people who had not yet undergone the full effects of industrialization and urbanization. The influential pathologist Lyle Cummins posited that Europeans owed their higher survival rates to longstanding low-level exposure to the disease coupled with the spread of new hygienic living practices which prevented the illness from
taking root in all but the most weakened or intemperate individuals. In contrast, non-European peoples were characterized by Cummins as biologically inferior and culturally backward, which rendered them susceptible to TB as a ‘disease of civilization’. The high rates of TB experienced in Africa, India and elsewhere in the colonial world were widely seen as an inevitable and necessary marker on the path to a Westernized society which had achieved a more stable relationship between the human immune system and the virulence of the TB bacillus.3 Yet at the heart of this tubercularization debate lay a profound confusion over whether the observed racial differences in mortality could be attributed to a Lamarckian process of acquired immunity or to a longer term history of Darwinian evolution. Arguments about the relative significance of inherited or acquired immunological characteristics were supplemented by the proposal of a cultural hierarchy of disease resistance ranging from the ‘childlike’ susceptibility of colonized peoples to the supposedly hardier responses of urbanized European societies. In the United States the control of TB amplified middle-class antipathy towards the ‘lower classes’ and heightened anxieties over immigration and racial mixing. Surveys carried out in the early twentieth century revealed that the rate of TB mortality was three times higher for black Americans than for white Americans.4 These general figures mask even greater differences in many of the larger towns and cities. In Charleston, South Carolina, for example, the rate of TB mortality for black people in 1900 was seven times higher than that for white people. How were these disparities to be explained? A variant of the tubercularization thesis suggested that former slaves had been protected from the disease through their ‘healthy’ outdoor life on Southern plantations. The implication was that high rates of TB among African Americans were an unfortunate yet inevitable consequence of their emanicipation.5 Yet the social conditions under which most African Americans lived could not be discounted altogether as a cause of their higher mortality. In 1920, for example, George E Bushnell, a colonel in the US Medical Corps and director of the National Tuberculosis Association, combined a version of the tubercularization thesis with a recognition of the impact of poverty on ill health. ‘Because of his color the negro is barred from much productive industry,’ Bushnell wrote. ‘As he therefore cannot compete with the white people in earning capacity, he is relegated to the worst habitations in the most insalubrious locations and to arduous or poorly paid toil everywhere.’ But instead of calling for government action to improve living conditions, Bushnell chose instead to insist on improvements in the behaviour of poor black people, the majority of whom he characterized as ‘extraordinarily untrained, improvident and
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reckless; so that there must be taken into account not only poverty but a poverty which is tenfold worse because of the failure to make proper use of the scanty means at hand.’6 A new concern with what the historian Marion Torchia describes as the ‘Negro health problem’, which combined nineteenth-century moralism with white self-interest in order to avoid the possibility of infection by black maids, servants and other workers in daily contact with affluent middle-class homes, emerged.7 As the historian Jessica Robbins notes of the shifting politics of TB in the United States: The acceptance of the germ theory had given TB a new and threatening social dimension. The tuberculous patient was not only an individual sufferer but also a potential source of infection and danger to others. The overwhelming majority of these patients were among the working-class poor. The prescription for health, physicians believed, was fresh air, good food, and plenty of rest – all of which were beyond the means of the urban poor. Professionals and reformers engaged in a protracted debate over what, if anything, should be done about this social problem.8
To acknowledge fully the structural causes of TB threatened to open up a much wider progressive agenda for social reform. For conservative health commentators it was essential, therefore, to persist with individualized modes of explanation which emphasized putative connections between ‘immoral living habits’ and susceptibility to infection. In Canada, for example, the chief medical officer, Peter Bryce, described TB as one of a group of social diseases along with alcoholism, syphilis and feeble-mindedness: ‘We find them so often intermingled,’ Bryce wrote, ‘that it seems quite impossible to determine which disease is the determinant or dominant one.’9 The idea of differential degrees of immunity provided a scientific veneer for official indifference towards much higher levels of TB among poor and marginalized sections of society. Evolutionary conceptions of TB implied that control of the disease would occur through a long-term immunological transition rather than through any kind of medical intervention.10 At root, however, anxieties over class, race and disease flowed from fears that these stigmatized groups would act as reservoirs for the contagion of wider society. Hereditarian views persisted in the post-bacteriological era as part of an emerging discourse of disease and national identity which would find its most virulent expressions under European fascism. Jews, for example, were denounced in Nazi Germany as ‘a racial TB among nations’.11 Thus even in the context of the widespread retreat of the disease across Europe and North America TB retained a powerful metaphorical resonance for racial and ethnic hatred. Improvements in diagnosis after the discovery of the TB bacillus in 1882 were not matched by major advances in treatment for many decades. Koch’s claim, for example, to have discovered a cure for TB in 1890 through the production of the bacterial culture tuberculin was discredited. Although the incidence of TB declined during the twentieth century, those who contracted the disease still suffered a high mortality rate. And even when improved treatments became available, the most vulnerable sections of society – principally the urban poor – were often unable to gain access to adequate medical care.12 In the post-bacteriological era there were repeated inoculation experiments aimed at furthering scientific understanding of bacterial immunity. In 1914, for example, the American physician Guy Hinsdale predicted that ‘future generations will be provided with a practical and efficient
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method of destroying this insatiate monster.’ It would be some years, however, before the efforts of Trudeau, Gilliand, de Schweinitz and others would lead towards any definitive advance in the development of an effective vaccine. The most critical advance in TB inoculation was achieved by the French scientists Albert Calmette and Camille Gue´rin who began testing a bovine-derived vaccine in 1922. Initially the Bacillus Calmette-Gue´rin (BCG) vaccine was only widely adopted in France and other countries – such as Spain and Canada – with strong cultural ties to French science.13 In the USA, by contrast, the rejection of the BCG vaccine reflected a long-standing antipathy towards universal health interventions which might strengthen the role of the state in the advancement of public health (despite the pioneering early efforts of some municipal authorities). American scientists feared that the introduction of BCG would subvert the self-improvement ethos of the New Deal and at the same time draw attention to the persistence of the disease despite the twentieth-century rhetoric of scientific success.14 In essence, the varied national responses to the BCG vaccine reflected different conceptions of the relationship between healthcare and social policy, a tension temporarily obscured by advances in the antibiotic treatment of TB sufferers from the 1940s onwards.15 In 1944 the treatment for TB was transformed with the first use of the antibiotic streptomycin by Selman Waksman to cure infected patients. This was followed in 1951 by the use of another powerful antibiotic, isoniazid. Taken together these new drugs revolutionized the treatment of TB and contributed towards a sharp decline in the environmental emphasis of the past. Unlike the BCG vaccine which aimed to prevent the progression from infection to illness, the widespread use of antibiotic drugs from the early 1950s onwards sought to cure patients who had already become ill. Within 30 years the rate of TB mortality in the developed world fell by more than 90%. The discovery of streptomycin instituted a new phase in the control of TB which would increasingly emphasize issues of patient compliance over any wider discussion of the social and economic dimensions to disease epidemiology. The very success of the antibiotic revolution in healthcare served to disengage clinical medicine from the wider public health agendas of the past. The historical construction of the term ‘non-compliance’ reveals how biomedical perceptions of patient deviance emphasized that particular groups are ‘difficult’ or ‘recalcitrant’ in terms of cooperating with medical authorities. Thus the issue of uneven access to adequate treatment in the antibiotic era became widely framed in terms of individual deficiencies or anti-rational belief systems rather than any acknowledgment of the social context in which the disease might be spread.16 In Apartheid South Africa, for example, persistent racial disparities in rates of infection were routinely dismissed on the grounds of cultural difference and a preference for traditional medicine. Yet a wealth of evidence from South Africa showed how poor housing and working conditions, combined with inequalities in access to medical care, had contributed towards widening health disparities in the twentieth century.17 At a global scale, the antibiotic revolution of the 1940s and 1950s was highly uneven in its social and geographical impact, leaving much of the world’s population languishing under high rates of infection with only haphazard access to treatment. Most critically, however, the early success of antibiotic drugs served to mask the continuing prevalence of TB infection. The ‘magic bullet’ of drug therapy diverted attention from the social and economic conditions in which the TB bacillus could continue to thrive.
CHAPTER
Tuberculosis and social justice
GLOBAL POVERTY AND THE ‘NEW’ TUBERCULOSIS The antibiotic revolution of the 1940s and 1950s led a range of leading public health campaigners, scientists and physicians confidently to predict the eradication of TB by the year 2000.18 By the early 1980s TB appeared to be largely a disease of historical interest in the West, a consensus that indicated a dangerous complacency in the face of the continuing high prevalence of the disease in many developing countries. As recently as 1987, for example, the Oxford Textbook of Medicine predicted the virtual eradication of TB in ‘most technically advanced countries’ before the year 2050.19 Yet those who considered TB in a global context were far less optimistic. In 1964, for instance, the executive director of the International Union against Tuberculosis, John Holm, issued this warning: For about half of the world’s population no organized efforts are made to control TB, and this is the half where the problem is most serious. For the other half, efforts to control TB are conducted in a haphazard manner. Only a small fraction of the world’s population is covered by well-organized programs in which the most modern means to control TB are systematically employed.20
The turning point in global efforts to control TB can be traced to the United States in the mid-1980s where a sudden increase in cases was observed in urban areas: between 1985 and 1992 there was a rise in TB cases of over 20%.21 Cities such as New York faced a rapid and unexpected spread of TB which quickly escalated into a public health emergency. This surge in reported cases can be attributed to increases in poverty and homelessness during the 1980s combined with the effects of human immunodeficiency virus (HIV) infection and the spread of drug-resistant TB strains. The emerging public health crisis facing deprived inner city neighbourhoods represented a microcosm of the changing global incidence of the disease. It soon became apparent that the problems facing inner-city America were surfacing on a global scale in response to the combined effects of drug resistance, HIV and poverty. The development of drug resistance is thought to be responsible for around 10% of new TB cases worldwide.22 The problem of drug resistance was encountered soon after the discovery of streptomycin and other antituberculous drugs and led to the gradual emergence of multidrug treatment programmes. Factors involved in the emergence of drug resistance include the poor supervision of therapy, the use of badly prepared combination preparations, inconsistent prescribing practices, erratic drug supplies and unregulated over-the-counter sales of drugs.23 The most commonly encountered resistance is to a single drug, usually streptomycin or isoniazid, and most TB bacteria with such resistance respond adequately to a multidrug treatment programme. The emergence of resistance to rifampicin is much more serious, however, as this is the most powerful antituberculous drug with the ability to sterilize lesions by destroying near-dormant ‘persister’ bacilli. Furthermore, most rifampicin-resistant strains are also resistant to isoniazid; by convention, TB due to strains resistant to these two agents, with or without additional resistances, is said to be multidrug resistant. The use of standard short-course treatment becomes not only ineffectual but may even be positively harmful as resistance to other drugs such as pyrazinamide and ethambutol also develops as part of the so-called amplifier effect.24 As Vivien Stern observes in Russia and other states of
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the former Soviet Union, mutant forms of TB, variously referred to as multidrug-resistant (MDR) TB, have been rapidly spreading in response to chronic overcrowding in the prison system and severe cutbacks in primary healthcare. The problems and costs of managing each case of MDR-TB are enormous. Successful therapy requires prolonged courses of less effective, more expensive and more toxic drugs, under long-term supervision.25 The incidence of MDR-TB in New York City has been reduced by such a strategy, although at very great cost: the cost of the management of a single case can exceed US$250,000.24 In the case of New York, the spread of MDR-TB was facilitated by reductions in public health expenditure during the 1980s, but the city ended up having to spend ten times more than it saved in order to bring TB under control.26 A second factor behind the resurgence of TB is the acquired immunodeficiency syndrome (AIDS) pandemic. This is estimated to contribute around 10% of TB cases worldwide. In Africa, however, HIV is responsible for at least 20% of TB cases.27 Given that one-third of the world’s population carry quiescent TB infection the effects of immune system damage can be expected to have devastating consequences: the most recent data suggest that in parts of sub-Saharan Africa, for example, more than one-quarter of the adult population are now infected with HIV. Infection by HIV is currently the most important predisposing factor for the development of overt TB in those infected by TB before or after becoming HIV-infected and by the late 1990s there were estimates of at least 10 million coinfected persons.28 The increasing recognition of links between TB and HIV among patients has had the adverse effect of adding to the stigma of TB symptoms and has hindered cooperation between patients, healthcare workers and local communities.29 The return of TB has also exposed tensions between different conceptions of medicine and individual liberty: in the USA, for example, the threat of MDR-TB and coinfection with HIV has led to calls for punitive public health strategies based on mandatory screening and treatment, case notification to public agencies, aggressive contact tracing and the use of quarantine. Such measures, reminiscent of early twentieth-century approaches to public health, are in conflict with contemporary conceptions of individual liberty.30 A third dimension to the ‘new’ TB is the effects of global social and economic change. Mass movements of people in response to war, increased economic insecurity, community breakdown and other factors have been involved in the spread of TB and other infectious diseases associated with overcrowding, makeshift housing and poor sanitation.31 In addition to short-term disruption we must consider the longer term social and economic shifts which have emerged since the early 1970s. There is now increasing evidence that growing poverty, infrastructural decay and declining health services have facilitated the spread of TB, diphtheria, sleeping sickness and other preventable diseases.32 In the case of Viet Nam, for instance, recent research has shown how the scaling down of established public healthcare systems during the 1990s has resulted in increased costs, more erratic drug availability and sinking morale among low-paid community health workers at the forefront of healthcare provision.33 A substantial body of evidence suggests that TB has a disproportionate impact on the economically poor: 95% of all TB cases and 98% of TB deaths occur in the developing world where problems of ill health contribute towards cycles of economic hardship in the context of high unemployment and weak social security and healthcare provision. Similarly, the spread of TB and other preventable diseases in the so-called de-developing enclaves
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of urban America and the poverty-stricken cities of the former Soviet Union can only be fully understood with reference to the dynamics of global political and economic change since the Second World War.34 Changing patterns of economic and social investment have contributed towards a new geography of wealth and poverty with significant implications for the epidemiology of disease. With the advent of more diffuse patterns of urbanization and the greater mobility of capital investment it has become far easier for public health crises to be effectively ignored where they present no generalized threat to the overall well-being of an increasingly globalized economic system. In 1948 the newly created World Health Organization defined health as ‘a state of complete physical, mental and social well-being, not merely the absence of disease and infirmity’.35 This definition rests on an explicit recognition of the connections between healthcare and wider ethical and political ideals; yet, recent advances in biomedicine have served to obscure any meaningful connection between health and social justice. The past 30 years has seen a shift from collective forms of healthcare to an increasing emphasis on health as an individualized dimension to personal development. The historical synergy between health reform and social justice has been displaced by an increasing emphasis on the individual patient (or consumer) rather than the wider social and political context for disease. The profit-driven restructuring of global healthcare has led to widening health inequalities as the world’s poor find themselves unable to benefit from the latest technological and pharmaceutical advances. In comparison with other major health afflictions, TB remains relatively neglected; the funding of TB control worldwide, for example, continues to be very low in comparison with other infectious diseases: just $8 of external aid is spent for each patient death compared with $137 dollars for malaria, $925 for AIDS and over $38,000 for leprosy.36 Of the 1,240 new drugs licensed between 1975 and 1996 only 13 dealt with the world’s killer diseases that primarily afflict people from tropical and poor countries. In 1998, for example, the World
REFERENCES 1. Castiglioni A. History of tuberculosis. trans. Emilie Recht. Medical Life 1933;40:5. 2. See, for example, Craddock S, City of Plagues: Disease, Poverty, and Deviance in San Francisco, Minneapolis: University of Minnesota Press, 2000;Gilman SL, Difference and Pathology: Stereotypes of Sexuality, Race, and Madness, Ithaca, NY: Cornell University Press, 1985;Gilman SL, Disease and Representation: Images of Illness from Madness to AIDS, Ithaca, NY: Cornell University Press, 1988. 3. Harrison M, Warboys M. A disease of civilization: tuberculosis in Africa and India. In: Marks L, Warboys M, eds. Migrants, Minorities and Health: Historical and Contemporary Studies. London/New York: Routledge, 1997:93–124. Warboys M. Tuberculosis and race in Britain and its empire, 1900–50. In: Ernst W, Harris B, eds. Race, Science and Medicine, 1700–1960. London/New York: Routledge, 1999:144–166. 4. Feldberg GD, Disease and Class: Tuberculosis and the Shaping of Modern North American Society. Rutgers, NJ: Rutgers University Press, 1995. Bates B, Bargaining for Life: A Social History of Tuberculosis, 1876–1938. Philadelphia: University of Pennsylvania Press, 1992. On the surveys, see McBride D, From TB to AIDS: Epidemics among Urban Blacks since 1900. Albany, NY: State University of New York Press, 1991. 5. See Harrison, Warboys, A disease of civilization, esp. 102.
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Health Organization failed to persuade pharmaceutical leaders to collaborate over the development of a combined drug for TB to make public health campaigns simpler and more cost-effective because the potential profit margins were too low.37 The problems of poverty and community breakdown have had a devastating effect on global public health and threaten to overwhelm the prospects for greater social cohesion and economic development. Whilst new technological advances may play a useful role in the treatment of TB the eventual eradication of the disease will rest on wider structural changes in modern societies. Most sufferers from TB have limited political and economic power and their plight remains of only marginal significance in global affairs. Yet the corrosive effect of ill health on social development threatens to expose the specious logic behind a new world order in which much of humanity is condemned to poverty and serfdom. If there is one lesson to be learned from the diseased cities of nineteenth-century Europe and North America, it is that the contemporary global public health crisis will not be solved by medical intervention but by political transformation.
ACKNOWLEDGEMENTS Many thanks to Michael Warboys for his helpful comments on an earlier draft of this chapter. Thanks also to Ana Francisca de Alvezedo for assistance with the translation of the article by Diego Armus. The principal data sources used were the British Library, the New-York Historical Society, the London School of Hygiene and Tropical Medicine and the Wellcome Library for the History and Understanding of Medicine, London. This is an edited extract of the essay ‘Life without Germs’, first published in Matthew Gandy and Alimuddin Zumla, eds. The Return of the White Plague: Global Poverty and the ‘New’ Tuberculosis. London/New York: Verso, 2003.
6. Bushnell GE, A Study in the Epidemiology of Tuberculosis with Especial Reference to Tuberculosis of the Tropics and of the Negro Race. London: John Bale, Sons & Danielsson, 1920:210, 155, 156. 7. Torchia MM. The tuberculosis movement and the race question, 1890-1950. Bull Hist Med 1975;49:161. See also Torchia MM. Tuberculosis among American Negroes: medical research on a racial disease, 1830–1950. J Hist Med Allied Sci 1977;32:252–279. 8. Robbins JM. Class struggles in the tubercular world: nurses, patients, and physicians. Bull Hist Med 1997;71:412–434. 9. Bryce P. Tuberculosis in Relation to Feeblemindedness. Tuberculosis Monograph No. 3. New York: Department of Health, 1917:5. 10. Harrison, Warboys, A disease of civilization. 11. Sontag S. Illness as Metaphor. New York: Vintage, 1979:83. 12. Hinsdale G. Atmospheric air in relation to tuberculosis. Trans Am Climatolog Clin Assoc 1914;30: i–136.1. On the development of a vaccine, see Flexner S, Immunity in Tuberculosis, Washington, DC: Smithsonian Institution, 1908:627–645; Hays JN, The Burdens of Disease: Epidemics and Human Response in Western History, Rutgers, NJ: Rutgers University Press, 1998. 13. Feldberg, Disease and Class. 14. Moulin AM. The impact of BCG on the history of tuberculosis. In: Pa¨lfi G, Dutour O, Dea´k J, et al. Tuberculosis Past and Present. Budapest/Szeged: TB Foundation and Golden Book Publisher, 1999: 77–86.
15. See, for example, Lerner BH, From careless consumptives to recalcitrant patients: the historical construction of noncompliance, Soc Sci Med 1997;45:1423–1431. 16. Typical examples of cultural explanations for high black rates of TB in the Apartheid era include Barker A, New doctors for an altered society, S Afr Med J 1971;45:558–561; and Dubovsky H, Tuberculosis and art, S Afr Med J 1983;64:823–826. 17. Zaki MH, Hibberd ME. The tuberculosis story: from Koch to the year 2000. Caduceus 1996;12:43–60. 18. Millard FJC. The rising incidence of tuberculosis. J R Soc Med 1996;89:497. 19. Myers JA. Tuberculosis: A Half Century of Study and Conquest. St Louis: Warren H Green, 1970:309. 20. See Brudney K, Dobkin J. Resurgent tuberculosis in New York City: human immunodeficiency virus, homelessness, and the decline of tuberculosis control programs. Am Rev Respir Dis 1991;144:745–749. 21. Neville K, Bromberg A, Bromberg R. The third epidemic—multidrug-resistant tuberculosis. Chest 1994;105:45–48. Nolan CM. Nosocomial multidrugresistant tuberculosis—global spread of the third epidemic. J Infect Dis 1997;76:748–751. Small P, Moss A. Molecular epidemiology and the new tuberculosis. Infect Agents Dis 1993;2(3):132–138. Small P, Shafer R, Hopewell P, et al. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993;328(16):1137–1144. 22. See Okeke IN, Lamikanra A, Edelman R. Socioeconomic and behavioural factors leading to acquired bacterial resistance to antibiotics in developing countries. Emerg Infect Dis 1999;5:18–27.
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Tuberculosis and social justice 23. See, for example, Long ER, A History of the Therapy of Tuberculosis and the Case of Fre´de´ric Chopin. Lawrence: University of Kansas Press, 1956. 24. Farmer P, Kim JY. Community-based approaches to the control of multidrug resistant tuberculosis: introducing ‘DOTS-plus’. BMJ 1998;317:671–674. 25. Kochi A, Vareldzis B, Styblo K. Multidrug-resistant tuberculosis and its control. Res Microbiol 1993;144: 104–110. 26. Boseley S. Warning as TB cases increase. The Guardian, 14 December 1999. 27. See Zumla A, Johnson M, Miller RF, eds. AIDS and Respiratory Medicine. London: Chapman and Hall, 1997. 28. Altman LK. Parts of Africa showing HIV in 1 in 4 adults. New York Times, 24 June 1998. 29. Van Cleef M, Chum HJ. The proportion of tuberculosis cases in Tanzania attributable to human immunodeficiency virus. Int J Epidemiol 1995; 24:637–642.
30. See Bayer R, Public health policy and tuberculosis, J Health Politics Policy Law 1994;19:149–154; Coker RJ, From Chaos to Coercion: Detention and the Control of Tuberculosis, New York: St Martin’s Press, 2000. 31. See, for example, Smallman-Raynor M, Cliff A, Civil war and the spread of AIDS in Africa, Epidemiol Infect 1991;107:69–79. 32. See Farmer P, Social scientists and the new tuberculosis, Soc Sci Med 1997;44:347–358. 33. Naterop E, Wolffers I. The role of the privatization process on tuberculosis control in Ho Chi Minh City Province, Vietnam. Soc Sci Med 1999; 48:1589–1598. 34. Tulchinsky TH, Varavikova EA. Addressing the epidemiologic transition in the former Soviet Union: strategies for health system and public health reform in Russia. Am J Publ Health 1996;86:313–323. Wallace R, Wallace D, Andrews H, et al. The spatiotemporal dynamics of AIDS and TB in the New York metropolitan region from a sociogeographic
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perspective: understanding the linkages of central city and suburbs. Environ Planning A 1995; 27:1085–1108. Wallace R, Wallace D. The destruction of US minority urban communities and the resurgence of tuberculosis: ecosystem dynamics and the white plague in the dedeveloping world. Environ Planning A 1997; 29:269–291. 35. World Health Organization 1948, cited in Blaxter M. Health. In: Outhwaite W, Bottomore T, eds. The Blackwell Dictionary of Twentieth-Century Social Thought. Oxford: Blackwell, 1993:254. 36. World Health Organization. TB—A Global Emergency. Geneva: World Health Organization, 1994. 37. Garrett L. Betrayal of Trust: The Collapse of Global Public Health. New York: Hyperion, 2000.
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The history of the DOTS strategy Achievements and perspectives Dermot Maher and Mario Raviglione
INTRODUCTION Since 1994, the World Health Organization (WHO) has promoted the implementation of a policy package for TB control (Box 105.1),1 which became known as the DOTS strategy.2 ‘DOTS’ is the strategy’s brand name, derived from ‘directly observed treatment, short-course’. Although new and improved drugs, methods of diagnosis and vaccines will be developed eventually, which could have a great impact on the global burden of TB, until then control of the disease is mainly based on interruption of its transmission through the rapid identification and cure of infectious cases. With proper treatment, a person with infectious TB very quickly becomes non-infectious and so can no longer spread disease to others. Prompt diagnosis and effective treatment of TB are at the heart of the DOTS strategy. Not only are they the key elements in the public health response to TB and the cornerstone of TB control, they are also essential for good patient care.3,4 This chapter describes the history of the DOTS strategy, beginning with an outline of the first of the two twentieth-century revolutions in TB control, namely the development in the late 1940s and early 1950s of specific antituberculous chemotherapy. The story for 20 years thereafter of applying the principles of TB control based on case-finding and successful treatment is one of success in developed countries and failure in developing countries. Karel Styblo’s pioneering work in the 1970s heralded the second revolution – the development of a model of TB control applicable in the resource-poor countries that are home to the vast majority of patients with TB worldwide. From 1994 to 1995 this model has been promoted as the DOTS strategy, with ongoing refinements.5 The achievements in implementation of the DOTS strategy are described, and the chapter ends with an account of the development of the new Stop TB Strategy launched in 2006. The Stop TB Strategy incorporates and goes beyond the DOTS strategy in seeking to overcome the largely health system challenges in TB control over the next decade, while paying due attention to the two specific threats of human immunodeficiency virus (HIV)-related and drug-resistant TB.
THE FIRST REVOLUTION – THE DEVELOPMENT OF SPECIFIC ANTITUBERCULOUS CHEMOTHERAPY THE ERA BEFORE CHEMOTHERAPY In the pre-chemotherapy era, the aim of TB treatment was to strengthen host resistance (through special diets and rest in bed in
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a sanatorium) and to rest the diseased part of the lung (by various techniques of collapse therapy). Sanatorium treatment was expensive and associated with a 5-year case fatality of about 50%.6 Before the 1950s, of the many TB patients worldwide, only a select few among those living in industrialized countries had access to treatment. During the first half of the twentieth century the TB situation in industrialized countries steadily improved as socioeconomic conditions improved.6 Although little is known about the TB burden and its trend in developing countries at that time, it is likely that the TB epidemic was generally uncontrolled, since there was little political commitment and funding for TB control, little improvement in socioeconomic conditions, little if any social support for TB patients and few facilities for the care and isolation of TB patients.
TRIALS AND TRIBULATIONS – THE EARLY DEVELOPMENT OF COMBINATION CHEMOTHERAPY The following account draws on the excellent review of TB control in the twentieth century by Christopher Holme.7 The first antituberculous drugs were developed in the 1940s – streptomycin by Waksman (Fig. 105.1) and Schatz, and para-aminosalicylic acid (PAS) by Lehmann. Following its discovery in 1944 streptomycin became available in 1946,8 and its efficacy was demonstrated in a pioneering randomized controlled clinical trial in 1948 run by the British Medical Research Council (MRC) Tuberculosis Research Unit established under Philip D’Arcy Hart.9 The trial was pivotal as the first high-profile demonstration of the therapeutic benefit of a drug using the principles developed by Austin Bradford Hill to eliminate bias. It not only confirmed the efficacy of streptomycin but it also represented the broad intellectual revolution for evaluation of interventions using randomized clinical trials. However, the initial promise of streptomycin often proved a disappointment as the problems of resistance and toxicity soon became apparent. A subsequent MRC trial of streptomycin and PAS showed for the first time that combination chemotherapy decreased the emergence of drug resistance and provided the basis for antituberculous chemotherapy for the next 20 years. Following the advent of isoniazid in 1952, Sir John Crofton led the team that put Edinburgh on the map, at least concerning global TB control (Fig. 105.2). The Edinburgh approach was based on the administration of triple combination chemotherapy (streptomycin, PAS and isoniazid) with intensive support to ensure adherence throughout the 18 months of treatment and scrupulous
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Box 105.1 Policy package for tuberculosis control1 1. Government commitment to a TB programme aiming at nationwide coverage, as a permanent health system activity, integrated into the existing health structure with technical leadership from a central unit; 2. Detection of TB cases among persons with symptoms indicative of TB presenting themselves to a health worker; 3. Administration of standardized short-course antituberculous chemotherapy under proper case management conditions; 4. Establishment of a system of regular drug supply of all essential antituberculous drugs; and 5. Establishment and maintenance of a monitoring system to be used for both programme supervision and evaluation.
Fig. 105.2 Sir John Crofton.
(with relatively small numbers of TB patients, ample resources and sophisticated health systems). It was expensive, long (18–24 months) and difficult to ensure adherence to. Subsequent MRC trials in the 1950s were aimed at demonstrating the applicability of triple combination chemotherapy in developing countries. Trials in East Africa, India and Hong Kong demonstrated the efficacy and safety of what became ‘standard treatment’ lasting 1 year, using streptomycin, isoniazid and thiacetazone (replacing PAS). With the principles of the successful application of standard treatment firmly established by the 1960s, the road ahead was clear for the development of ‘short-course’ (6–8 months) chemotherapy in the 1970s when rifampicin became available.13
THE POTENTIAL FOR MASS BENEFIT Fig. 105.1 Selman Waksman.
monitoring of each patient’s progress through bacteriological analysis.10 By 1954 it had been conclusively demonstrated that this combination of the first three antituberculous drugs discovered could cure virtually all TB patients, however severe their disease (in the absence of drug resistance). The very high cure rates under this approach coupled with intensive case-finding had a swift public health impact, with the previously rising TB case notification rates falling by half between 1954 and 1957.11 In 1959 Canetti and Rist at the Pasteur Institute in Paris organized an international collaborative trial, the first of its kind, that resulted in acceptance of the Edinburgh approach in the leading hospitals of 23 countries.12 Triple combination chemotherapy (with streptomycin, PAS and isoniazid) was effective but problematic in developed countries
A series of studies supported by the Indian Government, WHO and the British MRC in two Indian institutions (National TB Institute in Bangalore and TB Chemotherapy Centre in Madras) provided the foundations for the integration of programmes for TB case detection and treatment into the general health services, thus potentially making the benefits of chemotherapy widely available. The Bangalore studies showed how most sources of Mycobacterium tuberculosis infection could be detected among patients presenting with respiratory symptoms to general health services.14,15 The Madras studies showed that treatment in specialized institutions (hospital or sanatoria) was not necessary because treatment at home was effective and safe.16,17 These results provided a rational basis to promote TB programmes in developing countries which should ensure nationwide access to simplified technologies for TB control delivered through the general health services.
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IDENTIFYING THE SOURCES OF MYCOBACTERIUM TUBERCULOSIS INFECTION The problem with case-finding at specialized centres was the usual one associated with the vertical TB programme, that only a fraction of those who needed the service had access to it. The National TB Institute in Bangalore showed that most sources of M. tuberculosis infection could be diagnosed by sputum smear microscopy of patients with respiratory symptoms attending general health services.14,15 These findings were in line with those of the Kolin study which showed little added diagnostic yield of active case-finding.18
SANATORIA SAYONARA The results of the Madras studies overturned the usual policy of administration of treatment through hospitalization in the early years of antituberculous chemotherapy (the 1950s and 1960s).16,17 The main reasons for a policy of hospitalization were the following: 1. The provision of TB care was generally specialized, involving TB specialists in specialized units in hospitals, which were the only health facilities providing TB care, and since most TB patients lived too far away for ambulatory treatment, they needed admission to hospital; 2. Tuberculosis specialists were continuing the sanatorium traditions of isolation and bedrest; 3. Hospitalization provided a way of supervising treatment and monitoring progress (e.g. sputum microscopy at the end of the initial phase of treatment); 4. There were doubts about the feasibility and effectiveness of ambulatory treatment; 5. There were concerns that an inability to ensure adherence to treatment by ambulatory patients would lead to continuing M. tuberculosis transmission and increased risk of development of drug-resistance.19 The policy of hospitalization changed following the demonstration that ambulatory antituberculous chemotherapy was effective and not associated with an increased risk of TB among the household contacts of infectious index cases.16,17 Madras was specifically chosen as the study site to demonstrate feasibility under difficult conditions. In the words of Wallace Fox, ‘We deliberately picked Madras because everything was unfavourable. I think people believed these results for the reason that we had patients with very severe disease so they couldn’t say it was trivial.’7 The results from Madras had a tremendous impact worldwide: developed countries closed their sanatoria and the developing countries started to abandon hospitalization in favour of ambulatory treatment.
TWENTY YEARS’ SUCCESS AND FAILURE The outcome of the studies in Madras and Bangalore generated optimism that, despite its imperfections, curative chemotherapy had the potential to benefit TB patients worldwide and to decrease the global burden of TB. However, the story in realizing this potential over the next 20 years from the 1950s to the 1970s was one of success in developed countries and failure in developing countries. Overall, ‘the methodological breakthroughs which made a universal cure possible were wasted because of poor doctoring and a lack of concerted international effort.’7
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SUCCESS IN DEVELOPED COUNTRIES In the pre-chemotherapy era, as socioeconomic conditions improved in many industrialized countries during the first half of the twentieth century, the TB situation steadily improved. This was reflected by the annual risk of TB infection (ARI) decreasing by about 5% annually in many of these countries. The widespread application of antituberculous chemotherapy with intensive casefinding through a vertical programme approach led to an accelerated decline in ARI. For example, in the Netherlands, the annual decrease in ARI was about 5% over the decades between 1910 and 1940, and accelerated to 13% after the introduction of chemotherapy in the 1950s.20 From the 1970s the ARI declined more slowly (to about 8% in the 1980s) as the risk fell to very low levels (less than 10 new infections per 100,000 population per year). The trend in the Netherlands was typical of many developed countries.21
FAILURE IN DEVELOPING COUNTRIES The information available on ARI in developing countries painted a different picture.22 The ARI fell very slowly at between 1% and 2% per year in many developing countries from the 1950s to the 1970s, while the application of chemotherapy in developed countries led to a rapid fall of at least 10% per year.23 Developing countries with high TB incidence failed to realize the benefit of curative chemotherapy for individual TB patients and for public health, as the international public health pendulum swung from the vertical TB programme approach (1948–1963) to the approach of integration of TB service delivery (1964–1976) and then later of TB programme managerial functions (1977–1988) within general health services (in keeping with the spirit of the Alma Ata primary healthcare movement).24,25 The vertical programme approach failed because, with limited resources, the reach of its specialized structure extended to only a fraction of the population.26 The integrated approach failed because of the lack of an organizational framework, managerial expertise, funding and health infrastructure. Unfortunately, the abandonment of hospitalization in favour of ambulatory treatment is likely to have contributed to this failure. Doctors’ interest in patients with TB generally started with diagnosis and ended with prescription of antituberculous drugs. Without a systematic organizational approach to ensuring patient support and follow-up, ambulatory treatment was often interrupted, inadequate and incomplete.
THE SECOND REVOLUTION – THE DEVELOPMENT OF THE STYBLO MODEL Supported by the International Union against Tuberculosis and Lung Disease (IUATLD), Karel Styblo (Fig. 105.3) pioneered the development of a model of TB control in Tanzania in the 1970s. This model was based on the sound epidemiological principles of case-finding among symptomatic patients and the application of chemotherapy and was delivered using the existing district-based government health infrastructure. The model encompassed the comprehensive organizational and managerial approach to TB control that had previously been lacking,2 despite it being clearly spelled out in the recommendations of the WHO Expert Committee on TB that met in 1973.27 The use of standard longcourse treatment (1 year of isoniazid and PAS) in the first few years of pioneering this approach did not achieve high rates of
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POLICY AND PRACTICE Adoption of the Styblo model as the WHO strategy for tuberculosis control The new WHO TB programme started to implement its new strategy for global TB control in 1991 based on the Styblo model.29 From 1994–1995 onwards the new strategy became known as the DOTS strategy. The deliberations of WHO’s Expert Committees on TB during the doldrums of global TB control in the 1960s and 1970s provided principles and policies that proved practical and effective in implementing the new strategy in this new era of renaissance of interest in TB control. The Expert Committee in 1973 formulated four principles for NTPs that remain valid. The NTP should be: 1. integrated into general health services, within the Ministry of Health; 2. nationwide; 3. permanent because of the nature and chronicity of the disease; and 4. adapted to the needs of the people, with TB services being as close to the community as possible to facilitate diagnosis, treatment and follow-up.27 The strategy was formulated as a five-point policy package (see Box 105.1).1 Fig. 105.3 Karel Styblo
treatment success, and so was abandoned in favour of short-course chemotherapy (SCC), with rifampicin during the initial 2-month phase (when agreement was finally reached to make rifampicin available not only in developed but also in developing countries). The model made use of the available government district hospitals, relying on hospitalization to ensure adherence to treatment during the initial phase treatment. This was controversial since ambulatory treatment was the norm at the time.19 The Tanzania National Tuberculosis Programme (NTP) was the first of the IUATLD model programmes with successful nationwide coverage. From the 1980s many NTPs, especially in subSaharan Africa, relied on hospitalization for supervised administration of treatment during the initial phase. Between 1978 and 1991, the IUATLD supported NTPs in nine resource-poor countries with high TB incidence in implementing the recommended policy package for TB control.
MAKING TUBERCULOSIS CONTROL AVAILABLE FOR ALL FROM PILOT PHASE TO AUTO-PILOT By 1991 the pilot phase of implementing the Styblo model was over, paving the way for worldwide implementation through a global alliance of partners.3,28 The challenge now was to put TB control activities on autopilot, so that in each country they ultimately became routine, self-sustaining and guaranteed to reach the goal. WHO’s twin-track approach was, on the one hand, to pursue policy and practice and, on the other, publicity and promotion.
‘Citius, altius, fortius’ The experience of steady expansion of implementation of the DOTS strategy during the 1990s proved the strategy’s five elements to be robust and provided lessons on how to make the strategy ‘faster, higher, stronger’, i.e. how to speed up progress towards the international targets established in 1991 by the World Health Assembly of at least 70% case detection and at least 85% treatment success (initially set for 2000 and then postponed to 2005).30 On account of progress in implementation of the DOTS strategy that was too slow, the first ad hoc Committee on the TB Epidemic met in London in 1998 and reviewed the barriers to faster progress. It made several key recommendations to overcome them, including: 1. to form a global alliance to harness the efforts of, and obtain synergy from, the increasing number and range of stakeholders in global TB control; 2. to develop a coordinating mechanism for technical cooperation and country-level planning; and 3. to establish a global mechanism to help ensure uninterrupted access to quality-assured antituberculous drugs at affordable prices.31 Each of these recommendations was put into action. A global alliance of partners met in Amsterdam in 2000 as the Global Tuberculosis Initiative,32 which became the Global Partnership to Stop TB. The global partners under the leadership of WHO developed the Global DOTS Expansion Plan, setting out the activities oriented towards achieving the targets for 2005 and the associated costs.33 In 2001 the Stop TB Partnership established the Global Drug Facility, which by the end of 2006 had made available 10 million TB treatments.34
Adapting the DOTS strategy The particular threats to successful implementation of the DOTS strategy posed by the HIV epidemic and the emergence of antiTB drug-resistance necessitated adaptations to the strategy. HIV has dramatically fuelled TB in populations with high HIV prevalence.35 WHO developed a strategy of expanded scope to
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counter the HIV-driven TB epidemic, consisting of measures aimed directly against TB (full implementation of the DOTS strategy with intensified case-finding and preventive treatment) and measures against HIV (and therefore indirectly against TB), including prevention of HIV transmission and provision of antiretrovirals.36,37 Recognition of the extent of the global problem of drug-resistant TB led to the adaptation of the DOTS strategy as ‘DOTSPlus’ to counter multidrug-resistant (MDR) TB.38,39 The DOTS strategy is the starting point for managing drug-resistant TB, which also involves quality-assured drug-susceptibility testing and the use of second-line drugs in recommended treatment regimens.40 The establishment by a group of partners of the Green Light Committee hosted by WHO enabled the negotiation of lower prices with the drug industry, the use of pooled procurement and the coordination of technical assistance to ensure the quality of programmatic management of patients with MDR-TB.41,42
PUBLICITY AND PROMOTION Who put the DOT in the DOTS strategy? Marketing techniques were enthusiastically embraced by WHO in promoting its TB control strategy worldwide. Generating and maintaining media interest was key to raising the profile of TB as a problem which needed solving, and as a problem for which the solution was available (i.e. the policy package). Drawing attention to the global problem capitalized on the resurgence of interest due to the TB comeback in the USA, particularly in New York. WHO’s declaration of TB as a global emergency in 1993 generated unprecedented media interest.43 Successful marketing of the policy package as the solution depended on ‘branding’, i.e. giving it a distinctive, simple and memorable name. The name chosen was ‘DOTS’. This name was successful in terms of widespread uptake of the brand, but also generated confusion and controversy in some circles. The confusion arose not surprisingly because ‘DOT’ (directly observed treatment) was widely identified with DOTS, resulting in a common misapprehension that the TB control strategy was centred on DOT, instead of consisting of the full fivepoint policy package.44 The controversy arose because DOT proved to be the most contentious (and probably the only contentious) feature of the strategy.45 Those looking for evidence of the value of DOT through systematic reviews of controlled trials failed to find it. A lot of time, energy and effort went into promoting the DOTS brand, and into trying to persuade opponents of DOT that, counter to common sense, DOTS was more than DOT. What became clear was that branding was important in helping to promote the uptake of the strategy worldwide, but that perhaps the choice of brand name also resulted in the locking of the strategy to a contentious issue debated at length in the medical press. Adherence to treatment as one of the keys to successful treatment Leaving aside the debate about DOT, WHO’s advice on adherence to treatment as one of the keys to successful treatment was otherwise uncontroversial. Regarding medical treatments in general, there has often been a gap between the recognition of the importance of adherence and the extent of efforts to implement measures to improve adherence. This gap needs to be closed, considering for example that ‘increasing the effectiveness of adherence interventions may have far greater impact on the health of the population than any improvements in specific medical treatments’.46
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Regarding TB treatment specifically, improved adherence is crucial to obtaining the individual and public health benefits of TB treatment. Interruption of TB treatment results in uninterrupted M. tuberculosis transmission in the community, with perpetuation of the epidemic. In many countries, a significant proportion of TB patients for various reasons stop treatment before the end, with consequent risks of treatment failure, relapse, death and acquired drug resistance. Since TB is a transmissible disease, premature interruption of treatment poses risks not only for patients but also for the community. The importance of providing intensive support to TB patients to promote adherence to treatment was recognized in the 1950s when combination antituberculous chemotherapy was pioneered.47 NTPs have the responsibility to ensure a comprehensive approach to promoting adherence, aimed at service providers and patients. Recommended measures aimed at promoting adherence include placing the patient at the centre of TB control activities, ensuring confidentiality and consideration of patients’ needs, organizing TB services so that the patient has treatment as close to home as possible, addressing factors that may make patients interrupt or stop treatment by identifying potential problems in advance, considering incentives, keeping accurate address records and taking defaulter actions.2,48 There is now increasing recognition of the role in promoting adherence of a treatment partner or supporter who is acceptable to the patient and is trained and supervised by health services, and of patient and peer support groups. Support for patients must be context-specific and patient-sensitive, with particular attention paid to groups with particular needs, including prisoners, drug users and some people with mental health disorders. Assessment of the extent of adherence is crucial to determine the success of measures to promote adherence and ensure that treatment is completed. Direct observation of treatment may best be viewed as the most practical means of assessing adherence, which also provides an opportunity of promoting adherence through the human interaction between patient and treatment observer. Under the heading of ‘supervision and patient support’, WHO’s most recent advice concerning DOT is that achieving cure and preventing drug resistance involves ‘supervised treatment that may have to include DOT’.49
PROGRESS IN IMPLEMENTING THE DOTS STRATEGY THE FINAL REPORT ON PROGRESS AGAINST THE TARGETS FOR 2005 The report on progress against the global targets for 2005 represents a defining moment in the history of the DOTS strategy, since it was formulated to achieve these targets. When WHO first established the targets in 1991,50 there was no system for measuring the global burden of TB, and the global effort to implement the international strategy for TB control that subsequently became known as the DOTS strategy was in its early stage. Following the establishment of the global TB monitoring and surveillance system in the mid1990s, the first results showed a case detection rate of 11% (for 1995) and treatment success rate of 77% (for 1994).51 The WHO Global TB Monitoring and Surveillance Project has provided the latest global estimates of progress against the targets for 2005.52 They indicate that among patients with sputum smear-positive pulmonary TB diagnosed and treated under the DOTS strategy the case detection rate was 60% (for the cohort of patients diagnosed in 2005) and the treatment success rate was 84% (for the cohort of patients
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implementation of the DOTS strategy. In four out of six WHO regions (the Americas, Eastern Mediterranean, South-East Asia and Western Pacific), per capita TB incidence has been stable or falling over the past decade. In two regions (Africa and Europe) per capita TB incidence had been increasing for over a decade, but appears to have reached a peak.
Case detection rate, smear-positive cases (%)
80 WHO target 70%
70
105
60 50 40 30 20
DOTS begins
THE STOP TB STRATEGY THE DEVELOPMENT OF THE STRATEGY
10 0 1990
1995
2000
Year
2005
2010
2015
Fig. 105.4 Progress from 1995-2005 towards the 70% case detection target. Open circles mark the number of smear-positive cases notified under DOTS, expressed as a percentage of estimated new cases in each year.
treated in 2004). More than 26 million TB patients were treated by DOTS programmes over the 11 years from 1995 to 2005. The global achievement of a case detection rate of 60% and treatment success rate of 84% (compared with the global targets of 70 and 85%, respectively) represents tremendous progress in implementation of the DOTS strategy and in global TB control since 1991. Over the past decade the case detection rate has thus increased from 11% to 60% with an acceleration during the past 5 years (see Fig. 105.4), and the treatment success rate has increased from 77% to 84% (at the same time as an approximately 10-fold increase in cases detected). Table 105.1 shows as of the end of 2006 the latest estimates of progress against the targets for 2005. All regions have made progress, with the Western Pacific Region having achieved and surpassed the targets, and with considerable variation in progress among different countries.
THE CURRENT STATUS OF THE GLOBAL TUBERCULOSIS EPIDEMIC The latest estimates of the global TB burden refer to cases arising in 2005. There were an estimated 8.8 million new cases of TB in 2005, of which 3.9 million were sputum smear-positive and 0.6 million were in HIV-infected adults. The total number of MDR-TB cases estimated to have occurred worldwide in 2004 was 0.4 million. An estimated 1.6 million people died from TB in 2005, including 0.2 million people coinfected with HIV.52 After over a decade of increase, global per capita TB incidence appears to have stabilized, attributable in large part to wide
In 2003 WHO and the Stop TB Partnership convened a second ad hoc Committee on the TB Epidemic to seek solutions to constraints to more rapid progress in global TB control and to make recommendations to overcome those constraints.53 At its meeting in Montreux, Switzerland, in 2003, the Committee acknowledged the progress made in TB control in all regions, but stressed the urgent need to speed up progress. The Committee recognized that progress in TB control can contribute to improved health and poverty reduction, and depends on strengthening not only the specifics of traditional TB control programme activities but also general health systems. In setting the mid-term strategic direction towards the international targets for 2015, the Committee made the following recommendations (many of which cut across the different aspects of TB control) to Stop TB partners: 1. consolidate, sustain and advance achievements; 2. enhance political commitment (and its translation into policy and action); 3. address the health workforce crisis; 4. atrengthen health systems, particularly primary care delivery; 5. accelerate the response to the TB/HIV emergency; 6. mobilize communities and the corporate sector; and 7. invest in research and development to shape the future.54 It became apparent that a new strategy for global TB control which encompassed the Committee’s emphasis on health systems and reflected key developments such as the adaptations of the DOTS strategy in response to the problems posed by HIV and MDR-TB, while retaining the principles of case detection and treatment success (documented through strict programme monitoring) that lie at the heart of the DOTS strategy, was necessary. The formulation of WHO’s new Stop TB Strategy was informed by the Committee’s recommendations, with each of the six elements reflecting the key constraints to further progress faced by many countries (Table 105.2). The Strategy was developed through a
Table 105.1 Progress towards the tuberculosis control targets for 2005 Regions
AFR AMR EMR EUR SEAR WPR Global
Progress towards targets for 2005 Case detection (in 2005) (%)
Number of countries achieving 70% target
Treatment success (in 2004) (%)
Number of countries achieving 85% target
Number of countries achieving both targets
50 65 44 35 64 76 60
9 18 7 13 5 15 67
74 80 83 74 87 91 84
7 7 7 11 7 18 57
1 4 5 5 3 8 26
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Table 105.2 Formulation of the elements of the Stop TB Strategy reflecting key constraints Element of strategy
Constraint
Pursue high-quality expansion and enhancement of the DOTS strategy. Address HIV-related TB, multidrug-resistant TB and other challenges.
Limitations in geographical coverage of, and access to, the DOTS strategy, and in the quality of DOTS implementation. The impact of HIV in fuelling the TB epidemic, the occurrence in some countries in all regions of MDRTB (including extensive drug-resistant TB) due to inadequate TB treatment practices, and the challenge posed by risk factors, e.g. smoking. Health system weaknesses regarding system-wide policy, human resources, financing, management, service delivery (especially through primary care), and information systems. Inadequate engagement of the full range of care providers, particularly those in the non-state sector. Insufficient mobilization of people with TB and of communities to promote case-finding, patient-centred support and quality care, and their limited engagement in partnerships to Stop TB; lack of ‘bottom-up’ pressure on politicians and decision-makers to ensure delivery of quality care. Under-investment in research aimed at improving the use of the currently available interventions for control and at developing the new diagnostics, drugs and vaccines that are urgently needed.
Contribute to health system strengthening. Engage all care providers. Empower people with TB, and communities.
Enable and promote research.
process of extensive consultation, approved by WHO’s TB advisory committee, endorsed by the Stop TB Partnership and launched on 17 March 2006 (in a joint press event with The Lancet). The Stop TB Strategy (Box 105.2) is aimed at achieving the Stop TB Partnership’s targets for 2015, which are linked to the United Nations Millennium Development Goals (MDGs).55 The MDGs provide a framework and opportunity for international cooperation in improving the health of the poor. As a disease of poverty, responsible for the loss of more years of healthy life than any other curable communicable disease, TB is one of the priorities to which these goals apply. The goal relevant to TB (Goal 6, Target 8) is ‘to have halted and begun to reverse incidence by 2015’. In addition to interpreting Target 8 as an incidence rate that should be falling by 2015, the Stop TB Partnership has endorsed international targets linked to Target 8, to decrease TB prevalence and deaths by half by 2015 (in comparison with a 1990 baseline).30
IMPLEMENTING THE STRATEGY How all Stop TB partners, starting with the governments of TBendemic countries, will implement the Stop TB Strategy is set out in the Partnership’s Global Plan to Stop TB, 2006–2015, launched on 27 January 2006 at the World Economic Forum in Davos, Switzerland.56 The Plan (see Chapter 107) was developed through a process of extensive consultation with a wide range of governmental and non-governmental partners, including activist groups, civil society, academia, non-governmental organizations and technical experts. As the blueprint for implementation of the Stop TB Strategy, the Plan sets out the steps in research and development for new tools (diagnostics, drugs and vaccines) and the planned implementation of currently available interventions expected to make an impact on the global TB burden resulting in global achievement of the targets for 2015. These activities include scaling up interventions against MDR-TB and against HIV-related TB. The Plan sets out the
Box 105.2 The WHO Stop TB Strategy55 Goal
To dramatically reduce the global burden of TB by 2015 in line with the Millennium Development Goals and the Stop TB Partnership targets Objectives Achieve universal access to quality diagnosis and patientcentred treatment. Reduce the human suffering and socioeconomic burden associated with TB. Protect vulnerable populations from TB, TB/HIV and drug-resistant TB. Support development of new tools and enable their timely and effective use. MDG 6, Target 8: Halt and begin to reverse the incidence Targets of TB by 2015. Targets linked to the MDGs and endorsed by Stop TB Partnership: 2005: detect at least 70% of infectious TB cases and cure at least 85% of them 2015: reduce prevalence of and deaths due to TB by 50% 2050: eliminate TB as a public health problem. Components of the Strategy and Implementation Approaches 1. Pursue quality DOTS expansion and enhancement a. Political commitment with increased and sustained financing b. Case detection through quality-assured bacteriology c. Standardized treatment, with supervision and patient support Raviglione M, Uplekar, M. The new Stop TB Strategy of WHO. Lancet 2006;367:952.
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3.
4.
5.
6.
d. Effective drug supply and management system e. Monitoring and evaluation system, and impact measurement. Address TB/HIV, MDR-TB and other challenges TB/HIV collaborative activities. Prevention and control of drug-resistant TB. Addressing prisoners, refugees and other risk groups and special situations. Contribute to health system strengthening Active participation in efforts to improve system-wide policy, human resources, financing, management, service delivery and information systems. Sharing innovations that strengthen systems, including the Practical Approach to Lung Health. Adapting innovations from other fields. Engage all care providers Public–public and Public–private mix approaches. International Standards for TB Care. Empower people with TB, and communities Advocacy, communication and social mobilization. Community participation in TB care. Enable and promote research Programme-based operational research. Research to develop new diagnostics, drugs and vaccines.
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resources needed for actions, underpinned by sound epidemiological analysis with robust budget justifications. The Plan’s total cost (US$56 billion) over 10 years includes US$47 billion for implementation of currently available interventions and US$9 billion for research and development. The estimated funding gap is US$31 billion, since an estimated US$25 billion is likely to be available based on projections of current domestic and external funding trends.
FUTURE PERSPECTIVES The future of TB control will largely depend on successful implementation of the new Stop TB Strategy, with the adequate resources made available, whether human or financial, in all countries. The starting point, at the moment and with no new revolutionary discovery on the horizon, remains the five elements of the DOTS strategy. These elements represent a focused and specialized approach to TB control based on proper TB diagnostic, treatment and monitoring activities within functioning health systems and services. Since health systems are crucial for the effective implementation of any disease-specific package such as the DOTS strategy, the Stop TB Strategy represents a widening and enhancement of the DOTS strategy to embrace those components of the health system relevant to TB care and control. Without, for instance, involvement of national HIV/AIDS programmes, HIV-related TB cannot be tackled successfully. Similarly, active engagement in the process of strengthening health systems, and especially the primary health services, is necessary to obtain the synergies between a categorical programme such as TB and overall health system developments. Finally, the intensity of involvement of all practitioners, especially those from the non-state sector, and of communities and patients with TB themselves will determine the capacity of a national TB programme to effectively control and in the long-term eliminate TB. However, developments in sectors beyond health will certainly determine the future of TB control. As with any other disease with strong socioeconomic determinants, the removal of the upstream determinants of disease will have the potential to speed up progress in disease control. The upstream determinants (‘causes of causes’) that maintain TB, among other diseases, in a community include poverty, urbanization, housing, nutrition and the general level of education which influences the response to any community health threat. These upstream determinants are often shaped by new socioeconomic forces that are part of ‘globalization’. These upstream factors pertaining to sectors beyond health generate in turn more downstream factors directly relevant to the cycle of TB transmission in a society. These factors include conditions normally beyond the reach of those directly involved in TB control, yet within the health system capacity to influence them, e.g. tobacco use, diabetes, malnutrition, indoor pollution and, of course, HIV infection. The Stop TB Strategy does not directly address the more direct causes of TB (with the exception of HIV) and their upstream determinants. However, those interested in the long-term goal of TB elimination need to assess the importance of both the upstream and the more direct determinants of TB in a community. Understanding the ‘causes of causes’, i.e. identifying the upstream determinants of TB, will enable those interested in TB control to join a coalition of those interested in addressing the range of illnesses with strong socioeconomic determinants in advocacy efforts to alleviate these determinants. This can contribute to better health for all societies. Addressing the more direct factors, e.g. HIV, tobacco and diabetes, of great relevance specifically to TB control and also to general public health implies the joint engagement of TB programmes with others in the health sector concerned with
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these problems. Socioeconomic conditions in many countries are likely to facilitate, rather than impede, disease among society’s most vulnerable members. With further understanding of the causes of TB, those responsible for national and international efforts to control TB can work together with other health sector stakeholders towards removing these causes, thereby enhancing the Stop TB Strategy’s effectiveness and the likelihood of future TB elimination.
CONCLUSION There is encouraging progress in the Stop TB Partnership’s efforts to mobilize popular and political support to fully fund and implement the Global Plan, ranging from the promotion of grassroots advocacy to the engagement of national and world leaders in the campaign to Stop TB. Working towards universal access to quality TB care under the Stop TB Strategy implies a continued focus on the key elements of the DOTS strategy that lie at the heart of the Stop TB Strategy – prompt diagnosis in detecting cases and effective treatment (documented through strict monitoring of programme performance). In all countries, the expected epidemiological impact on the TB burden in terms of incidence, prevalence and mortality depends on high performance of national TB programmes in ensuring the highest possible case detection and treatment success rates. Maximizing the expected epidemiological impact on the TB burden depends, for countries that have not reached the programme performance targets by 2005, on reaching them as soon as possible, and for countries that have reached the targets for 2005, on sustaining and surpassing this achievement. Measuring the expected impact of implementation of the Stop TB Strategy on the TB burden requires the use of impact indicators (TB incidence, prevalence and deaths), in addition to continued measurement of operational TB programme performance indicators (case detection and treatment success rates). There are two priority actions at country level for service delivery in achieving high levels of case detection and treatment success. The first is to engage all care providers: government services (whether Ministry of Health services or not – e.g. social security schemes, prisons, military) and non-government services, e.g. NGOs, community groups, private practitioners and employers,57–59 so that they provide quality care consistent with the International Standards.60 The second concerns case detection and is to strengthen the network of public and private sector laboratories that also play a crucial role in disease surveillance, including drug-resistant TB. The central importance of achieving a high cure rate among patients diagnosed with TB runs as a strand of continuity from the Edinburgh approach in the 1950s, through the Styblo model of the 1980s and the DOTS strategy of the 1990s to the Stop TB Strategy in the early twenty-first century (Table 105.3). The recognition of extensive drug-resistant (XDR) TB serves as a stark reminder of the peril of ignoring the basics of TB control. The generation of XDR-TB in countries with high HIV prevalence, e.g. South Africa and some neighbouring countries,61 is a chronicle of cases and deaths foretold a decade ago: Weak NTPs in developing countries with a high prevalence of HIV infection should focus on the diagnosed new smear-positive patients who can be cured at a high rate, with available means. If the cure rate is low, an increasing proportion of uninfected subjects will be infected with (multi)resistant tubercle bacilli and the disease may become incurable with the means currently available and achievable in these countries.62
The lesson learned for the Stop TB Strategy is that at the same time as embracing the necessary innovations, attention to the basics of case detection and cure will be as important in the future as in the past.
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Table 105.3 Chronology of key events in the development of global tuberculosis control strategies Date
Event
1944 1946 1948
Streptomycin discovered. Streptomycin made available. Efficacy of streptomycin demonstrated in pioneering randomized controlled clinical trial in 1948 run by the British Medical Research Council (MRC) Tuberculosis Research Unit established under Philip D’Arcy Hart. Demonstration of efficacy of triple combination chemotherapy (streptomycin, PAS and isoniazid) by team led by Sir John Crofton in Edinburgh, Scotland Development of ‘standard treatment’ (streptomycin, isoniazid and thiacetazone) in MRC trials in East Africa, India and Hong Kong. Demonstration in Madras, India, that ambulatory antituberculous treatment was effective and not associated with an increased risk of TB among the household contacts of infectious index cases. Demonstration in Bangalore, India, of effectiveness of case-finding based on detection by smear microscopy among symptomatic patients presenting to general health services. WHO policy of vertical programme approach to TB control. WHO policy of approach to TB control based on integration of service delivery. WHO policy of approach to TB control based on integration of managerial functions (in keeping with the spirit of the Alma Ata primary healthcare movement). Following availability of rifampicin, development of ‘short-course’ (6–8 months) chemotherapy by the British MRC Tuberculosis Research Unit under the leadership of Wallace Fox. WHO Expert Committee on Tuberculosis in 1973 formulated four principles for NTPs, that they should be: 1. integrated into general health services, within the Ministry of Health; 2. nationwide; 3. permanent; and 4. adapted to the needs of the people. Development of a model of TB control by Karel Styblo in Tanzania based on sound epidemiological principles of case-finding and the application of chemotherapy, use of the existing district-based government health infrastructure and a comprehensive organizational and managerial approach. NTPs supported by the International Union Against Tuberculosis in nine resource-poor countries with high TB incidence in implementing the Styblo model of TB control. Start of implementation of WHO strategy for global TB control based on the Styblo model. Adoption by World Health Assembly of international targets of at least 70% case detection and 85% treatment success by 2000. Declaration of TB as a global emergency by WHO. World Bank considers TB control as one of the most cost-effective of available health interventions (World Development Report, 1993) Development of global drug-resistance surveillance project and network of supranational reference laboratories. ‘Branding’ of WHO TB control strategy as ‘DOTS’, consisting of a policy package with five elements: 1. government commitment to a TB programme aiming at nationwide coverage, as a permanent health system activity, integrated into the existing health structure with technical leadership from a central unit; 2. detection of TB cases among persons presenting themselves to a health worker with symptoms indicative of TB; 3. administration of standardized short-course antituberculous chemotherapy under proper case management conditions; 4. establishment of a system of regular drug supply of all essential antituberculous drugs; and 5. establishment and maintenance of a monitoring system to be used both for programme supervision and evaluation. Development of global TB monitoring and evaluation system. Meeting in London of first ad hoc Committee on the TB epidemic. Adaptation of DOTS strategy as ‘DOTS-Plus’ to counter MDR-TB. Postponement by World Health Assembly of ‘70/85’ targets to 2005. Ministerial meeting in Amsterdam leading to the formation of a global alliance of partners as the Global Tuberculosis Initiative, which became the Global Partnership to Stop TB. Establishment of Green Light Committee to provide access to second-line drugs for MDR-TB and to build capacity for MDR-TB management. Adoption by United Nations of Millennium Development Goals (Goal 6, target 8 is ‘to have halted and reversed the incidence (of TB) by 2015’). Development of Global DOTS Expansion Plan. Launch of first Global Plan to Stop TB (2002–2005). Establishment of Global Drug Facility to provide affordable, quality-controlled antituberculous drugs. Formalization of governance of Stop TB Partnership. Development of WHO’s strategic framework to counter HIV-related TB, which informed the later development of WHO’s TB/HIV policy. Meeting in Montreux of second ad hoc Committee on the TB Epidemic. Adoption by Stop TB Partnership of international targets to halve TB prevalence and death rates by 2015 (compared to a 1990 baseline). Launch of second Global Plan to Stop TB, 2006–2015. Launch of WHO’s new Stop TB Strategy incorporating and going beyond the DOTS strategy. Appointment by the UN Secretary-General Koffi Annan of former President of Portugal Jorge Sampaio as Special Envoy to Stop TB. Final report on progress towards ‘70/85’ targets: Case detection rate 60% for 2005 cohort (compared to 11% in 1995); Treatment success rate 84% for 2004 cohort (compared to 77% in 1994); More than 26 million TB patients treated by DOTS programmes from 1995 to 2005.
1954 1950s
1948–1963 1964–1976 1977–1988 1970s 1973
Late 1970s
1978–1991 1991 1993 1993 1994 1994–1995
1996 1998 2000
2001
2002 2003 2005 2006
2007
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REFERENCES 1. World Health Organization. Framework for Effective Tuberculosis Control. WHO/TB/94.179. Geneva: World Health Organization, 1994. 2. World Health Organization. What is DOTS? A Guide to Understanding the WHO-Recommended Tuberculosis Control Strategy Known as DOTS. WHO/CDS/CPC/ TB/99.270. Geneva: World Health Organization, 1999. 3. Maher D. Smear-positive pulmonary tuberculosis: good clinical management is good public health. Africa Health 1999;21(4):6–9. 4. International Standards for Tuberculosis Care. The Hague: Tuberculosis Coalition for Technical Assistance, 2006. 5. World Health Organization. An Expanded DOTS Framework for TB Control. WHO/CDS/ TB/2002.297. Geneva: World Health Organization, 2002. 6. Styblo K. Selected Papers. Vol. 24: Epidemiology of Tuberculosis. The Hague: Royal Netherlands Tuberculosis Association, 1991. 7. Holme CI. Trial by TB. Proc R Coll Physicians Edinb 1997;27(1):Suppl 4. 8. Schatz A, Waksman SA. Effect of streptomycin and other antibiotic substances upon Mycobacterium tuberculosis and related organisms. Proc Soc Exp Biol Med 1944;57:244–248. 9. MRC Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948;2:769–783. 10. Ross JD, Grant IWB, Horne NW, et al. Hospital treatment of pulmonary tuberculosis. BMJ 1958;1:237–242. 11. Crofton J. Tuberculosis undefeated. BMJ 1960;2:679–687. 12. Crofton J. Science and Society. London: Weidenfeld and Nicolson, 1995. 13. Fox W. Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical research Council Tuberculosis Units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;10(suppl 2): S231–237. 14. Banerji D, Andersen S. A sociological study of awareness of symptoms among persons with pulmonary tuberculosis. Bull World Health Organ 1963;29:665–683. 15. Banerji D. Tuberculosis: a problem of social planning in developing countries. Med Care 1965;3:151–161. 16. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of home and sanatorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959;21:51–144. 17. Kamat SR, Dawson JJY, Devadatta S, et al. A controlled study of the influence of segregation of tuberculosis patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India. Bull World Health Organ 1966; 34:517–532. 18. Styblo K, Dankova D, Drapela J, et al. Epidemiological and clinical study of tuberculosis in the district of Kolin, Czechoslovakia. Bull World Health Organ 1967;37:819–874. 19. Ogden J, Walt G, Lush L. The politics of ‘branding’ in policy transfer: the case of DOTS for tuberculosis control. Soc Sci Med 2003;57:179–188. 20. Styblo K. Recent advances in epidemiological research in tuberculosis. Adv Tuber Res 1980; 20:1–63. 21. Styblo K, Meijer J. Recent advances in tuberculosis epidemiology with regard to formulation or re-adjustment of control programmes. Bull Int Union Tuberc 1978;53:283–294.
22. Cauthen GM, Pio A, ten Dam HG. Annual Risk of Tuberculous Infection. WHO/TB/88.154. Geneva: World Health Organization, 1988. 23. Styblo K. The impact of HIV infection on the global epidemiology of tuberculosis. Bull Int Union Tuberc 1991;66:27–32. 24. Raviglione MC, Pio A. Evolution of WHO policies for tuberculosis control, 1948–2001. Lancet 2002;359:775–780. 25. World Health Organization. Alma-Ata 1978, Primary Health Care. Health for All Series 1. Geneva: World Health Organization, 1978. 26. Mahler H. The tuberculosis programme in the developing countries. Bull Int Union Tuberc 1966;37:77–82. 27. World Health Organization Expert Committee on Tuberculosis, 9th report. World Health Organization Technical Report Series 552. Geneva: World Health Organization, 1974. 28. Maher D, Nunn P. Commentary: making tuberculosis treatment available for all. Bull World Health Organ 1998;76(2):125–126. 29. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1–6. 30. Dye C, Maher D, Weil D, et al. Targets for global tuberculosis control. Int J Tuberc Lung Dis 2006; 10(4):460–462. 31. World Health Organization. Global Tuberculosis Programme. Report of the ad hoc Committee on the Tuberculosis Epidemic. London, March 17–19, 1998. WHO/TB/98.245. Geneva: World Health Organization, 1998. 32. Stop TB Initiative. Amsterdam 22–24 March 2000— ‘Tuberculosis and Sustainable Development.’ Report of a Conference. WHO/CDS/STB/2000.6. Geneva: World Health Organization, 2000. 33. World Health Organization. Global DOTS Expansion Plan—Progress in TB Control in High-Burden Countries One Year after the Amsterdam Ministerial Conference. WHO/CDS/STB/2001.11. Geneva: World Health Organization, 2001. 34. Stop TB Partnership. Supplied 10 Million in 6 Years: Global Drug Facility Achievements Report. Geneva: World Health Organization, 2007. 35. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1009–1021. 36. World Health Organization. Strategic Framework to Decrease the Burden of TB/HIV. WHO/CDS/TB/ 2002.296 WHO/HIV_AIDS/2002.2. Geneva: World Health Organization, 2002. 37. World Health Organization. Interim Policy on Collaborative TB/HIV Activities. WHO/HTM/TB/ 2004.330. Geneva: World Health Organization, 2004. 38. Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance, 1994-1997. N Engl J Med 1998;338:1641–1649. 39. Espinal MA, Dye C, Raviglione M, et al. Rational ‘DOTS Plus’ for the control of MDR-TB. Int J Tuberc Lung Dis 1999;3:561–563. 40. World Health Organization. Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization, 2006. 41. Gupta R, Kim JY, Espinal MA, et al. Responding to market failures in tuberculosis control. Science 2001;293:1049–1051. 42. Gupta R, Cegielski JP, Espinal MA, et al. Increasing transparency in partnership for health - Introducing the Green Light Committee. Trop Med Intern Health 2002;7:970–976.
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43. World Health Organization. WHO declares tuberculosis a global emergency [press release]. Geneva: World Health Organization, 23 April 1993. 44. Bayer R, Wilkinson D. Directly observed therapy for tuberculosis: history of an idea. Lancet 1995; 345:1545–1548. 45. Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000; 355:1345–1350. 46. Haynes RB. Interventions for helping patients to follow prescriptions for medications. Cochrane Database System Rev 2001;Issue 1. 47. Fox W. The problem of self-administration of drugs; with particular reference to pulmonary tuberculosis. Tubercle 1958;39:269–274. 48. World Health Organization. Treatment of Tuberculosis. Guidelines for National Programmes, 3rd edn. WHO/ CDS/TB/2003.313. Geneva: World Health Organization, 2003. 49. World Health Organization. The Stop TB Strategy. Building on and Enhancing DOTS to Meet TB-Related Millennium Development Goals. WHO/HTM/TB/ 2006.368. Geneva: World Health Organization, 2007. 50. World Health Organization. 44th World Health Assembly: Resolutions and Decisions—Resolution WHA44.8. WHA44/1991/REC/1. Geneva: World Health Organization, 1991. 51. Raviglione MC, Dye C, Schmidt S, et al. Assessment of worldwide tuberculosis control. Lancet 1997; 350:624–629. 52. World Health Organization. Global Tuberculosis Control: Surveillance, Planning and Financing. WHO/ HTM/TB/2007.376.Geneva: World Health Organization, 2007. 53. Stop TB Partnership and World Health Organization. Background Document Prepared for the Meeting of the Second ad hoc Committee on the TB Epidemic, Montreux, Switzerland: 18–19 September 2003. WHO/HTM/STB/2004.27. Geneva: World Health Organization, 2004. 54. Stop TB Partnership and World Health Organization. Report on the Meeting of the Second ad hoc Committee on the TB Epidemic, Montreux, Switzerland: 18–19 September 2003. Recommendations to Stop TB Partners. WHO/ HTM/STB/2004.28. Geneva: World Health Organization, 2004. 55. Raviglione M, Uplekar, M. The new Stop TB Strategy of WHO. Lancet 2006;367:952. 56. Stop TB Partnership and World Health Organization. Global Plan to Stop TB 2006–2015. Actions for life—Towards a World Free of Tuberculosis. WHO/ HTM/STB/2006.35. Geneva: World Health Organization, 2006. 57. World Health Organization. Community Contribution to TB Care: Practice and Policy. WHO/CDS/TB/ 2003.312. Geneva: World Health Organization, 2003. 58. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912–916. 59. World Health Organization and International Labour Office. Guidelines for Workplace TB Control Activities. WHO/CDS/TB/2003.323. Geneva: World Health Organization, 2003. 60. Hopewell P, Pai M, Maher D, et al. International Standards for Tuberculosis Care. Lancet Infect Dis 2006;6:710–725. 61. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients coinfected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368:1575–1580. 62. Styblo K, Raviglione M. Enyclopedia of Human Biology, 2nd edn. Vol. 8. 1997:537–558.
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The WHO Stop TB Strategy for the coming decade Mukund W Uplekar, Mario C Raviglione, and Diana E C Weil
BUILDING ON THE PAST The past decade has seen major progress in global TB control.1 In large part, this has been due to the development and widespread implementation of a well-defined approach in countries with a high burden of TB. This approach – known as the Directly Observed Therapy, Short-Course (DOTS) strategy – comprises five essential elements: government commitment, case detection by sputum smear microscopy among symptomatic patients, standardized short-course chemotherapy with directly observed treatment, uninterrupted drug supply and a standardized recording and reporting system. Building on current achievements and in accordance with the 2005 World Health Assembly resolution on sustainable financing for TB control,2 the major task for the next decade is to achieve the Millennium Development Goals (MDGs) and related Stop TB Partnership targets relevant for TB control, which have been set for 2015.3,4 Meeting these targets requires a coherent and comprehensive strategy capable of sustaining existing achievements and addressing remaining constraints and new challenges effectively. In June 2005, the World Health Organization’s (WHO) Strategic, Technical and Advisory Group on TB approved a new ‘Stop TB Strategy’ which was then endorsed by a 400-strong Stop TB Partnership meeting held in October 2005. Many of the meeting participants – TB programme managers, technical and financial partners, non-governmental organizations (NGOs), researchers, policy makers, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) experts, health activists and WHO staff – had contributed to the development of this Strategy, which is summarized in this chapter (Box 106.1). The Stop TB Strategy sets out the steps that national TB programmes (NTPs) and their partners need to embark upon, assisted actively by the global public health and clinical community. Implementation of the Strategy should ensure equitable access to care of the highest international standards for all TB patients, irrespective of whether they are receiving care from a public or private provider, whether they are infectious or non-infectious, men, women or children, with or without HIV and with or without drug-resistant TB. The Stop TB Strategy presented here provides the strategic context for the Stop TB Partnership’s Global Plan to Stop TB 2006–2015. It was launched and published on World TB Day of 2006.5 The following sections, respectively, outline the current challenges to global TB control and opportunities to address them effectively; present the goals, objectives and targets that the Stop
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TB Strategy is designed to achieve; outline the six components of the Stop TB Strategy; and discuss monitoring the implementation of the Strategy, including financial monitoring, and measuring the impact of global TB control efforts. The chapter concludes by highlighting the wide acceptance of the Stop TB Strategy by high-TB-burden countries and the challenges they are currently experiencing in rolling out the Strategy.
CHALLENGES AND OPPORTUNITIES Tackling TB effectively requires addressing all the risk factors that make individuals vulnerable to being infected with TB, and/or to developing the disease. It also means reducing the adverse effects of the disease including social and economic consequences. Stopping TB must therefore be seen within the framework of country-owned strategies to reduce poverty and advance development, and the Stop TB Strategy must be aligned with other strategies and partnerships to face all major public health challenges. The main focus of the Stop TB Strategy, the targets of which are essentially for the implementers of TB control activities, is on the risk factors that can be directly addressed through use of currently available tools for diagnosis, treatment and prevention of TB and the improved tools likely to become available in the near future through research and development. An analysis of the outcomes of TB control efforts worldwide shows that recent rates of progress, although accelerated, are insufficient to achieve the TB-related MDG targets of halving TB mortality and prevalence by 2015 (Fig. 106.1).6 Particularly urgent action is needed where the epidemic is stabilizing but not improving, notably in Africa but also in Eastern Europe. Sub-Saharan Africa has had to face the challenge of managing the rapid rise in TB cases produced by the HIV epidemic, often in places where the human resources and the services available in the healthcare sector were already overburdened. In Eastern Europe, socioeconomic crises in the early 1990s and outdated public health systems have contributed to a major increase in the incidence and prevalence of TB, including multidrug-resistant (MDR) TB. While these two regions have experienced worsening trends until recently, Asia continues to bear the largest burden of TB, with India, China and Indonesia at the top three positions in terms of total number of TB cases. The emerging HIV epidemic and MDR-TB in these regions also threaten recent progress in TB control. In all regions, identifying and reaching all those in need of care, especially the poorest of the poor, pose major challenges. Related to this, efforts to control TB must progress
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Box 106.1 The Stop TB Strategy at a glance Vision Goal
A TB-free world To dramatically reduce the global burden of TB by 2015 in line with the Millennium Development Goals and the Stop TB Partnership targets Objectives Achieve universal access to quality diagnosis and patientcentred treatment. Reduce the human suffering and socioeconomic burden associated with TB. Protect vulnerable populations from TB, TB/HIV and drug-resistant TB. Support development of new tools and enable their timely and effective use. MDG 6, Target 8: Halt and begin to reverse the incidence Targets of TB by 2015. Targets linked to the MDGs and endorsed by Stop TB Partnership: 2005: detect at least 70% of infectious TB cases and cure at least 85% of them. 2015: reduce prevalence of and deaths due to TB by 50%. 2050: eliminate TB as a public health problem. Components of the strategy and implementation approaches 1. Pursue quality DOTS expansion and enhancement a. Political commitment with increased and sustained financing b. Case detection through quality-assured bacteriology
2.
3.
4.
5.
6.
c. Standardized treatment, with supervision and patient support d. Effective drug supply and management system e. Monitoring and evaluation system, and impact measurement. Address TB/HIV, MDR-TB and other challenges TB/HIV collaborative activities. Prevention and control of drug-resistant TB. Addressing prisoners, refugees and other risk groups and special situations. Contribute to health system strengthening Active participation in efforts to improve system-wide policy, human resources, financing, management, service delivery and information systems. Sharing innovations that strengthen systems, including the Practical Approach to Lung Health. Adapting innovations from other fields. Engage all care providers Public–public and Public–private mix approaches. International Standards for TB Care. Empower people with TB, and communities Advocacy, communication and social mobilization. Community participation in TB care. Enable and promote research Programme-based operational research. Research to develop new diagnostics, drugs and vaccines.
Estimated new TB cases (all forms) per 100,000 population No estimate
0 24
25 49
50 99
100 299
300 or more
Global tuberculosis control: suveillance, planning, financing. WHO Report 2007. Geneva, World Health Organization, 2007
Fig. 106.1 Estimated TB incidence rates, 2005.
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hand-in-hand with efforts to strengthen health systems as a whole. Furthermore, the ultimate goal of eliminating TB will be elusive without new diagnostics, drugs and vaccines, and while new strategies to overcome obstacles to TB control have been developed, far more resources are needed so that they can be widely implemented. Any enhanced strategy to control and eventually eliminate TB must build on the progress made since the 1995 launch of the DOTS strategy – with 184 countries having adopted DOTS and 26 million patients treated to date under this approach. WHO and partners have worked on complementary policies and strategies to address the remaining major constraints to achieving global TB control targets. These include expanding access to diagnosis and treatment through community TB care,7 and public–private mix (PPM) approaches aimed at engaging all care providers, not just designated public providers, in DOTS implementation.8 Innovative mechanisms such as the Global Drug Facility (GDF) and the Green Light Committee (GLC) have been developed to improve access to quality-assured and affordable drugs.9,10 The collaborative activities that need to be implemented by TB and HIV/AIDS programmes have been defined,11 and strategies for preventing and managing drug-resistant TB have been developed and tested.12 To evaluate progress towards the MDGs, impact assessment is being pursued. New public–private partnerships and academic research initiatives for development of new tools are beginning to produce results. New resources are becoming available, from increased domestic funding in high-burden countries and rising external funding, including the Global Fund to Fight AIDS, TB and Malaria and the recently launched UNITAID. Partnerships are being developed across and within countries and among a wide array of stakeholders to respond to health system and disease control challenges. As explained above, a variety of new policies and strategies which, if implemented more widely, would make a major contribution to improving TB control have been developed. The Stop TB Strategy packages them with a view to achieve the following well-defined goals, objectives and targets.
GOALS, OBJECTIVES AND TARGETS The Stop TB Strategy has been developed within the context of an overall vision for TB control. This vision is a TB-free world. The goal of the Strategy is to dramatically reduce the global burden of TB by 2015 in line with the MDGs and the Stop TB Partnership targets (Box 106.2), and to achieve major progress in the research and development needed for improved efficacy of MDR and TB/HIV care, and for TB elimination. It has four major objectives, which in combination are designed to achieve the goal. These are: 1. to achieve universal access to quality diagnosis and treatment for people with TB; 2. to reduce the human suffering and socioeconomic burden associated with TB; 3. to protect the public, especially poor and vulnerable populations, from TB, TB/HIV and drug-resistant TB; and 4. to support development of new tools and enable their timely and effective use. Targets for TB control have been established by the World Health Assembly, by the United Nations as part of the MDGs and by the Stop TB Partnership.4 These are summarized in Box 106.1.
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Box 106.2 Millennium Development Goal, targets and indicators for tuberculosis and the Stop TB Partnership targets Millennium Development Goal 6 Goal: Combat HIV/AIDS, malaria and other diseases. Target 8: Have halted by 2015 and begun to reverse the incidence of malaria and other major diseases. Indicator 23: Prevalence and death rates associated with TB. Indicator 24: Proportion of TB cases detected and cured under DOTS. Stop TB Partnership Targets By 2005: At least 70% of people with infectious TB will be diagnosed (under the DOTS strategy), and at least 85% cured. By 2015: The global burden of TB (disease prevalence and deaths) will be reduced by 50% relative to 1990 levels. Specifically, this means reducing prevalence to 155 per 100,000 per year or lower and deaths to 14 per 100,000 per year or lower by 2015 (including TB cases coinfected with HIV). The number of people dying from TB in 2015 should be less than approximately 1 million, including those coinfected with HIV. By 2050: The global incidence of TB disease will be less than 1 case per million population per year.
COMPONENTS OF THE STRATEGY The following paragraphs summarize the six components and the sub-components of the Stop TB Strategy.
PURSUE QUALITY DOTS EXPANSION AND ENHANCEMENT To address known constraints and new challenges, further strengthening of the basic components of the DOTS strategy is required along the following lines:
Political commitment with long-term planning, and increased and sustained financing Clear and sustained political commitment by national governments is crucial if the Stop TB Strategy is to be effectively implemented. Political commitment is needed to foster national and international partnerships, which should be linked to a long-term strategic action-plan prepared by the NTP and embedded within overall health sector plans. Tuberculosis-related and other relevant indicators should be included in national strategic plans and, where appropriate, political commitment should be backed up by national legislation.13 Adequate funding is essential as current resources are inadequate. Even with adequate TB control financing, critical deficiencies in human resources in the public health sector will impede progress in many low- and middle-income countries, especially in Africa. Political commitment is required to support the overall structural and financial changes needed to improve the availability, distribution and motivation of competent health workers.14,15 Case detection through quality-assured bacteriology The recommended method of TB case detection remains bacteriology, first using sputum smear microscopy, and culture and drug-susceptibility tests when indicated. Wide availability and access to quality-assured bacteriological services will require additional investments in the laboratory network in many countries, including a well-resourced and functioning
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The WHO Stop TB Strategy for the coming decade
national reference laboratory. Culture and drug-susceptibility testing (DST) services are lacking at sub-national level in most low-income countries and urgently need to be rolled out. Their functions should also include diagnosis of smear-negative TB, diagnosis of TB among HIV-infected patients and children, diagnosis and monitoring of drug-resistant TB and testing related to periodical surveys of the prevalence of drug resistance. Maintaining the quality of the laboratory network should be based on regular training, supervision and support, and motivation of laboratory staff. Existing public and private laboratories should be optimally used.
Standardized treatment, with supervision and patient support The mainstay of TB care and control is organizing and providing standardized treatment for all adult and paediatric TB cases – sputum smear-positive, smear-negative or extrapulmonary TB. In all cases, WHO-recommended and -published guidelines on patient categorization and management should be followed.16 These guidelines emphasize the use of the most effective standardized, short-course regimens, and of fixed-dose combinations (FDC) to facilitate adherence and prevent the risk of acquiring drug resistance. Separate WHO guidelines are also available for management of patients with drug-resistant TB.12 Patient-centred services that enable patients to enrol and fully complete treatment to cure should be a priority. This includes addressing and identifying factors that may make patients interrupt or stop treatment. Supervised treatment helps patients to take their drugs regularly and complete treatment, protect others from being infected once treatment has begun and prevent the development of drug resistance. Supervision, often referred to as directly observed therapy (DOT), must be carried out in a context-specific and patient-sensitive manner, and is meant to ensure adherence on the part of both providers (so that they give proper care and support) and patients (so that they can adhere and any treatment problems can be addressed). Depending on the local conditions, supervision may be undertaken at a health facility, in the workplace, in the community or at home. When not at a health facility, it should be provided by a treatment partner or treatment supporter who is acceptable to the patient and is trained and supervised by health services. Patient and peer support groups can help to encourage adherence to treatment as can material and non-material incentives and enablers. Strict supervision to watch ingestion of each dose of the prescribed medication is needed for persons facing social or other difficulties that inhibit their capacity to adhere to treatment. Effective drug supply and management system An uninterrupted and sustained supply of quality-assured antituberculous drugs is fundamental to TB control. For this purpose, an effective and reliable drug supply and management system is essential. The TB recording and reporting system is designed to provide the information needed to plan, procure, distribute and maintain adequate stocks of drugs. Antituberculous drugs should be available free of charge to all TB patients, both because many patients are poor and may find them difficult to afford, and because treatment has benefits that extend to society as a whole (successful treatment prevents transmission to others). Legislation related to drug regulation should be in place and use of antituberculous drugs by all providers should be strictly monitored. The use of FDC and innovative packaging such as patient kits can help improve drug supply logistics as well
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as drug administration, and can reduce non-adherence to treatment and prevent development of drug resistance. The GDF and GLC offer countries with limited capacity the benefit of access to quality-assured TB drugs at affordable prices and also facilitate access to training and technical assistance for drug management.9,10
Monitoring and evaluation system, and impact measurement Strengthening a TB monitoring and evaluation system with reliable and regular communication between the central and peripheral levels is vital, and needs to be embedded within general health information systems. This requires standardized recording of individual TB patient data, including information on treatment outcomes, which are then used to compile quarterly treatment outcomes in cohorts of patients. Regular programme supervision should be carried out to verify the quality of information and to address performance problems. Implementing the Stop TB Strategy will also require some modifications to the recording and reporting systems currently in use. WHO and its partner organizations have recently developed such a system considering which additional data should be routinely collected and how these data should be compiled, collated, analysed and used to inform TB control.17 Use of electronic recording systems should be considered where appropriate. ADDRESS TB/HIV, MDR-TB AND OTHER CHALLENGES Implement TB/HIV collaborative activities HIV promotes the progression of recent and latent infection due to Mycobacterium tuberculosis to active TB. It also increases the rate of TB recurrences. The HIV epidemic has caused a substantial increase in the number of TB cases in high-HIV-prevalence settings, and in the percentage of TB cases that have smear-negative pulmonary and extrapulmonary TB disease. HIV-infected, smearnegative pulmonary TB patients have inferior treatment outcomes and higher early mortality compared with HIV-infected smearpositive pulmonary TB patients. Interventions to reduce HIV-related TB morbidity and mortality as well as additional care for HIVinfected TB patients need to be implemented in line with the Universal Access principle.18 WHO has published an interim policy on collaborative TB/HIV activities.10 Twelve collaborative activities are recommended in three broad categories: establishing the mechanisms for collaboration, decreasing the burden of TB in people living with HIV/AIDS and decreasing the burden of HIV in TB patients. Tuberculosis programmes should undertake all relevant collaborative activities and build the necessary referral systems with HIV programmes, and help build integrated primary care systems. These activities should be a part of the national TB control plans. Prevent and control multidrug-resistant tuberculosis Evidence shows that MDR-TB is a threat to global TB control. This is aggravated by inadequate treatment of those already affected with MDR-TB; the progressive acquiring of additional drug resistance resulting from widespread uncontrolled use of second-line antituberculous drugs; and the current absence of new effective drugs to treat TB. Global surveillance of antituberculous drug resistance indicates that drug-resistant TB is present across the globe, and that it is especially severe in countries of the former Soviet Union and parts of China. Recently, the emergence of extensively drug-resistant (XDR) TB has been signalled in several countries, but is particularly serious in South Africa where it is largely associated with
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HIV infection.19 Tuberculosis cannot be controlled if MDR-TB is not properly addressed. This means that every patient with MDRTB should receive adequate treatment and that second-line antituberculous drugs should be rationally used. MDR-TB treatment under programmatic conditions is feasible, effective and cost-effective when implemented in the context of a well-functioning DOTS-based programme. Detection and treatment of all forms of drug-resistant TB should be an integral part of NTP activities. The WHO guidelines on the management of drug-resistant TB, prepared on the basis of evidence, provide full details about how to implement activities to control drug-resistant TB.12
Address prisoners, refugees and other high-risk groups and situations Tuberculosis programmes need to pay specific attention to certain population groups and communities facing special situations that mean they are at higher risk of contracting TB. In healthcare and congregate settings, where people with or without active TB and/or HIV infection are frequently crowded together, the risk of infection with TB is increased.11 The risk groups which need special attention include, for example, prison populations, refugees, migrant workers, undocumented immigrants, cross-border populations, the orphaned and homeless, ethnic minorities, other marginalized groups and alcohol and injecting drug users. Diabetics and smokers are also at significantly higher risk of developing TB and of poor outcomes. Special situations requiring extra attention include unexpected population movements such as those resulting from political unrest, war and natural disaster. In these circumstances, there may be a disruption of social networks. Breakdown of social support adds to the effects of poverty and malnutrition, alters health-seeking behaviour and limits access to services. Tuberculosis services need to address the specific needs of the special risk groups and situations.20 The first step towards addressing the needs of special groups is identifying them, and determining their special requirements. These steps should be undertaken in collaboration with the beneficiaries and others engaged in serving their needs. Each healthcare and congregate setting should have a TB infection control plan which includes administrative, environmental and personal protection measures to minimize the risk of TB transmission.11 Implementation should be undertaken in a phased manner in collaboration with relevant partners and care providers.20 CONTRIBUTE TO HEALTH SYSTEM STRENGTHENING Health system strengthening is defined by WHO as ‘improving and combining six key health system strengthening building blocks in ways that achieve more equitable and sustained improvements across health services and outcomes’.21 (These building blocks are service delivery, leadership and governance of health systems, information, medical products and technologies, health workforce, and financing.) Progress on all of the health-related MDGs depends, to a substantial degree, on the strengthening of health systems. This is particularly true in Africa. If access to quality health services can be increased and sustained, this should have major benefits for TB control, including the elements covered in the previous subsections. This component has the following three key elements:
Actively participate in efforts to improve system-wide policy, human resources, financing, management, service delivery and information systems Tuberculosis control programmes and their partners should participate actively in country-led as well as global initiatives to improve
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action across all of the major building blocks of health systems noted above. It also means working across all levels of systems and with all actors in the public sector, non-state sector and communities. In some cases, this will mean ongoing contributions to well-defined sector strategies and plans, and in others helping to build system-wide responses or in working on initiatives to devise, test and share new solutions, such as major new health worker extension schemes or service packages. WHO guidelines produced in 2002 are still highly relevant and will be supplemented with new tools from within and outside the TB community.22
Share innovations in tuberculosis control that strengthen systems Tuberculosis programmes are implementing a variety of new approaches for accelerating and sustaining TB control impact, and these are now part of the Stop TB Strategy. Among these are community TB care, public–private mix approaches for engaging all care providers, a syndromic approach for addressing respiratory care (see below) and innovations in health information and drug management systems. These innovations should be adapted and scaled-up in ways that allow their broader application to advance a range of health outcomes, and best practices need to be shared across health systems and countries. Practical Approach to Lung Health (PAL) Pulmonary TB almost always manifests as a cough, and persons with TB symptoms first present themselves to primary care services as respiratory patients. By linking TB control activities to proper management of all common respiratory conditions, TB programmes and staff implementing DOTS services at local level can help to improve the efficiency and quality with which care is provided. At the same time, this increases the possibility of properly diagnosing patients and placing them on appropriate treatment. Based on operational research in diverse country settings, WHO has developed the Practical Approach to Lung Health (PAL).23 This is designed to help integrate TB services within primary care, strengthen general health services, prevent irrational use of drugs and improve management of resources.24 Tuberculosis programmes should implement PAL using the available evidence-based guidelines. Adapt innovations from other fields To respond to all six elements of the Stop TB Strategy, TB programmes and their partners can adapt approaches that have been applied in other priority public health fields, and build further on some of the common systems already in place. This may include further integration of TB control activities within the community and primary care outreach pursued in maternal and child health programmes, social mobilization along the lines used by HIV/AIDS programmes and partners, etc. Effective integration of delivery systems depends on testing, adapting, scaling-up and evaluating common approaches and measuring impacts for specific health outcomes and for specific populations. ENGAGE ALL CARE PROVIDERS Public–public and public–private mix (PPM) approaches In most settings, patients with symptoms suggestive of TB seek care from a wide array of heathcare providers besides the public sector TB services. These may include private clinics operated by formal and informal practitioners, and institutions owned by the public, private, voluntary and corporate sectors (e.g. general and specialty public hospitals; NGOs; prison, military, and railway health
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The WHO Stop TB Strategy for the coming decade
services; and health insurance organizations). These non-NTP providers may serve a large proportion of TB symptomatics and patients, while not always applying recommended TB management practices or reporting their cases to NTPs.25 Some settings have large private and NGO sectors while others have public sector providers (such as general and specialty hospitals) that do not collaborate with TB programmes. The basic premises of PPM-DOTS are that the financial resources to set up and sustain the collaboration are provided or facilitated by the NTP, that the provision of drugs is free of charge to patients and that fees for tests and consultations are waived or kept to a minimum to facilitate access for the poor. WHO has produced guidelines on how to engage all care providers in TB control.8 The feasibility, effectiveness and cost-effectiveness of involving different types of care providers using a PPM approach have been demonstrated.26 NTPs should aim to engage all care providers in DOTS implementation to help achieve the TB control targets, improve access to care, standardize the quality of TB care across providers and save costs of care for patients.
International Standards for TB Care (ISTC) Evidence-based ‘International Standards for TB Care’ have been formulated through a wide global consensus of appropriate practices in TB diagnosis and treatment.27 They should be actively promoted and used to help engage all care providers in TB service implementation, and are particularly complementary to the PPM approaches described above. They can be used to secure a broad base of support for TB control efforts – from NTPs, professional medical, paediatric, and nursing societies, academic institutions, NGOs and HIV-focused organizations. They can also help to create peer pressure to encourage providers to conform to the principles, and can serve as a basis for pre- and in-service training.28 EMPOWER PEOPLE WITH TUBERCULOSIS, AND COMMUNITIES Advocacy, communication and social mobilization (ACSM) In the context of wide-ranging partnerships for TB control, ACSM consists of advocacy to influence policy changes and sustain political and financial commitment; two-way communication between the care providers and people with TB as well as communities to improve knowledge of TB control policies, programmes and services; and social mobilization to engage the society, especially the poor, and all allies and partners in the fight against TB. Each of these activities can help build greater commitment to fighting TB. Advocacy is intended to secure support of key constituencies in relevant local, national and international policy discussions and is expected to prompt greater accountability from governmental and international actors. Communication is concerned with informing and enhancing knowledge among the general public and people with TB, and facilitating their empowerment to enable them to express their needs and take action. Encouraging providers, at the same time, to be more receptive to expressed ‘wants and views’ of people with TB and community members will make TB services more responsive to community needs. Social mobilization is the process of bringing together all feasible and practical intersectoral allies to raise people’s knowledge of and demand for quality TB care and healthcare in general, assist in the delivery of resources and services and to strengthen community participation for sustainability. ACSM is essential for achieving TB elimination
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and is relevant to all aspects of the Stop TB Strategy. ACSM efforts in TB control should be linked with overarching efforts to promote public health and social development.29
Community participation in tuberculosis care and control Community participation in TB care and control implies establishing a working partnership between the health sector and the community – the local population especially the poor in general and TB patients, current as well as cured, in particular. Tuberculosis patients’ unique illness experiences can help fellow patients cope better with their illness and inform TB programmes to help deliver services responsive to patients’ needs. Enabling people with TB and communities to be informed about TB, to enhance general awareness about the disease and to share responsibility for TB care can lead to effective patient empowerment and community participation, by increasing the demand for health services and bringing care closer to the community. For this purpose, TB programmes should provide support to frontline health workers to help create an empowering environment by, for example, facilitating the setting-up of patient groups, encouraging peer education and support and linking with other self-help groups in the community. Tuberculosis patient and community representation in TB partnership bodies as well as in entities assessing quality of healthcare can advance accountability and outcomes. Community volunteers also need regular support, motivation, instruction and supervision. Where they exist, HIV/AIDS community-based initiatives can be built upon. Evidence shows that community-based TB care is cost-effective compared to hospital-based care and other ambulatory care models.7 Patients’ charter for tuberculosis care Developed by patients from around the world, the Patients’ Charter outlines the rights and responsibilities of people with TB and complements the International Standards for TB Care meant for healthcare providers.30 It is based on the principles of various international and national charters and conventions on health and human rights. It is meant to empower people with TB and communities, and make the patient–provider relationship mutually beneficial. The charter provides a useful tool for achieving greater involvement of people in TB care as well as increasing the accountability of health services. NTPs should proactively promote the awareness of the charter among affected persons and the general public. ENABLE AND PROMOTE RESEARCH Programme-based operational research The Stop TB Strategy consolidates DOTS implementation and involves the implementation of several new approaches for tackling challenges facing NTPs. To put them into practice, programmebased operational research should be a core component of NTP work. For this purpose, collaboration between programme managers, service providers and researchers is essential. Acquiring basic skills in identifying and addressing issues related to programme operations and performance can help programme managers to initiate operational research with partners, and can sustain and strengthen existing activities and introduce new strategies effectively. Research to develop new diagnostics, drugs and vaccines Existing tools for TB prevention and treatment require much from both patients and their care providers. These tools have hindered the pace of progress in global TB control. Facilitating the concerted
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efforts of the Stop TB Partnership’s Working Groups on new TB diagnostics, drugs and vaccines and other research partners is central to the Stop TB Strategy. Tuberculosis programmes should actively encourage and participate in this R&D process. Countries should advocate new tools development, help speed up the field testing of new products and prepare for swift adoption and roll out of new diagnostics, drugs and vaccines as they become available, a process known as ‘retooling’.31
As more countries develop better systems for collecting health information routinely, it should be possible to assess the state of the epidemic and the quality of control using annual TB surveillance data, together with data from vital registration. To complement and check the quality of routine surveillance data, it will be important to carry out population-based surveys of disease prevalence or infection.
FINANCING FOR TUBERCULOSIS CONTROL
MONITORING PROGRESS AND MEASURING IMPACT MEASUREMENT OF PROGRAMME OUTCOMES AND IMPACT ON BURDEN OF DISEASE The Stop TB Strategy is designed to achieve the MDGs and related Stop TB Partnership targets. As well as a final assessment of whether targets have been reached in 2015, progress towards the targets needs to be regularly measured. Table 106.1 shows the indicators that apply for each of the targets, and how they can be measured. In assessing trends in the total burden of TB and the quality of TB control efforts, it is valuable to take into account, where possible, factors such as the age and sex of the patients, the level of MDR-TB and the prevalence of HIV, as well as socioeconomic characteristics of those served – all of which may affect case detection, treatment outcomes and impact.
Table 106.1 Selected indicators for monitoring tuberculosis programmes Indicator
Target
Measurement
Prevalence of disease: Number of people per 100,000 population who have TB disease at a given time. Incidence of disease: Number of new cases of TB disease (all forms) per 100,000 population per year. Mortality rate: Number of TB deaths (all forms) per 100,000 population per year.
Halve 1990 prevalence rate by 2015.
Cross-sectional surveys (preferably), or estimated from incidence and duration of disease (approximate). Longitudinal surveys, or from case notifications (where complete).
Case detection rate: Number of new smearpositive cases notified in 1 year divided by the annual incidence. Treatment success rate: Percentage of new smear-positive TB cases registered for treatment that are cured or complete treatment.
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Incidence rate in decline by 2015. Halve 1990 mortality rate by 2015.
70% by 2005.
85% by 2005.
From vital registration (where complete), verbal autopsy surveys or from incidence and casefatality rates (approximate). From notification data and estimates of incidence.
Routinely collected data on cohorts of patients undergoing treatment.
Achieving the MDG and Stop TB Partnership targets will require increased and sustained financing for TB control. Financing of TB control needs to be monitored and evaluated at sub-national, national and international level, to document trends in NTP budgets, available funding, funding gaps, expenditures and total TB control costs including costs associated with using general health services staff and infrastructure. A consistent categorization of budget line items and funding sources should be used to allow analysis of changes over time. WHO collects such financial data through a questionnaire that is sent to all countries on an annual basis. These data are analysed and presented in the annual WHO report on Global TB Control.1
IMPLEMENTING THE STRATEGY: PROGRESS AND CHALLENGES Since its launch in early 2006, all high-TB-burden countries have embraced the new Stop TB Strategy. This is a distinct and encouraging sign of progress. A preliminary analysis of information collected in preparation of the 2007 WHO report on Global TB Control, specifically to assess the progress made by the 22 highest TB-burden countries on the Stop TB Strategy, revealed that while it is only a beginning, most countries have embarked on addressing the relevant new components of the Strategy in addition to DOTS expansion based on their immediate needs and challenges (Tables 106.2 and 106.3). Several challenges have been coming to the fore in early implementation of the Stop TB Strategy, and countries, WHO and other partners are aiming to address all. The first and the foremost concern is how to maintain and sustain the high quality of basic services offered under DOTS. This has been a challenge particularly in settings where DOTS has been scaled-up rapidly in recent years, where health systems, especially human resources for health and laboratory capacity, are very weak and where the HIV epidemic and MDR-TB are most severe. Secondly, a catch-22 situation seems to exist: NTPs and partners with the least capacity, and in the lowest income settings, often have the greatest need for new approaches. Implementing new approaches while building capacity demands new resources and partners. Third, traditional ways of sequentially identifying, piloting, evaluating new strategies and then scaling-up in measured, incremental steps may not work if the global targets are to be met. New ways which drive scale-up even while interventions are still being assessed and adapted need to be pursued. Finally, the donor community and civil society are demanding documented results at record pace but such documentation should not be mandatory in a way that further burdens implementing countries and partners. Given rapid progress in many regions in scaling-up DOTS and driving down incidence, prevalence and mortality, and growing resources for TB control, there is a great opportunity for increasing the rate of progress. Through the Stop TB Strategy, countries can
Table 106.2 Progress made by 22 highest tuberculosis burden countries on the implementation of the Stop TB Strategy: a components 1, 2 and 3 Country
Afghanistan Bangladesh Brazil Cambodia China DR Congo Ethiopia India Indonesia Kenya Mozambique Myanmar Nigeria Pakistan Philippines Russia South Africa Thailand Uganda UR Tanzania Viet Nam Zimbabwe a
1. DOTS
2. TB/HIV, MDR-TB
Plan in line with GP2
No. of culture facilities
Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes No
0 2 137 3 317 1 1 5 41 1 1 2 3 3 3 159 16 80 2 3 30 1
% TB pts HIVtested
% HIVþ TB pts on ARV
47 3
85
2 3 3
1 29
15
20
2 11
31
22
33
8 4
28
3. HSS
DRS complete
GLCproject
HRD TB plan linked to HRH plans
Integrated staff at facility level
PAL activities
No No Yes Yes Yes Yes Yes Yes Yes Yes No Yes No No Yes Yes Yes Yes No Yes Yes No
No Approved No Approved Review Approved No Review No Approved No Preparation No No On-going On-going No No No No Preparation No
Yes No Yes No Yes Yes No Yes Yes No Yes Yes No Yes No Yes
No No Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes No No
No
Yes Yes Yes Yes Yes
Planned No Planned Planned No No No No Planned Planned No Planned No Planned No No Yes Planned Yes Planned Yes No
Yes Yes
Based on responses to a WHO questionnaire from 22 highest TB-burden countries, 2006.
Table 106.3 Progress made by 22 highest tuberculosis burden countries on the implementation of the Stop TB Strategy: a components 4, 5 and 6 Country
4. Engage all care providers
5. Empower people with TB, and communities % Country with community involvement
6. Operational research
PPM scale-up
Familiar with ISTC
Familiar with Patients’ Charter
Examples
Afghanistan Bangladesh Brazil Cambodia China
No Yes No No Yes
No No No Yes Yes
No Yes Yes Yes No
7% 50% 40% 70% 0%
DR Congo Ethiopia India Indonesia Kenya Mozambique Myanmar Nigeria Pakistan Philippines Russia South Africa Thailand Uganda UR Tanzania Viet Nam Zimbabwe
Yes No Yes Yes Yes Yes Yes No No Yes No No No No No Yes No
No Yes Yes Yes No Yes Yes Yes Yes Yes Yes
No Yes Yes Yes Yes Yes No Yes No Yes No
0% 30% 10% 25% 5% 20% 25% 30% 25% 0%
TB/HIV prevalence survey Health seeking behaviour in Dhaka Evaluation of information system HIV seroprevalence survey, KAP Diagnosis & treatment of smearnegative TB/HIV prevalence Isoniazid preventative therapy PPM cost evaluation TB/HIV seroprevalence survey, DRS Diagnosis (future) DRS, prevalence survey (future) Effectiveness of FDCs Smear-negative diagnosis (future) Tx adherence & default tracing Public–public DOTS effectiveness Drug resistance
Yes Yes Yes Yes No
No No Yes No Yes
5% 100% 5% 80% 25%
M&E in select provinces Diagnosis of smear-negative patients Tuberculin survey Service quality at commune level DRS
a
Based on responses to a WHO questionnaire from 22 highest TB-burden countries, 2006. DRS: Drug resistance surveillance; FDCs: Fixed dose combinations; Tx: treatment; M&E: monitoring and evaluation.
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continue to expand access and sustain impact, and those previously hindered in their progress by weak health systems, HIV/AIDS and drug-resistant TB also have opportunities to see new in-roads in serving those in need and controlling TB. The Stop TB Strategy underpins the Stop TB Partnership’s Global Plan to Stop TB,
REFERENCES 1. World Health Organization. Global Tuberculosis Control. Surveillance, Planning, Financing. WHO/ HTM/TB/2006.362. Geneva: World Health Organization, 2006. 2. World Health Organization. Resolution WHA58.14. Sustainable financing for tuberculosis prevention and control. In: Fifty-eighth World Health Assembly, Geneva, 16–25 May 2005. Resolutions and Decisions. WHA58/2005/REC/1, Annex: 79–81. Geneva: World Health Organization, 2005. 3. United Nations Statistics Division. Millennium Development Goal Indicators Database. [online]. Accessed 20 January 2006. Available at URL:http:// unstats.un.org/unsd/mi/mi_goals.asp 4. Maher D, Dye C, Weil D, et al. Targets for global tuberculosis control. Int J Tuberc Lung Dis 2006; 10(4):460–462. 5. Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006;367:952–955. 6. Dye C, Watt CJ, Bleed DM, et al. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 2005;293:2767–2775. 7. World Health Organization. Community Contribution to TB Care: Practice and Policy. WHO/CDS/TB/ 2003.312. Geneva: World Health Organization, 2003. 8. World Health Organization. Engaging All Care Providers in TB Control: Public–Private Mix Approaches. WHO/HTM/TB/2006.360. Geneva: World Health Organization, 2006. 9. World Health Organization. 4 Million Treatments in 4 Years. Achievement Report—Special Edition. WHO/ HTM/STB/2005.32. Geneva: World Health Organization, 2005. 10. Gupta R, Cegielski JP, Espinal MA, et al. Increasing transparency in partnership for health—introducing the Green Light Committee. Trop Med Int Health 2002;7:970–976. 11. World Health Organization. Interim Policy on Collaborative TB/HIV Activities. WHO/HTM/TB/ 2004.330. Geneva: World Health Organization, 2004.
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2006–2015, and resources need to be mobilized to fully implement this plan and apply all six components of the strategy.32 With this, affected countries, communities and partners should be able to move towards the next stage in TB control – TB elimination by mid-century.
12. World Health Organization. Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis. WHO/HTM/TB/2006.361. Geneva: World Health Organization, 2006. 13. Pinet G. Good Practice in Legislation and Regulations for TB Control: An Indicator of Political Will. WHO/CDS/ TB/2001.290. Geneva: World Health Organization, 2001. 14. World Health Organization. Human Resources Development for TB Control: Report of a Consultation Held on 27 and 28 August 2003. WHO/HTM/TB/ 2004.340. Geneva: World Health Organization, 2004. 15. World Health Organization. Check-list for the Review of Human Resource Development Component of National Plans to Control Tuberculosis. WHO/HTM/TB/ 2005.354. Geneva: World Health Organization, 2005. 16. World Health Organization. Treatment of Tuberculosis—Guidelines for National Programmes, 3rd edn. WHO/CDS/TB/2003.313. Geneva: World Health Organization, 2003. 17. World Health Organization. Revised TB Recording and Reporting Forms and Registers—Version 2006. Accessed 10 December 2006. Available at URL:http://www. who.int/tb/err/rr_forms_26oct06.pdf 18. Reid A, Scano F, Getahun H, et al. Towards universal access to HIV/AIDS prevention, treatment and care: the role of tuberculosis/HIV collaboration. Lancet Infect Dis 2006;6:483–495. 19. Gandhi NR, Moll A, Willem Sturm A, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575–1580. 20. World Health Organization. Addressing Poverty in Tuberculosis Control: Options for National TB Control Programmes. WHO/HTM/TB/2005.352. Geneva: World Health Organization, 2005. 21. World Health Organization. Everybody’s business: WHO’s health system strengthening strategy. Draft, WHO/EIP, December 2006. 22. World Health Organization. Expanding DOTS in the Context of a Changing Health System. WHO/CDS/ TB/2002.318. Geneva: World Health Organization, 2002.
23. World Health Organization. Practical Approach to Lung Health (PAL): A Primary Health Care Strategy for the Integrated Management of Respiratory Conditions in People Five Years of Age or Over. WHO/HTM/TB/ 2005.351. Geneva: World Health Organization, 2005. 24. Fairall LR, Zwarenstein M, Bateman ED, et al. Effect of educational outreach to nurses on tuberculosis case detection and primary care of respiratory illness: pragmatic cluster randomized controlled trial. BMJ 2005;331:750–754. 25. Uplekar M, Pathania V, Raviglione M. Private practitioners and public health: weak links in tuberculosis control. Lancet 2001;358:912–916. 26. Lo¨nnroth K, Uplekar M, Arora VK, et al. Public– private mix for DOTS implementation: what makes it work?. Bull World Health Organ 2004;82(2):580–586. 27. Hopewell PC, Pai M, Maher D, et al. International Standards for Tuberculosis Care. Lancet Infect Dis 2006;6:710–725. 28. Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care. Accessed 10 December 2006. Available at URL:http://www. stoptb.org/resource_center/assets/documents/ istc_report.pdf 29. World Health Organization. Advocacy, Communication and Social Mobilization to Fight TB: A 10 Year Framework for Action. Stop TB Partnership. WHO/ HTM/STB/2006.37. Geneva: World Health Organization, 2006. 30. World Care Council. Patients’ Charter for Tuberculosis Care. Accessed 10 December 2006. Available at URL: http://www.stoptb.org/globalplan/assets/documents/ IP_OMS_Charte_GB_Epreuve.pdf 31. Retooling Task Force, Stop TB Partnership. New Technologies for Tuberculosis Control: A Guide for Their Adoption, Introduction and Implementation. Geneva: World Health Organization, 2007. 32. Stop TB Partnership and World Health Organization. The Global Plan to Stop Tuberculosis 2006–2015. WHO/HTM/STB/2006.35. Geneva: World Health Organization, 2006.
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The Global Plan to Stop TB, 2006–2015 Dermot Maher, Marcos Espinal, and Katherine Floyd
INTRODUCTION Long-term planning for TB control provides an example of longterm planning to improve global health. As a follow-up to its first Global Plan to Stop TB (2001–2005), the Stop TB Partnership developed its second Global Plan (2006–2015), which was launched at the World Economic Forum in Davos, Switzerland, on 27 January 2006. In developing the Plan, estimations were made of the impact and costs of scale-up from 2006 to 2015 of the currently available interventions for TB control in scenarios judged to be ambitious but realistic by national TB control experts. Since the introduction of effective new technology will be a prerequisite for speeding up progress towards the international targets for TB control for 2015 and for meeting the goal of TB elimination by 2050, the Plan also indicates the expected steps in the development of the new and improved diagnostics, drugs, and vaccines so badly needed.
BACKGROUND Communicable diseases constitute a considerable proportion of the global burden of morbidity and mortality, accounting in 2002 for 23.5% of the global burden of disability-adjusted life-years (DALYs) and 19.1% of global deaths.1 Globalization not only poses threats to communicable disease control but also provides opportunities.2 Awareness of this has led to the development of many international partnerships and alliances to coordinate communicable disease control efforts. Perhaps the best examples of such international collaboration were the global campaign in the 1960s and 1970s that eradicated smallpox and the programme since 1974 to control onchocerciasis in West Africa.3,4 Recent examples include the Global Alliance for Vaccines and Immunization and the Global Partnership to Stop TB.5,6 Making the most of the communicable disease control efforts of these international collaborations, in terms of effectiveness and efficiency, depends on sound planning. Examples of plans for global control of an acute and a chronic communicable disease include poliomyelitis and leprosy, respectively.7–9 Since epidemics of chronic communicable diseases such as leprosy and TB change relatively slowly on account of their specific disease transmission dynamics, long-term planning is particularly necessary. With an estimated 8.8 million new cases of TB and 1.6 million deaths in 2005, the scale of the global epidemic demands urgent and effective action.10 This action is encapsulated in the World Health Organization’s (WHO) new Stop TB Strategy that builds on and
enhances the DOTS strategy.11,12 The Stop TB Strategy comprises the scaling-up of implementation of the currently available interventions for TB control, the promotion of research and development of improved diagnostics, drugs, and vaccines, and the related activities for advocacy, communications, and social mobilization (ACSM). The Stop TB Partnership has developed a Global Plan to Stop TB (2006–2015) that sets out the impact of currently available interventions on the global burden of TB, and the associated costs.13,14 The Partnership’s targets for 2015 involve reducing TB incidence – ;in line with the millennium development goals (MDGs) – and halving TB prevalence and deaths compared with 1990 levels.15 The Plan represents a step towards the elimination of TB as a global public health problem (i.e. the reduction in global incidence to less than one per million population) by 2050, and the realization of the Partnership’s vision of a TB-free world.16 The most productive approach to planning in development is the subject of some debate, with proponents of a comprehensive supplyside blueprint ranged against proponents of more specific solutions responding to local demand.17,18 In the best of both worlds, a determination of what could be supplied is matched against ground-level explorations of what is feasible.19 In planning for global TB control, determination of the available means of controlling TB was matched with explorations of what is feasible in countries badly affected by TB. This chapter describes this process and the policy and strategy implications of the results of global planning as an example of long-term planning to improve global health.
DEVELOPMENT OF THE GLOBAL PLAN The Stop TB Partnership was established in 2000 as a global movement to accelerate social and political action to stop the spread of TB. It provides a platform for international organizations, countries, donors (public and private sector), governmental and non-governmental organizations, patient organizations, and individuals to contribute to a collective and concerted campaign to Stop TB. One of the early steps of the newly formed Partnership was the development of the first Global Plan to Stop TB (2001–2005),20 which subsequently informed the development of the second Global Plan (2006–2015).
THE FIRST GLOBAL PLAN TO STOP TB (2001–2005) The development of this Plan was prompted by the need to provide a coherent agenda to rally key new partners, push forward research and development, and have a rapid impact on the TB epidemic in the
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Box 107.1 The seven Working Groups of the Stop TB Partnership
DOTS Expansion: assists countries in improving access to high-quality DOTS as a key element of the Stop TB Strategy. DOTS-Plus: assists countries in addressing MDR-TB. TB/HIV: assists countries in addressing HIV-related TB. New TB Vaccines: promotes the development of new TB vaccines. New TB Diagnostics: coordinates and facilitates the development of new TB diagnostics. New TB Drugs: promotes the development of new, affordable TB drugs. ACSM: promotes the mobilization of political, social, and financial resources at all levels to sustain and expand the Stop TB movement.
areas most badly affected. The Plan provided the first integrated plan of action for implementation and research, and identified the funding required. Most of the planned investment was for implementation of the DOTS strategy in the 22 priority countries with the largest number of TB cases (‘high-burden countries’). The DOTS Expansion Working Group, in collaboration with the DOTS-Plus and TB/HIV Working Groups (see Box 107.1), coordinated implementation of the DOTS strategy and its adaptations. The 22 high-burden countries established interagency coordination committees and implemented DOTS expansion plans. The research and development working groups indicated their plans on new TB vaccines, diagnostics, and drugs. Stop TB partners delivered impressive results in the implementation of this first Plan: the number of patients treated in DOTS programmes more than doubled over 5 years, from 2 million in 2000 to well over 4 million in 2004. This rise was driven, in part, by more ambitious programme budgets, which also more than doubled from US$400 million in 2002 to over US$800 million in 2005. Implementation of the Plan made a considerable contribution to the global progress made towards reaching the international targets of at least 70% case detection and 85% treatment success. In addition, there was significant progress in research and development, with a greater number than ever before of new products (diagnostics, drugs, and vaccines) entering the product development pipeline.
AFR high HIV AFR low HIV Eastern Europe Established Market Economy and Central Europe EMR LAC SEAR WPR
Fig. 107.1 The eight TB epidemiological regions.
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THE PROCESS OF DEVELOPING THE GLOBAL PLAN TO STOP TB (2006–2015) The development of the Partnership’s second Global Plan to Stop TB (2006–2015) started in May 2004 with building consensus on the Plan’s purpose and outline, taking into account feedback on the first Global Plan to Stop TB (2001–2005). The planning process took 18 months, culminating in the finalization then launch of the Global Plan to Stop TB (2006–2015) in January 2006. In line with the advice of the Partnership Coordinating Board, each of the Partnership’s seven Working Groups (see Box 107.1) developed its own strategic plan in contribution to the development of the overall Global Plan. These strategic plans were based on a common template: strategic vision, objectives, activities, key risk factors, monitoring and evaluation, and budget. Also in line with the Board’s advice, regional and global epidemiological scenarios, with accompanying costings, informed the development of the strategic plans of the Working Groups concerned with implementation of the currently available interventions (DOTS Expansion, DOTS-Plus, and TB/HIV) and of the overall Global Plan. The activities set out in the strategic plans of the implementation Working Groups are consistent with those in the regional and global scenarios. The Working Groups concerned with research and development (vaccines, diagnostics, and new drugs) and the Working Group on ACSM developed strategic plans based on the consensus view within each Working Group without estimating the expected epidemiological impact of each group’s activities.
REGIONAL AND GLOBAL SCENARIOS FOR IMPACT AND COSTS OF PLANNED ACTIVITIES These scenarios represent an analysis of the expected impact, with the accompanying costs, of the planned scale-up of activities oriented towards achieving the 2015 targets. The analysis required close interaction between representatives of the implementation Working Groups, WHO regional offices, and the team assessing the epidemiological impact and costs of interventions. The scenarios are indicative of what could be achieved, with ambitious but realistic assumptions. Scenarios were developed globally and for seven of the eight epidemiological regions shown in Fig. 107.1: Africa high HIV prevalence (AFR High
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of new diagnostics, drugs, and vaccines. The analysis related to implementation of currently available interventions was based on a set of seven Excel spreadsheet models (one for each of the seven epidemiological regions considered) that linked demographic, epidemiological, planning, and cost data.24
HIV) and Africa low HIV prevalence (AFR Low HIV), which are presented together; American region (AMR, Latin America only); Eastern European Region (EEUR); Eastern Mediterranean Region (EMR); South-East Asian Region (SEAR); and Western Pacific Region (WPR). The Established Market Economies (EME) and Central Europe were considered together as one epidemiological region because they have similarly high per capita income rates and low TB incidence rates. Since the main focus of the Global Plan is on the countries with high TB incidence, and the combined estimated incident cases in this region (EME and Central Europe) in 2003 represented only 1.7% of the global total, detailed implementation scenarios have not been developed for this region. Many of the countries in this region have developed national plans for TB control, e.g. the plan for the USA, developed by the Federal TB Task Force in 2004 (based on the recommendations made by the Institute of Medicine in its report in 200021) and the plan for England, published in 2004.22 The scenarios involved assumptions about the pace of scale-up and the implementation coverage of the activities set by the Global Plan study team in consultation with the Stop TB Partnership’s Working Groups, thus ensuring the contribution of views of representatives of civil society, governments, UN organizations, nongovernmental organizations, and technical experts. Estimates have been made of TB case detection and treatment outcomes over the next 10 years, as well of TB prevalence, incidence, and death rates in relation to the 2015 targets. The scenarios also include estimated costs of country implementation as well as external technical support.
RESULTS OF GLOBAL PLANNING Over the ten years of the Global Plan, about 50 million people will be treated for TB under the Stop TB Strategy, including about 800,000 patients with multidrug-resistant (MDR) TB, and about 3 million patients who have both TB and HIV will be enrolled on antiretroviral therapy (ART). This would result in about 14 million lives saved from 2006 to 2015 (see Fig. 107.2), compared to a situation without implementation of the DOTS strategy. In terms of targets, full implementation of the Global Plan would result in global achievement of the MDG ‘to have halted by 2015, and begun to reverse, the incidence’ of TB, and of the Partnership’s 2015 targets to halve prevalence and death rates (measured over the period 1990–2015). In addition, the Partnership’s 2015 targets would be achieved in four regions: Eastern Mediterranean, Latin America, South-East Asia, and Western Pacific (see Fig. 107.3). However, despite enormous progress over the period of the Plan (2006–2015), the progress of Eastern Europe and Africa (measured over the period 1990–2015) would most likely result in achievement of these targets later than 2015. To identify what extra measures would be necessary to achieve the 2015 targets, additional scenarios were developed for Eastern Europe and Africa. The analysis of what would be required to meet the targets in these regions indicated a range of actions, of which the scale, timing, and feasibility vary considerably. In most regions, the projected proportional reductions in prevalence and death rates are similar. The notable exception is Africa where, on account of the impact of HIV on TB case fatality, achieving the target of halving the death rate is much more difficult than halving prevalence. As an illustration of the further actions needed to achieve the 2015 targets in Africa and Eastern Europe, Table 107.1 shows what must be done to halve the death rate, with an assessment of feasibility of the measures. Figure 107.4 shows the estimated impact on global TB incidence of the continued implementation of the interventions set out in the Global Plan projected until 2050, the target year for the elimination of TB, i.e. the reduction in global TB incidence to less than one per million population.
ESTIMATION OF EPIDEMIOLOGICAL IMPACT OF PLANNED ACTIVITIES Based on previous mathematical modelling, the potential impact of the activities proposed under different scenarios to implement the currently available interventions was estimated.23 The model brings together data from studies of the biology of TB, and from the experience of TB control in diverse settings.
ESTIMATION OF COSTS, FUNDING, AND FUNDING GAPS The two main components in the estimation of costs, funding, and funding gaps were analyses related to (a) implementation of currently available interventions, and (b) research and development 16
Lives saved (millions)
14
Lives saved, 2006 2015
14
12 10 8 6
5.1 3.8
4 2
Fig. 107.2 Estimated number of lives to be saved under the Global Plan, 2006–2015.
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0
3.3 0.6
All regions
Africa high
Africa low
0.2
E. Europe
0.8
0.4
E. Med.
Latin America
SE Asia
West Pacific
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350 300 250 200 150 100
A
Expected under GP
50 40 30 20 10
50 0
Target
60
Expected under GP
Deaths/100,000/year
Prevalence/100,000
70
Target
Africa high
Africa low
E. Europe
E. Med
Lat. America
SE Asia
W. All Pacific regions
0
B
Africa high
Africa low
E. Europe
E. Med
Lat. America
SE Asia
W. All Pacific regions
Fig. 107.3 (a) Estimated TB prevalence in 2015 in comparison with targets. (b) Estimated TB death rates in 2015 in comparison with targets.
Table 107.1 Further actions needed to achieve the 2015 targets for deaths in Africa and Eastern Europe Action (under additional scenarios)
Assessment of feasibility
Africa ART much more rapidly available, e.g. as proposed by WHO/ UNAIDS, in line with the ‘3 by 5’ initiative. Very high rates of case detection and treatment success from 2006 to 2015 under DOTS, with 90% case detection for HIV-negative TB cases (both smear-positive and -negative) and 85% treatment success. Preventive therapy: 20% of people coinfected with MTB and HIV treated annually so that they do not develop active TB. This could be achieved with isoniazid (IPT), ART, or some combination of IPT and ART (or with some other drug yet to be discovered). HIV incidence rate cut to half the value forecast by UNAIDS in 2005 and held at that level from 2006 to 2015.
Vaccination from 2006 onwards, annually protecting 20% of uninfected people from ever acquiring TB infection (with the assumption that the vaccine does not protect people who are already HIV-positive).
Since the ‘3 by 5’ initiative will probably not achieve its target by 2005, it appears unlikely that ART access for TB patients can be made much more rapidly available. Very unlikely — the infrastructure and human resources in Africa are inadequate to allow these levels of case detection and treatment success, although the situation could be different if improved diagnostics and treatment regimens became widely available (towards 2010), and if investments now resulted in improvements in infrastructure and human resources (from 2010 onwards). Very unlikely — the infrastructure and human resources in Africa are inadequate to deliver these levels of preventive therapy, although the situation could be different if improved diagnostics for latent TB infection and preventive therapy became widely available (towards 2010). Extremely unlikely — the infrastructure and human resources in Africa are inadequate to deliver the measures available to control HIV transmission quickly enough and on a sufficiently large scale to result in this unprecedented rate of decline in HIV incidence. Extremely unlikely — the Working Group on Vaccines estimates that new vaccines will be available in 2015.
Eastern Europe Extreme DOTS (90% case detection with 85% treatment success in 2006–2015).
More rapid expansion of DOTS-Plus: 90% case detection for MDR-TB patients, as for DOTS; MDR-TB among culture-positive cases falls from 10% to 5% by 2010; the ratio of previously treated cases to new cases falls to 10% by 2010; 70% of MDR-TB patients are on DOTSPlus from 2006 onwards, rising to 100% by 2015; 85% treatment success among MDR-TB patients under DOTS-Plus, from 2006 to 2015; 100% DST for culture-positive patients 2006–2015.
Very unlikely that these levels could be reached so quickly, even though experience of rapid, large-scale DOTS implementation in China and India indicates that strong political support in large countries with reasonable health infrastructure, adequate funding, and strong financial management can result in high levels of case detection and treatment success. Improved drugs and diagnostics could help reach these levels. Very unlikely, largely because of the lack of political will, financial management capacity and laboratory infrastructure, and the lack of experience of large-scale and rapid scale-up of DOTS-Plus.
Box 107.2 shows the expected outcomes of the strategic plans based on the consensus view within each Working Group concerned with research and development. The total cost of the Plan (US$56 billion) represents a threefold increase in annual investment in TB control compared with the
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first Global Plan (2001–2005). As shown in Table 107.2, this total includes US$9 billion for research and development and US$47 billion for implementation of current interventions (over US$28 billion for DOTS expansion, an additional US$6 billion for DOTS-Plus, US$7 billion for TB/HIV activities, US$3 billion
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The Global Plan to Stop TB, 2006–2015 1600
10 000 Projected incidence 100¥ bigger than elimination threshold in 2050
Incidence/million/year
1200
1000
1000 100
800 600 400
Global Plan Incidence falls 5 6%/ year 2010 2015
Incidence/million/year
1400
10
200 0 1990
2000
2010
2020 Year
2030
2040
107
Box 107.2 Expected outcomes of strategic plans of Working Groups concerned with research and development Drugs The first new TB drug for 40 years will be introduced in 2010, with a new short TB regimen (1–2 months) shortly after 2015. Diagnostics By 2010, diagnostic tests at the point of care will allow rapid, sensitive, and inexpensive detection of active TB. By 2012, a diagnostic toolbox will accurately identify people with latent TB infection and those at high risk of progression to disease. Vaccines By 2015 a new, safe, effective, and affordable vaccine will be available with potential for a significant impact on TB control in later years.
1 2050
Fig. 107.4 Projected TB incidence, 1990–2050, plotted against a linear and logarithmic scale.
Table 107.2 Total costs and funding gaps, 2006–2015, by Working Group (US$ billions) Global Plan to Stop TB, 10-year period, 2006–2015
Costs
a
Available funding
First Global Plan, five-year period, 2001–2005
Funding gap
US$ billions
Costs US$ billions
Implementation DOTS Expansion Country needs
28.9
Country needs
5.8
Country needs
6.7
Country needs
2.9
DOTS-Plus TB/HIV ACSM International Agencies (technical cooperation)b Total implementation WG
Gap, US$ 22.5 billion, 51%
Other donor sources, US$ 1.7 billion, 4%
Domestic funding, US$ 19.2 billion, 43%
6.0
GFATM, US$ 0.9 billion, 2%
0.6
1.1
0.0
2.9
0.7
2.2
0.3
47.2
22.5
24.7
8.0
New tools R&D Vaccinesc Drugs Diagnostics Total new tools
3.6 4.8 0.5 9.0
2.1 0.6 0.1 2.8
1.5 4.2 0.4 6.1
0.4 0.3 0.2 0.9
Total needs Global Plan
56.1
25.3
30.8
9.1
a
Domestic funding assumes government commitments in 2005 are sustained and increase in line with inflation; GFATM commitments are based on results of rounds 1 to 5 (these cover 2006–2011); other donor funding assumes commitments reported in 2004 are sustained and increase in line with inflation. b Technical cooperation includes strategic and technical support, capacity building, monitoring and evaluation, operational research and policy development, and Working Group operations. c Includes costs for maintenance of the current BCG vaccination programme. N.B. Column totals may not add up exactly due to rounding.
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COST-EFFECTIVENESS
Cost per DALY gained by region 2006 2015
2500
2099
2000
US$
1500 1000 500 0
157
208
All regions
Africa high
310
Africa low
E. Europe
187
222
E. Med
Lat. America
62
73
SE Asia
W. Pacific
Fig. 107.5 Cost-effectiveness of implementing the currently available interventions to Stop TB.
for ACSM activities, and US$3 billion for technical cooperation). Of the US$47 billion for implementation of current interventions, US$44 billion (94%) are country-level costs, representing about 80% of the Plan’s total cost. The estimated funding gap is US$31 billion, since an estimated US$25 billion is likely to be available based on projections of current funding trends. Combining projected costs and impact of implementing the currently available interventions for TB control, the cost per DALY saved is US$157. Figure 107.5 shows the cost per DALY gained by region. The cost per DALY year averted is less than US$1 per day for all regions except Eastern Europe where it is close to US$2,100 per day because of the extensive reliance on relatively expensive hospitalization during the treatment of patients with fully drug-susceptible TB and because of the much higher costs associated with treating MDR-TB.
IMPLICATIONS OF THE GLOBAL PLAN LIKELIHOOD OF GLOBAL ACHIEVEMENT OF THE 2015 TARGETS Estimates of the impact of the planned TB control interventions indicate expected global achievement of the 2015 targets (measured against a 1990 baseline) with considerable progress in all regions (measured over the planning period 2006–2015). However, Africa and Eastern Europe would most likely achieve the targets later than 2015, because of the particular challenges posed by HIV and MDR-TB, respectively. An important reason why achievement of the Partnership’s targets to halve prevalence and death rate by 2015 will be reached later in the African region is that the targets were set with 1990 levels as baseline. Since there was a dramatic increase in TB incidence, prevalence, and death rates between 1990 and 2005 largely due to the HIV epidemic, the time remaining until 2015 is almost certainly too short to revert to 1990 levels. Additional scenarios identified the measures needed in theory to achieve the targets in Africa and Eastern Europe: massive improvements in general health systems; a reduction of 50% in HIV incidence; and the rapid availability of powerful new tools to increase diagnostic capacity, substantially shorten treatment duration, and effectively prevent TB. It is unlikely that even massive additional funding or even greater effort would be successful in achieving the targets in these regions.
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The cost-effectiveness globally of US$157 per DALY averted (and less than US$1 per day for all regions except Eastern Europe) compares favourably with that of other health interventions.25 Tuberculosis control in the South-East Asian and Western Pacific regions is particularly cost-effective, at about US$60–70 per DALY averted. The DOTS strategy is among the most cost-effective of all health interventions. The TB control interventions in the Global Plan represent an enhanced DOTS strategy as part of the new Stop TB Strategy, and despite being more comprehensive are still extremely cost-effective. In allocating resources to specific health interventions, cost-effectiveness is one consideration among others, including medical, ethical, cultural, and budgetary factors. Improving efficiency is complementary to increasing the resources for implementing health interventions within broader objectives, such as the MDGs.
REGIONAL AND NATIONAL PLANNING Realizing the Global Plan’s expected gains requires translation of global strategic directions into national-level action and funding, through more detailed planning tailored to the needs of regions and countries. The global planning approach, with estimation of impact and costs of proposed actions, is relevant to regional and national planning. Identification of lack of long-term national planning as a barrier to progress in TB control led to the adoption of the 2005 World Health Assembly resolution on sustainable financing for TB prevention and control.26
FUNDING GAP The Global Plan (2006–2015) builds on the track record of the first Global Plan to Stop TB (2001–2005) in which US$5 billion were budgeted, raised, and spent, although without estimation of impact on disease burden. The funding needed for implementation of currently available interventions is estimated at US$22.5 billion, out of a total need of US$47.2 billion (Table 107.2). The shortfall in available funding increases from US$1.4 billion in 2006 to US $3.1 billion in 2015. There are two major reasons for this increase in the funding gap. The first is that the estimates of available funding are based on the assumption that domestic and donor funding (excluding funding from the Global Fund to Fight AIDS, TB, and Malaria) will be sustained at 2005 and 2004 levels, respectively. The second is that the Plan includes large investments in new interventions, in line with the new Stop TB Strategy. These include new approaches to DOTS implementation as well as much more widespread implementation of DOTS-Plus, TB/HIV and interventions related to advocacy, communications, and social mobilization. The Plan also includes much more investment in technical cooperation, which is needed to support this substantial increase in both the number and scale of interventions. These additional large investments will require increased funding commitments from both governments of high-burden countries and donors. Given the existing distribution of funding for TB control and the size of the funding gap, it is likely that the governments of high-burden countries themselves will need to finance a large proportion of this gap (filling the funding gap would need donor funding to increase about eight times whereas domestic funding would need to double). Failure to fill the funding gap and ensure full implementation of the Global Plan carries an
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epidemiological cost, which lies not only in global failure to achieve the 2015 targets (measured against a 1990 baseline), but also in failure of regions to achieve their expected considerable gains (measured over the planning period 2006–2015).
PROSPECTS FOR LONG-TERM TUBERCULOSIS CONTROL The planning outcomes have implications for the prospects of longterm TB control. Projections show that continued implementation of the planned interventions beyond 2015 will not result in the elimination of TB by 2050 (Fig. 107.4). At the average rate of decline in TB incidence expected globally between 2010 and 2015 under this Global Plan, the incidence rate will still be about 100 times larger than the elimination target of 1 per million. The introduction of effective new technology will be a prerequisite for meeting this long-term goal. New technology is needed not only to more effectively reduce transmission and thereby prevent infection but also to prevent TB among people already infected by decreasing reactivation of latent infection, through mass treatment of latent infection (ideally with specific targeting of those infected people most likely to develop TB) or mass vaccination.27 For each of the new technologies (diagnostics, drugs, and vaccines) there is a considerable attrition rate on the journey along the pipeline that leads from a product that is potentially promising to one licensed for widespread field use. The chances of a successful product emerging from the end of the pipeline depend at least in part on the number of potential products entering the pipeline.28 A considerable boost in investment in basic research is necessary to ‘keep the pipeline stocked’.
EVALUATING SUCCESS Although the process of planning was successful, ‘the proof of the pudding is in the eating’ and the success of the Global Plan depends on how it is implemented.29 Success will depend on the extent to which the Plan serves to help mobilize the funds to fill the funding gap for planned activities, and the extent to which countries will take a course of action crystallizing around the Plan. Critical evaluation of progress in implementing the Plan will reveal the degree
REFERENCES 1. World Health Organization. World Health Report 2004. Changing history. Geneva: World Health Organization, 2004. 2. Yach D, Bettcher D. The globalization of public health, I: threats and opportunities. Am J Publ Health 1998;88:735–738. 3. Fenner F, Henderson DA, Arita I, et al. The intensified smallpox eradication programme, 1967–1980. In: Smallpox and Its Eradication. Geneva: World Health Organization, 1988: 421–538. 4. Editorial. Whither onchocerciasis control in Africa? Am J Trop Med Hyg 2005;72(1):1–2. 5. Jacobs L, Martin J-F, Godal T. A paradigm for international cooperation: The Global Alliance for Vaccines and Immunization (GAVI) and the Vaccine Fund. In: Levine MM, Kaper JB, Rappuoli R, et al. (eds) New Generation Vaccines, third edn. New York: Marcel Dekker, 2004. 6. Kumaresan J, Heitkamp P, Smith I, et al. Global Partnership to Stop TB: a model of an effective public health partnership. Int J Tuberc Lung Dis 2004; 8(1):120–129.
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of success or failure in translating into action the political commitment mobilized in developing and launching the Plan. While the assumptions that underpinned the development of the Plan were based on the best understanding of the planning and epidemiological parameters at the time, measurement of progress in implementation of the planned activities and of their impact will enable testing and refining of these assumptions. The need for responsiveness to demand is indicated by the call since the publication of the Plan to revise upwards the planned number of patients with MDRTB to be treated over the planning period. The need for flexibility in adopting and adapting the Plan is highlighted by, for example, the need to respond to the problem of extensively drug-resistant (XDR) TB, which has emerged as a key issue since the publication of the Plan.30
CONCLUSION The Global Plan to Stop TB has unique features, namely its 10year timeframe and its approach in setting out the proposed target-oriented activities, their cost, and their expected impact on the global disease burden. These features are likely to prove of value as an example of a long-term plan for improving global health. A plan based on sound epidemiological analysis with robust budget justifications presents a convincing argument for mobilizing the resources needed for action (regarding implementation of currently available interventions and the development of new technology). Such a plan also provides a means of ensuring accountability for agreed action, as progress is measured against the expected milestones. Future refinement of the process of global planning for TB control is likely to include estimating the impact on the TB epidemic of new technologies and of activities related to advocacy, communications, and social mobilization.
HOW TO ACCESS THE GLOBAL PLAN TO STOP TB (2006–2015) The Global Plan is available on the Stop TB Partnership’s website (http://www.stoptb.org/globalplan).
7. World Health Organization. Global Polio Eradication Initiative Strategic Plan 2004–2008. Geneva: World Health Organization, 2003. 8. World Health Organization. The Final Push towards Elimination of Leprosy: Strategic Plan 2000–2005. Geneva: World Health Organization, 2003. 9. World Health Organization. Global Strategy for Further Reducing the Leprosy Burden and Sustaining Leprosy Control Activities (Plan Period: 2006–2010). Geneva: World Health Organization, 2005. 10. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2007. Geneva: World Health Organization, 2007. 11. Raviglione MC, Uplekar M. WHO’s new Stop TB Strategy. Lancet 2006;367:952–955. 12. World Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes, 3rd edn. Geneva: World Health Organization, 2003. 13. Stop TB Partnership and World Health Organization. Global Plan to Stop TB, 2006–2015. Geneva: World Health Organization; 2006. 14. World Health Organization. Fifty-eighth World Health Assembly: Resolutions and Decisions, Resolution WHA 58.14. Geneva: World Health Organization; 2005. 15. Dye C, Maher D, Weil D, et al. Targets for global tuberculosis control. Int J Tuberc Lung Dis 2006; 10(4):460–462.
16. Stop TB Partnership. Basic framework for the Global Partnership to Stop TB. [online]. Accessed 28 April 2006. Available at URL:http://www.stoptb.org 17. Sachs J. The End of Poverty: Economic Possibilities for Our Time. New York: Penguin, 2004. 18. Easterly W. The White Man’s Burden: Why the West’s Efforts to Aid the Rest Have Done So Much Ill and So Little Good. New York: Penguin, 2006. 19. Sen A. The man without a plan. Foreign Affairs, March/April 2006. 20. Stop TB Partnership and World Health Organization. The Global Plan to Stop TB (2001–2005). Geneva: World Health Organization, 2002. 21. Institute of Medicine. Ending Neglect: The Elimination of Tuberculosis in the United States. Washington DC: National Academy Press, 2000. 22. Department of Health. Stopping Tuberculosis in England. London: Department of Health, 2004. 23. Currie CSM, Williams BG, Cheng RCH, et al. Tuberculosis epidemics driven by HIV: is prevention better than cure? AIDS 2003;17: 2501–2508. 24. Floyd K, Pantoja A. The Global Plan to Stop TB, 2006–2015: Methods Used to Estimate Costs, Funding and Funding Gaps. Geneva: World Health Organization, 2006. 25. Laxminarayan R, Mills AJ, Breman JG, et al. Advancement of global health: key messages from the
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SECTION
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SOCIAL AND STRUCTURAL ISSUES IN TUBERCULOSIS
Disease Control Priorities Project. Lancet 2006;367(9517):1193–1208. 26. World Health Organization. Fifty-Eighth World Health Assembly: Resolutions and Decisions (WHA58/2005/ REC/1). Geneva: World Health Organization, 2005. 27. Young D, Dye C. The development and impact of tuberculosis vaccines. Cell 2006;124:683–687.
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28. Glickman SW, Rasiel EB, Hamilton CD, et al. Medicine. A portfolio model of drug development for tuberculosis. Science 2006;311:1246–1247. 29. Maher D, Dye C, Floyd K, et al. Planning to improve global health: the next decade of tuberculosis control. Bull World Health Organ 2007;85:341–347.
30. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients coinfected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575–1580.
APPENDICES APPENDIX
1
Conversion of units for laboratory results H Simon Schaaf
The tests and corresponding units included in this appendix are those mentioned in the book for readers to be able to convert values to the units they are familiar with. Normal values are not included as they differ between laboratories. To convert from
the conventional unit to the Systeme International d’Unites (SI units), multiply by the conversion factor, and to convert from SI units to the conventional unit, divide by the conversion factor.
Test result
Conventional units
Conversion factor
SI units (Systeme International d’Unites)
Adenosine deaminase (ADA) Alpha-fetoprotein (AFP) Alanine aminotransferase (ALT) Albumin Aspartate aminotransferase (AST) Beta-human chorionic gonadotrophin (b-HCG) Bilirubin CA125 CD4 T-helper lymphocytes CD4 T-helper lymphocytes Corticotropin (ACTH) C-reactive protein (CRP) Creatinine Erythrocyte sedimentation rate (ESR) Ferritin Glucose Haemoglobin Interferon-gamma (IFN-g) Lactate dehydrogenase (LD or LDH) Leucocytes (WBC count) (blood) Leucocytes (WBC count) (blood) Leucocytes (WBC count—CSF/pleural fluid) Lysozyme Platelet count (thrombocytes) Prostate-specific antigen (PSA) Protein (total) Protein (CSF) Rheumatoid factor (RF) Sodium Thyroid function Thyroid-stimulating hormone (TSH) Free T3 (free triiodothyronine) Total T3 (total triiodothyronine) Free T4 (free thyroxine) Total T4 (total thyroxine) Triglycerides Urea (serum)
units/L ng/mL units/L g/dL g/dL mIU/mL mg/dL U/mL or IU/mL cells/mm3 cells 106/mL pg/mL mg/mL mg/dL mm/h ng/mL or mg/L mg/dL g/dL pg/mL units/L 103/mL 103/mL Leucocytes/mL mg/dL 103/mL ng/mL g/dL mg/dL IU/mL mEq/L
1 1 1 10 1 1 17.1 1 1 1 0.22 1 88.4 1 2.247 0.0555 10 0.02 1 1 0.001 1 10 1 1 10 0.01 1 1
U/L (IU/L) mg/L U/L (IU/L) g/L U/L (IU/L) IU/L mmol/L kU/L cells/mL cells x 109/L pmol/L mg/L mmol/L mm/h pmol/L mmol/L g/L IU/mL U/L or IU/L 109/L 109/L Leucocytes 106/L mg/L 109/L mg/L g/L g/L kU/L mmol/L
mIU/L pg/dL ng/dL ng/dL mg/dL mg/dL mg/dL
1 0.0154 0.0154 12.87 12.87 0.0113 0.357
mIU/L (mU/L) pmol/L nmol/L pmol/L nmol/L mmol/L mmol/L
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APPENDIX
2
Tuberculosis drug information Helen McIlleron
INDIVIDUAL DRUG PROFILES In this section brief notes on each of the anti-TB agents are presented (Tables A2.1-A2.21). Tables of side effects and the associated anti-TB agents (Table A2.22), and information on drug interactions (Tables A2.23-A2.26), follow. For more comprehensive information, other sources of information (e.g. those listed at the end of the section) should be consulted.
Table A2.1 Amikacin Pharmacokinetics: As for streptomycin (Table A2.21). Target amikacin plasma concentrations: peak > 30 mg/mL; trough < 1 mg/mL. Cautions: Contraindicated in myasthenia gravis or hypersensitivity to the drug. Use with caution in renal failure, impaired hearing or vestibular function, and in neonates in whom dosing should be guided by plasma concentrations (the dosing interval should be adjusted to keep trough concentrations < 5 mg/mL). Pregnancy and lactation: Crosses the placenta and may cause fetal ototoxicity or nephrotoxicity; avoid during pregnancy. As oral absorption is poor, breastfeeding is safe. Side effects: Nephrotoxicity; damage is related to accumulation in the proximal tubular cells; proteinuria and electrolyte disturbances are common (creatinine and potassium levels should be checked monthly, or more frequently in patients at greater risk). Dose-related ototoxicity (hearing loss, vertigo, nausea, vomiting) is initially reversible, but may become permanent. The risk of renal toxicity and 8th cranial nerve damage are increased if renal function is impaired, and elderly patients are more susceptible (monthly audiometry is advised in patients at risk of ototoxicity). Peripheral neuropathy, hypersensitivity, and skin rash may occur. Dosing: Adults: 15–20 mg/kg/day in a single intramuscular (or slow intravenous) dose (maximum 1.5 g/day). Children: 15–22.5 mg/kg/day (maximum 1,000 mg daily). Renal failure (glomerular filtration rate (GFR) < 60 mL/min): loading dose of 10 mg/kg with further doses guided by drug concentration monitoring.
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Table A2.2 Amoxicillin/clavulanate (coamoxiclav) Pharmacokinetics: Amoxicillin has good (85%) oral absorption and penetrates well into most body fluids, although cerebrospinal fluid (CSF) penetration is poor. Elimination of both components is rapid (half-life: 1–1.3 h); amoxicillin mostly by renal tubular secretion of unchanged drug (20–30% undergoes hepatic metabolism); clavulanate is more extensively metabolized (25–45% excreted unchanged). Cautions: Avoid in those with infectious mononucleosis, or hypersensitivity to any penicillin or cephalosporin. Use with caution if there is severe hepatic or renal impairment. Dose adjustments may be required in the elderly and in neonates due to age-related changes in renal function. Pregnancy and lactation: Widely used without harmful effect; amoxicillin and clavulanate are excreted in beast milk. Side effects: Gastrointestinal disturbances (related to the dose of clavulanic acid) are common. Rarely, serious anaphylactic reactions occur. Hepatitis and cholestatic jaundice have been reported. Dosing: Adults and children > 20 kg: 250–500 mg amoxicillin plus 125 mg clavulanic acid 8 hourly. Children < 20 kg: 10–15 mg/kg of amoxicillin plus 2.5–3.75 mg/kg of clavulanic acid 8 hourly. Neonates: 15 mg/kg amoxicillin plus 3.75 mg/kg clavulanic acid 12 hourly. Renal impairment: increase dosing interval to 12 hours for GFR 10–30 mL/min, or 24 hours for GFR < 10 mL/min.
APPENDIX
Tuberculosis drug information
2
Table A2.3 Capreomycin
Table A2.5 Clarithromycin
Pharmacokinetics: Capreomycin is delivered by intramuscular injection. Repeated use of the same injection site may lead to delayed distribution. Meningeal penetration occurs only when they are inflamed. 50–60% excreted by glomerular filtration. Cautions: Use with caution in patients with renal disease or hearing impairment; drug concentration monitoring is advised. Contraindicated in patients with hypersensitivity to capreomycin. Pregnancy and lactation: Limited data in humans; animal studies show teratogenic effect; avoid in pregnancy. Side effects: Nephrotoxicity is very common (20–25%); tubular dysfunction, azotaemia, proteinuria and electrolyte abnormalities are common manifestations. Monthly creatinine and electrolyte monitoring is recommended; more frequent monitoring is advised in high-risk patients. Ototoxicity (vestibular > auditory) occurs commonly; baseline and monthly audiometry is advised in patients at risk. Hypersensitivity reactions include urticaria and maculopapular rash. Neuromuscular blockade may occur with high doses or rapid infusion. Dosing: Adults < 50 years: 15–20 mg/kg daily; usually 1 g daily; during the continuation phase, the same dose can be given 2 or 3/week. Adults > 50 years: 10 mg/kg/day (maximum 750 mg). Children: 15–30 mg in a single daily dose (maximum 1g). Renal impairment: 12–15 mg/kg 2 or 3/ week should be used in patients with GFR < 30 mL/min, or receiving haemodialysis.
Pharmacokinetics: After oral absorption, clarithromycin is widely distributed with high tissue concentrations due to intracellular concentration. Hepatic metabolism is saturable leading to an increased half-life at higher doses. Renal excretion accounts for elimination of 20–40% of the unchanged drug. Cautions: Hypersensitivity to macrolides. Concurrent use of drugs that may prolong the QTc interval, or whose metabolism may be inhibited by clarithromycin. Pregnancy and lactation: Safety has not been established. Distributed to breast milk. Side effects: Gastrointestinal disturbances, headache, and altered taste or smell are common. CNS disturbances, vertigo, hearing loss, hypoglycaemia, leucenia, neutropenia, cholestatic hepatitis QTc interval prolongation, and ventricular arrhythmias have been reported. Hepatoxicity, hypersensitivity reactions (including severe skin reactions such as toxic epidermal necrolysis), pseudomembranous colitis, and thrombocytopenia occur rarely. Dosing: Adults: 500 mg twice daily. Children: 7.5–15 mg/kg (maximum 500 mg) 12 hourly. Renal failure (GFR < 30 mL/min): reduce dose by half.
Table A2.4 Ciprofloxacin
Table A2.6 Clofazimine
Pharmacokinetics: Well absorbed (70–85%) in the absence of divalent cations (see drug–drug interactions). Wide tissue distribution occurs to most tissues. CSF concentrations are 5–10% of those in plasma; but increased to 50–90% with inflamed meninges. Excretion is by renal and hepatic routes. Cautions: Contraindicated in patients known to have serious hypersensitivity to fluoroquinolones. Use with caution in epileptics and patients with disorders of the CNS, hepatic or renal impairment, children (because of the concern based on animal studies that cartilage development might be affected), and porphyrics. Pregnancy and lactation: Cartilage damage has been reported in animals exposed to fluoroquinolones in utero. Use during pregnancy or breastfeeding is not recommended because of the potential for arthropathy. Side effects: Generally well tolerated. Gastrointestinal effects include abdominal pain, nausea, vomiting, and diarrhoea. Pseudomembranous colitis has been reported rarely. Headaches, dizziness, restlessness, drowsiness, insomnia, tremor, agitation, confusion, or, rarely, hallucinations may occur. Arthralgia is reported. Hypersensitivity includes skin rash, urticaria, pruritus, photosensitivity, or, rarely, vasculitis, Stevens–Johnson syndrome or anaphylaxis. There are rare reports of hepatic necrosis, interstitial nephritis, tendon rupture, peripheral neuropathy, and blood dyscrasias. Dosing: Adults: 1000–1500 mg/day. Renal impairment: if GFR < 30 mL/min, 1,000–1,500 mg should be given 3/week. Children: 20–30 mg/kg/day in two divided doses (maximum 1.5 g).
Pharmacokinetics: Absorption of clofazimine (20–70% of an oral dose) is enhanced when taken with food. It is widely distributed accumulating in fat, skin, liver, kidneys, and reticuloendothelial cells. The drug is gradually released from these tissues before biliary elimination (< 1% is excreted in urine) with a half-life of about 10 days after a single dose, increasing to 2–3 months with long-term therapy. Cautions: Porphyria. Patients with impaired hepatic and renal function should have regular monitoring of their renal and hepatic status. Pregnancy and lactation: Pigmentation (which fades gradually over months once exposure ceases) may occur in the fetus or breast-fed infant. Not recommended during pregnancy or breastfeeding. Side effects: Clofazimine may impart a red colour to urine, faeces, sweat, and sputum. Red to brown pigmentation of conjunctiva, cornea, retina and skin, and dry skin with ichthyosis are common. Diarrhoea, nausea, vomiting, and abdominal pain are uncommon with doses < 100 mg/day; gastrointestinal symptoms may be alleviated by taking the dose with a meal or a glass of milk. Pruritus, acneiform eruptions, skin rashes, and photosensitivity also occur. Prolonged use of high doses is rarely associated with accumulation of crystals in the medullary sinuses causing infarction of the spleen and mesenteric lymph nodes. Dosing: Adults: the usual dose in adults is 100 mg daily (50–300 mg daily). Toxicity limits the use of higher doses in many patients.
959
APPENDICES
Table A2.7 Cycloserine and terizidone
Table A2.9 Ethionamide and prothionamide
Pharmacokinetics: The drugs are readily absorbed and widely distributed to tissues and fluids including the CSF. Excretion is largely renal by glomerular filtration. The half-life is approximately 10 hours, but prolonged in renal impairment. Cautions: Contraindicated in epilepsy, depression, psychosis, severe anxiety, severe renal impairment, alcohol abuse, and porphyria. Use with caution in the elderly and those with renal impairment as accumulation occurs easily. Pregnancy and lactation: Limited data; use only when there are no suitable alternatives; pyridoxine supplementation should be given to the breast-fed infant. Side effects: Common dose-related nervous system effects include anxiety, confusion, depression, psychosis, aggression, irritability, and paranoia. Headache, vertigo, drowsiness, speech difficulties, tremor, paresis, hyperreflexia, dysarthria, paraesthesia, coma, and convulsions may also occur. Neurotoxicity appears to be more common with cycloserine than with terizidone. Pyridoxine (vitamin B6) should be prescribed to prevent the nervous system effects. Patients with renal insufficiency, or receiving doses > 500 mg/day are at greatest risk of neurological effects; plasma concentrations should remain below 30 mg/mL. Reduce the dose or discontinue if central nervous system toxicity occurs. Rashes (allergic dermatitis, photosensitivity), abnormal liver function tests, megaloblastic anaemia, and heart failure have been reported. Dosing: Adults and children: 10–20 mg/kg/day in one or two doses (maximum 1 g/day). The usual adult dose is 500–750 mg/day in two divided doses. Renal impairment: extend dose interval and adjust by monitoring plasma concentrations (the target range for peak concentrations is 20–35 mg/mL). If concentration monitoring is not available extend the dosing interval to 24 hours if GFR 10–50 mL/min, and to 36–48 hours if GFR < 10 L/min.
Pharmacokinetics: Oral absorption is unaffected by food. Widely distributed, reaching concentrations in the CSF equal to those in plasma. Extensively metabolized in the liver to active and inactive metabolites which are eliminated by the kidneys. The half-life is about 3 hours. Cautions: Contraindicated in patients with hypersensitivity to ethionamide or prothionamide, severe hepatic disease, or porphyria. Use with caution in depression, psychiatric illness, chronic alcoholism, epilepsy, hypothyroidism, and diabetes. Pregnancy and lactation: Teratogenicity has been reported in animals but has not been documented in humans; avoid if possible. Safety during breastfeeding has not been established. Side effects: Gastrointestinal intolerance is common; nausea, vomiting, anorexia, metallic taste, abdominal discomfort, and diarrhoea may lead to loss of weight. Nervous system effects include seizures, pellagra-like encephalopathy (which may respond to treatment with niacin), acute psychosis, anxiety, depression, optic neuritis, and peripheral neuropathy (responsive to pyridoxine; consider prophylactic dosing with pyridoxine in patients at risk). Hepatotoxicity is reported in about 2% of patients. Rarely, gynaecomastia, impotence, amenorrhoea, hypothyroidism, goitre, hypoglycaemia, hypersensitivity reactions, alopecia, photosensitivity, arthralgia, thrombocytopenia, or purpura may occur. Diabetes may be difficult to control when the patient is started on ethionamide. Dosing: Adults: 15–20 mg/kg/day as a single dose (maximum 1 g/day). Children < 10 years old: 10 mg/kg/day, increased gradually provided it is well tolerated to 15–20 mg/kg/day (maximum 1 g/day); given in a single daily dose if well tolerated; alternatively in two doses. Children > 10 years: 15–20 mg/kg/day as a single dose (maximum 1 g/ day). Renal impairment: reduce dose by 50% in patients with GFR < 30mL/min or on dialysis.
Table A2.8 Ethambutol Pharmacokinetics: Although generally well distributed, inadequate concentrations are achieved in the CSF (10–50% penetrates when the meninges are inflamed). Elimination is mainly by excretion of unchanged drug in the urine. Up to 15% is metabolized in the liver. The half-life is 3–4 hours; longer in renal failure. Cautions: Contraindicated in optic neuritis and advanced renal failure. Use with caution in patients with eye defects, hyperuricaemia, or renal impairment. Ethambutol is not recommended in children whose visual symptoms cannot be monitored, e.g. those < 8 years. However, it should be considered in children with severe or extrapulmonary TB, or if infected with organisms resistant to other drugs. Pregnancy and lactation: The dose should not exceed 15 mg/kg/day during pregnancy; no congenital abnormalities have been documented in humans. No known adverse effects on the nursing infant. Side effects: Dose-dependent ocular toxicity is uncommon (< 1%) with doses of 15 mg/kg/day; < 5% with 25 mg/kg/day. Central or peripheral retrobulbar neuritis may affect one or both eyes. It usually presents after 2 months of use and is often reversible if therapy is discontinued in the early stages. Daily self-monitoring (e.g. reading fine print) is advised and regular visual testing should be conducted as some visual defects may be asymptomatic. Hyperuricaemia associated with arthralgia may be caused by inhibition of uric acid excretion. Acute gout may be precipitated in susceptible patients. Mild gastrointestinal disturbances, peripheral neuropathy, skin rashes and dermatitis, dizziness, mental confusion, thrombocytopenia, direct toxic damage to the kidneys, and, rarely, hepatitis may also occur. Dosing: Adults: oral, 15–20 mg/kg/day in a single dose. The dose should not exceed 15 mg/kg/day in the elderly. Children: 15–25 mg/kg in a single daily dose (maximum 1,000 mg). Doses at the higher end of the range should be used in patients with multidrug resistant TB (MDR-TB). Renal impairment: dose intervals should be prolonged (GFR < 10 mL/min: 15 mg/kg every 48 hours).
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Table A2.10 Gatifloxacin Pharmacokinetics: Absorption is essentially complete in the absence of divalent cations (see drug–drug interactions), and wide distribution occurs to the tissues including the CSF. Excretion is primarily by renal elimination of the unchanged drug. Cautions: As for ciprofloxacin (Table A2.4). Avoid in patients with prolonged QTc interval. Pregnancy and lactation: Use during pregnancy or breastfeeding is not recommended because of the potential for arthropathy. Side effects: As for ciprofloxacin. Gatifloxacin may cause dysglycaemia more often than other fluoroquinolones. QTc interval prolongation may occur. Dosing: Adults: 400 mg daily. Renal impairment: if the GFR is reduced to < 30 mL/min use 400 mg 3/week. Children: 7.5–10 mg/kg daily (maximum 400 mg).
APPENDIX
Tuberculosis drug information
2
Table A2.11 Isoniazid
Table A2.13 Levofloxacin
Pharmacokinetics: Absorption is reduced by food and antacids. Bioavailability is reduced by first-pass metabolism. Distribution is wide, and there is good CSF penetration. The major metabolic pathways are hepatic acetylation and dehydrazination. Inactive metabolites and some unchanged isoniazid are excreted in the urine. The half-life varies widely, from 1 to 6 hours; acetylator genotype is the main determinant. Cautions: Previous hypersensitivity to isoniazid; pre-existing liver disease; epilepsy; porphyria. Pregnancy and lactation: With wide use no adverse effects on the human fetus are documented. Breast milk concentrations may be relatively high, but the risk of complications is low; monitoring of the infant for adverse effects including pyridoxine deficiency is advised. Side effects: Transient elevation of liver enzymes occurs in 10–20% of patients; overt hepatitis, which may be fatal, has an incidence of < 1% when isoniazid is given alone. The risk of hepatotoxicity is increased in older patients, women, patients with pre-existing liver impairment, and by the concurrent use of other potentially hepatotoxic drugs (rifampicin, in particular) or alcohol. Dose-related neurotoxicity: peripheral neuropathy occurs with chronic exposure; seizures, psychosis, ataxia, and optic neuritis usually present more acutely. Higher doses of pyridoxine are used to reverse neurotoxicity and prophylactic supplementation of 10–25 mg/day is recommended in those at risk (e.g. pregnant women, malnourished patients, alcoholics, diabetics, human immunodeficiency virus (HIV)-infected patients, and MDR-TB patients receiving terizidone). Haematological effects include pyridoxine-responsive sideroblastic anaemia, haemolytic anaemia, thrombocytopenia, neutropenia and, rarely, aplastic anaemia. Up to 20% of patients produce antinuclear antibodies. A small percentage of these develop drug-induced lupus erythematosus. Renal involvement is rare; interstitial nephritis usually resolves on cessation of therapy. Skin rashes occur in 2% of patients; a pellagra-type dermatitis occurs in malnourished patients and responds to niacin therapy; acneiform eruptions are common. Mild gastrointestinal disturbances occur commonly. Dosing: Adults: 5 mg/kg/day in a single daily dose (maximum 300 mg/day), or 10–15 mg/kg 3 /week (maximum 900 mg). Children: 5–10 mg/kg daily, up to 15 mg/kg daily for TB meningitis and miliary TB (maximum 300 mg), or 10–15 mg/kg 3/week (maximum 900 mg); high doses should be used with caution in communities with a high prevalence of infectious hepatitis.
Pharmacokinetics: Absorption is essentially complete in the absence of divalent cations (see drug–drug interactions), and wide distribution occurs to the tissues. CSF concentrations reach 30–50% of plasma levels when the meninges are inflamed. Most of a dose is excreted unchanged in the urine. Cautions: As for ciprofloxacin (Table A2.4). Avoid in patients with prolonged QTc interval. Pregnancy and lactation: Use during pregnancy or breastfeeding is not recommended because of the potential for arthropathy. Side effects: As for ciprofloxacin. QTc interval prolongation may occur. Dosing: Adults: 750 mg daily. Renal impairment: if the GFR is reduced to < 30 mL/min use 750–1,000 mg 3/week. Children: 7.5–10 mg/kg daily (maximum 750 mg).
Table A2.12 Kanamycin Pharmacokinetics: As for streptomycin (Table A2.21). Cautions: Contraindicated in myasthenia gravis or hypersensitivity to the drug. Use with caution in renal failure, impaired hearing, or vestibular function, and in neonates in whom dosing should be guided by plasma concentrations. Pregnancy and lactation: It crosses the placenta and may cause fetal ototoxicity or nephrotoxicity; avoid during pregnancy. As oral absorption is poor, breastfeeding is safe. Side effects: As for amikacin (Table A2.1). Nephrotoxicity; damage is related to accumulation in the proximal tubular cells; proteinuria and electrolyte disturbances occur; creatinine and potassium levels should be checked monthly, or more frequently in patients at greater risk of nephrotoxicity. The risk of ototoxicity is increased if renal function is impaired, in elderly patients and in those with a genetic predisposition. Monthly audiometry is advised in susceptible patients. Dosing: Adults: 15 mg/kg in a single daily intramuscular dose (usually 750–1,000 mg, 5–6 days/week; maximum daily dose 1.5 g); during continuation phase treatment, the dosing interval is increased such that three doses are given in a week. Children: 15–30 mg/kg/day (maximum 1 g). Renal failure: drug concentration monitoring is advised; for GFR < 30mL/min 12–15 mg/kg can be given 2 or 3/week. Rotation of the injection site reduces local discomfort.
Table A2.14 Linezolid Pharmacokinetics: Oral absorption is complete. Peak concentrations are achieved in 1–2 hours. Distributed to well-perfused tissues. Metabolized largely by oxidation of the morpholine ring. About 30% is excreted unchanged in the urine. Elimination is more rapid in children. Cautions: Hypersensitivity to linezolid. Concomitant use of adrenergic drugs, serotonergic agents, tyramine-containing foods, or drugs that may cause myelosuppression. Pregnancy and lactation: Safety is not established. Use only if the potential benefit justifies the potential risk to the fetus. Side effects: Nausea and diarrhoea are common. Peripheral neuropathy (40–50%) and myelosuppression are common with prolonged use; anaemia (12–80% of MDR-TB patients in small series), neutropenia, leucopenia, thrombocytopenia, and pancytopenia have been reported. Moniliasis, pseudomembranous colitis, lactic acidosis, pancreatitis, and optic neuropathy may occur. Dosing: Adults: 400–600 mg 12 hourly. Children: 10 mg/kg 8 hourly.
Table A2.15 Moxifloxacin Pharmacokinetics: Absorption is good (about 90%) in the absence of divalent cations (see drug–drug interactions), and wide distribution occurs to the tissues. About 45% is excreted unchanged, via renal and biliary routes. Cautions: As for ciprofloxacin (Table A2.4). Avoid in patients with prolonged QTc interval. Pregnancy and lactation: Use during pregnancy or breastfeeding is not recommended because of the potential for arthropathy. Side effects: As for ciprofloxacin. QTc interval prolongation may occur. Dosing: Adults: 400 mg daily. Children: 7.5–10 mg/kg daily (maximum 400 mg). No dose adjustment in renal impairment or in patients with mild to moderate hepatic insufficiency.
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APPENDICES
Table A2.16 Ofloxacin
Table A2.19 Rifabutin
Pharmacokinetics: Absorption is essentially complete in the absence of divalent cations (see drug–drug interactions), and wide distribution occurs to the tissues including the CSF; 65–80% of a dose is excreted unchanged, by glomerular filtration and renal tubular secretion. Cautions: As for ciprofloxacin (Table A2.4). Avoid in patients with prolonged QTc interval. Pregnancy and lactation: Use during pregnancy or breastfeeding is not recommended because of the potential for arthropathy. Side effects: As for ciprofloxacin. Dosing: Adults: 800 mg daily or 400 mg 2/day. Renal impairment: if the GFR is reduced to < 30 mL/min the recommended dose is 800 mg 3/week. Children: 15–20 mg/kg in one or two doses (maximum daily dose: 800 mg).
Pharmacokinetics: Rifabutin is lipophilic; absorption is slowed by highfat meals and there is extensive intracellular distribution. It is metabolized in the liver; the half-life is approximately 45 hours (range: 16–69 hours); 5% of the unchanged drug is excreted in the urine. Cautions: Contraindicated in patients hypersensitive to rifamycins and those with severe hepatic or renal dysfunction. Use with caution in porphyria. Pregnancy and lactation: High doses in rats were associated with fetal abnormalities; insufficient human data. Side effects: Rash, nausea, vomiting, anorexia, abdominal pain and diarrhoea, headache, leucopenia, neutropenia, thrombocytopenia, and anaemia are common. The white blood cell and platelet counts should be monitored regularly. Uveitis and corneal opacities are a concern especially with higher doses or when drugs that inhibit its metabolism are used concurrently. Patients should be warned to report eye pain, redness, or loss of vision. Although elevated serum transaminase levels are common; hepatitis occurs in less than 1% of patients. Hypersensitivity reactions (flu-like syndrome, chest pain, eosinophilia, bronchospasm, shock) are reported rarely. Rifabutin colours urine, tears, and other body fluids red–orange; permanent staining of contact lenses may occur. Dosing: Adults: 300–450 mg daily. The dose may need adjustment when given with inhibitors or inducers of its metabolism. Children: dose not established.
Table A2.17 Para-aminosalicylic acid (PAS) Pharmacokinetics: Absorption is incomplete (60–65%); increased doses are sometimes required to reach therapeutic concentrations. CSF concentrations are 10–15% of those in plasma. Hepatic acetylation of PAS yields metabolites excreted by renal glomerular filtration and tubular secretion. Cautions: Contraindicated in those with allergy to aspirin or PAS. Avoid in advanced renal impairment as PAS may exacerbate acidosis. Use with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Pregnancy and lactation: Congenital defects have been described in babies exposed during the first trimester; avoid. Concentrations excreted in breast milk are low. Side effects: Common side effects include anorexia, diarrhoea, and hypothyroidism (thyroid-stimulating hormone (TSH) levels should be monitored; increased risk with concomitant ethionamide). Hepatitis occurs in 0.3–0.5%. Other reported effects include hypersensitivity reactions, goitre, a malabsorption syndrome, and prolonged prothrombin time. Dosing: Adults: 150 mg/kg/day or 10–12 g/day in two divided doses. Children: 150 mg/kg/day in two or three divided doses (maximum 12 g/day).
Prothionamide — See ethionamide table A2.9
Table A2.18 Pyrazinamide Pharmacokinetics: The drug is readily absorbed and widely distributed. It reaches concentrations in the CSF equal to those in the plasma. A small proportion (4–14%) is eliminated unchanged in the urine; the rest is metabolized in the liver. The half-life is 9–10 hours. Cautions: Contraindicated in cases of severe hepatic damage or porphyria. Use with caution in gout, diabetes, or renal impairment; hypersensitivity to pyrazinamide, isoniazid, ethionamide, or niacin. Liver function and serum uric acid concentrations should be monitored if possible. Pregnancy and lactation: No harmful effects to the human fetus or nursing infant are reported. Side effects: Hepatotoxicity occurs in < 1% of patients taking 25 mg/ kg/day, or less. High rates of toxic hepatitis limit the use of higher doses. Hyperuricaemia is common and associated with arthralgia, which is usually self-limiting; anti-gout therapy is sometimes required. Acute gout may be precipitated in susceptible patients. Gastrointestinal complaints include nausea, anorexia and vomiting and may be alleviated by taking the drug with food. Flushing, pruritus, and skin rashes may develop Photosensitivity, thrombocytopenia, and sideroblastic anaemia are rare. Dosing: Adults and children: 20–30 mg/kg daily (maximum 2 g/day). In renal impairment use doses at the lower limit of the recommended range; in end-stage renal failure, the dose frequency should be reduced to 3/week after dialysis.
962
Table A2.20 Rifampicin Pharmacokinetics: Oral absorption is reduced when it is taken with food. Bioavailability is also reduced by first-pass metabolism. CSF concentrations reach 10–20% of plasma concentrations. Distribution to other tissues is good. Protein binding is 80–90%. Hepatic metabolism is rapid, and elimination is enhanced with repeated doses due to autoinduction of the metabolic pathways. The half-life of 2–5 hours is prolonged in liver disease. Biliary excretion of rifampicin and its active metabolite (25-deacetylrifampicin) accounts for 60–65% of a dose, the remainder is excreted in the urine. Doses up to 10 mg/kg can be used safely in patients with renal insufficiency. Cautions: Avoid in patients with serious hypersensitivity reactions to rifampicin. Use with caution in hepatic dysfunction, alcoholism, and porphyria. Pregnancy and lactation: Vitamin K should be administered to the infant at birth because of the risk of postnatal haemorrhage. Although teratogenicity has been described in animals given high doses, adverse effects on the fetus have not been reported with wide use in humans. The small amounts excreted in breast milk are unlikely to be harmful to the nursing infant. Side effects: Elevated serum transaminase levels are common; progression of liver injury is unpredictable; clinical hepatitis is rare but may be fatal. Use of alcohol or other potentially hepatotoxic drugs enhances the risk of hepatitis developing. Inhibition of bilirubin excretion may cause jaundice at the onset of treatment, but this usually clears with ongoing therapy. Gastrointestinal effects include nausea and vomiting, anorexia, mild abdominal discomfort, and diarrhoea. Taking the drug with food may alleviate the symptoms, although administration on an empty stomach is recommended for optimal absorption. Hypersensitivity reactions are mainly associated with intermittent or discontinuous therapy and include a ‘flu-like’ syndrome with fever, urticaria, haemolysis, eosinophilia, thrombocytopenia, leucopenia, interstitial nephritis, and acute tubular necrosis. CNS effects such as drowsiness, headache, mental confusion, and muscular weakness are described. Induction of glucocorticosteroid metabolism may precipitate adrenal insufficiency. Rifampicin colours urine, tears, and other body fluids reddish-orange to reddish-brown; permanent staining of contact lenses may occur.
APPENDIX
2
Tuberculosis drug information
Dosing: Adults: 10 mg/kg (maximum 600 mg) in a single daily dose, or 3/weekly. Children: 10 mg/kg (up to 20 mg/kg for TB meningitis or miliary TB; maximum 600 mg) for daily and 3/week dosing regimens. High doses should be used with caution in communities with a high prevalence of infectious hepatitis. Intravenous: 10 mg/kg/day over 3 hours (maximum 600 mg/day). Hepatic impairment: dose should be reduced to 8 mg/kg/dose.
Table A2.21 Streptomycin Pharmacokinetics: Distributed rapidly to the extracellular fluid of the tissues following intramuscular injection. High concentrations are found in well-perfused tissues and in the urine. Penetration into the CSF is poor. Elimination is by renal excretion of the unchanged drug; the halflife of 2–3 hours is prolonged in renal impairment, and in neonates. Cautions: Contraindicated in patients with hypersensitivity to streptomycin or myasthenia gravis. Use with caution in renal failure, impaired hearing, or vestibular function. Pregnancy and lactation: Crosses the placenta and may cause fetal ototoxicity; avoid during pregnancy. As oral absorption is poor, breastfeeding is safe. Side effects: Dose-related ototoxicity affects vestibular more than cochlear function; it is initially reversible, but may become permanent; risk is increased if renal function is impaired; elderly patients are more susceptible; some are genetically predisposed. Renal toxicity is related to accumulation of the drug in the proximal tubular cells. Circum-oral tingling and numbness are common shortly after injection. Hypersensitivity and skin rash may occur. Dosing: Adults: 15–20 mg/kg/day given intramuscularly (maximum 1 g/day); the dose should be reduced to 10 mg/kg/day in the elderly (maximum 750 mg/day). After the intensive treatment phase the dosing interval should be increased to 2 or 3/week. Children: 20–40 mg/kg by daily injection (maximum 1 g/day). Renal impairment: dose intervals must be prolonged (GFR 10–50 mL/min, 24–72 hours; GFR < 10 mL/min, 72–96 hours).
SIDE EFFECTS OF ANTITUBERCULOSIS DRUGS Selected side effects of anti-TB agents are listed in Table A2.22, together with the associated drugs and brief comments. For a listing of side effects by agent, the individual profiles (above) should be consulted. Agents such as thioacetazone and amoxicillin/clavulanic acid, which are seldom used, or with restricted availability, have not been included. For management of adverse effects refer to Chapter 66.
DRUG–DRUG INTERACTIONS Drug–drug interactions associated with anti-TB agents are shown in Tables A2.23-2.26. Those involving the rifamycins are listed in Table A2.23 (rifampicin) and Table A2.24 (rifabutin). The interactions of isoniazid, pyrazinamide, ethambutol, and the aminoglycosides are described in Table A2.25, and those of ethionamide, PAS, the fluoroquinolones, cycloserine, and capreomycin appear in Table A2.26. The intention has been to list the interactions of clinical importance. For more comprehensive listings useful sources of information are listed at the end of the section. Moreover, as drug–drug interactions are an area of intensive research new information is available on an ongoing basis.
Terizidone — See cycloserine table A2.7
Table A2.22 Selected side effects of antituberculosis agents Gastrointestinal disturbance, or abdominal complaint Anorexia, nausea, abdominal discomfort and vomiting occur commonly; diarrhoea, occasionally. Rifampicin,a rifabutin Isoniazid Anorexia, nausea, abdominal discomfort and vomiting occur commonly; diarrhoea, occasionally. Pancreatitis occurs rarely. Pyrazinamide Mild nausea and anorexia are common. Severe vomiting and nausea are rare at the currently recommended doses. Ethambutol Anorexia, abdominal discomfort, nausea, and vomiting are uncommon (occurring in about 0.5%). Nausea and bloating, abdominal pain, vomiting, and diarrhoea occur commonly (in up to 2%). Gastritis, dry mouth, loss or Fluoroquinolonesb perversion of taste, and pseudomembranous colitis occur less frequently or rarely. Ethionamide Anorexia, nausea, abdominal discomfort, vomiting (often severe), diarrhoea, and metallic taste are very common. Weight loss may result. PAS Nausea, vomiting, abdominal pain, and diarrhoea are common. The granular form is better tolerated. Rarely, it is associated with peptic ulcers and gastric haemorrhage. Malabsorption of vitamin B12, folate, iron, and lipids may result in clinically important erythrocyte abnormalities. Clofazimine Diarrhoea, nausea, vomiting, and abdominal pain are usually dose related and uncommon with doses < 100 mg/day. Rarely, prolonged use of high doses may cause crystal deposition in the medullary sinuses of the spleen or mesenteric lymph nodes resulting in infarction of these tissues. Linezolid Diarrhoea is common; Clostridium difficile-associated colitis is rare; pancreatitis and lactic acidosis (which characteristically presents with recurrent nausea and vomiting) have been reported. Clarithromycin Abdominal pain, cramping, nausea, vomiting, and diarrhoea occur commonly (in about 3% of patients). Abnormal taste is reported to occur in 3%. Glossitis, stomatitis, oral candidiasis, pseudomembranous colitis, and pancreatitis are uncommon. (Continued)
963
APPENDICES
Table A2.22
Selected side effects of antituberculosis agents—(cont’d)
Skin rash Skin rashes occur during treatment in about 2% of TB patients without HIV infection. HIV-infected patients are about five times more likely to develop rashes during anti-TB treatment. Rifampicin Pruritus with or without rash occurs commonly (in up to 6% of patients). Hypersensitivity occurs in 0.07–0.3%. Urticaria, acneiform eruptions, pemphigoid reactions, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, sore tongue and mouth, and exfoliative dermatitis have also been reported. Rifabutin Implicated to cause rashes in < 0.1%. Isoniazid Acneiform eruptions are common. Pellagra-type dermatitis (responsive to niacin) is reported in malnourished patients. Rarely, hypersensitivity reactions such as rash with fever, or Stevens–Johnson syndrome, occur. Pyrazinamide Morbilliform rashes are usually self-limiting. Acne, maculopapular rashes, and photosensitive dermatitis are also reported. Hypersensitivity with urticaria and pruritus is rare. Ethambutol Pruritus and dermatitis occur. Rash may be associated with fever or arthritis; uncommonly (0.2–0.7%), discontinuation of the drug is required. Streptomycin Rashes are common and often associated with fever as part of a hypersensitivity reaction. Fluoroquinolones Rashes, urticaria, pruritus and photosensitivity reactions are uncommon (up to 0.5%). Rarely, maculopapular rash, erythema multiforme, and Stevens–Johnson syndrome occur. Ethionamide Photosensitivity may develop. Dermatitis or photosensitivity occurs uncommonly. Cycloserinec Clofazimine Red to brown discoloration of the skin and conjunctiva, dry skin and ichthyosis occur commonly. Pruritus, acneiform eruptions, skin rashes, and photosenstivity are less frequent. PAS Hypersenstitivity may cause pruritus, rashes, vasculitis, and exfoliative dermatitis. Clarithromycin Urticaria, Stevens–Johnson syndrome, and toxic epidermal necrolysis are rare. Mild skin eruptions are also reported in clinical practice. Capreomycin Hypersenstitivity reactions include urticaria, photosensitivity, and maculopapular rash. Hepatotoxicity Several anti-TB agents are associated with hepatic toxicity. The mechanisms are poorly understood. For many of the drugs, the risk of toxicity seems to be poorly related to dose. Rifampicin may potentiate the toxicity of isoniazid and pyrazinamide. The combination of rifampicin and pyrazinamide is associated with paradoxically high rates of hepatitis when used in healthy individuals for chemoprophylaxis. Rifampicin, rifabutin Mild increases in transaminase concentrations are common. Rifampicin-induced hepatitis is almost always in association with other drugs (2.7% with isoniazid). In addition to elevated hepatic transaminases, disproportionate increases in alkaline phosphatase and bilirubin may occur. Isoniazid Reported in about 0.6% when isoniazid is given alone. The risk is increased with concomitant use of rifampicin (2.7%), with other drugs, and in patients with chronic liver disease or regular alcohol consumption, women or older patients (2% in 50–64 year olds). Pyrazinamide Reported in < 1% of patients, but is more frequent with higher doses (> 40 mg/kg) and when used for longer periods. Fulminant hepatitis may result from continued dosing despite rising levels of liver enzymes. Fluoroquinolones Rarely associated with the development of hepatitis. Ethionamide The development of hepatitis is reportedly common (about 2%). Cycloserine Liver function test abnormalities are reported. PAS Hepatitis is uncommon (0.3%). It is usually accompanied by hepatomegaly, and often by leucocytosis, lymphadenopathy, and eosinophilia. Clarithromycin Hepatocellular or cholestatic hepatitis may occur rarely. Renal impairment Rifampicin Isoniazid Pyrazinamide Streptomycin, amikacin, kanamycin
Fluoroquinolones Capreomycin
PAS
Rarely (< 0.1%) causes interstitial nephritis and acute tubular necrosis; may be associated with a ‘flu-like’ syndrome. Interstitial nephritis is rare. It usually resolves on cessation of therapy. Interstitial nephritis has been reported to occur rarely. Renal toxicity occurs commonly (3.4%), and very commonly (in up to 20%) in the presence of other risk factors (such as pre-existing renal impairment and older age). Toxicity is related to the use of other nephrotoxic agents, the extent of exposure and aminoglycoside accumulation in the proximal tubular cells. It ranges from milder forms presenting with urinary casts, albuminuria, or defective ability to concentrate the urine, to acute renal failure. Interstitial nephritis occurs rarely. Nephrotoxicity is very common (> 20%) and often necessitates discontinuation of the drug; proteinuria and electrolyte disturbance (decreased potassium, sodium, magnesium, calcium and chloride concentrations, and alkalosis) are frequent. Elderly patients, patients with impaired renal function, and patients using other nephrotoxic drugs are at greater risk. Crystalluria may develop. It is prevented by maintaining an alkaline or neutral urinary pH.
Central nervous system toxicity Rifampicin Rifabutin Isoniazid
964
Drowsiness, confusion, headache, fatigue, ataxia, inability to concentrate, behavioural changes and weakness may occur; they are more likely with overdose. Headaches reported commonly. Seizures, psychosis, mental depression, euphoria or other mental changes, encephalopathy, tinnitus, and ataxia occur rarely. They are more likely to develop with higher doses, malnutrition and in slow acetylators.
APPENDIX
2
Tuberculosis drug information
Ethambutol Ethionamide Cycloserine
Fluoroquinolones
Clarithromycin
Confusion, disorientation, and headache occur uncommonly (in about 0.5%). Seizures, acute psychosis, anxiety, and depression are uncommon. Pellagra-like encephalopathy may be responsive to niacin. Nervous system side effects are common. Dose-related anxiety, confusion, depression, psychosis, aggression, irritability, paranoia, headache, vertigo, drowsiness, speech difficulty, tremor, paresis, hyperreflexia, dysarthria, paraesthesia, coma, and convulsions are reported. Pyridoxine may be helpful for prevention and treatment. Headache, dizziness, restlessness, drowsiness, anxiety, and insomnia (reported in about 0.5%) occur more commonly than emotional lability, depression, abnormal dreams, tremor, agitation, amnesia, and hallucinations. Seizures occur rarely, but are more common in patients with underlying CNS disease. Headache occurs commonly (in about 2%). Other side effects reported in clinical practice include anxiety, dizziness, insomnia, hallucinations, bad dreams, vertigo, tinnitus, disorientation, depersonalization, confusion, hearing loss, and convulsions.
Peripheral neuritis A higher incidence is reported in TB patients with HIV infection. Isoniazid Common. Pyridoxine (10–25 mg/day should be prescribed to prevent neuropathy in those at risk (patients with HIV infection, diabetes mellitus, chronic renal failure, alcoholism, malnutrition, patients > 65 years old, pregnant women, and patients taking anticonvulsant medications). Ethambutol Rare. Fluoroquinolones Rare. Ethionamide Less frequent; may respond to pyridoxine. Cycloserine Rare; may respond to pyridoxine. Linezolid An incidence of 40–50% has been reported with long-term use in small cohorts of MDR-TB patients. Circumoral paraesthesias Streptomycin
Common; occurring shortly after injection.
Optic neuritis Isoniazid Ethambutol
Ethionamide Linezolid PAS Uveitis Rifabutin
Rare. The risk is increased in malnourished patients and slow acetylators. Rare at the currently recommended doses. Reduced visual acuity or red–green colour discrimination. Usually associated with higher (> 25 mg/kg) daily doses and > 2 months of treatment; usually reversible after discontinuation of the drug. Patients with impaired renal function are at increased risk. Rare. Reported in two of a series of eight patients exposed to prolonged treatment for MDR-TB. Rare.
Rare with doses up to 300 mg but common (8%) with higher doses, or if clearance is inhibited by drugs such as macrolides or protease inhibitors.
Ototoxicity Streptomycin
Amikacin, kanamycin Capreomycin
Common. Vestibular damage is more likely than cochlear. Transient giddiness is common; severe and persistent giddiness, vertigo, tinnitus, ataxia, and deafness may occur with sustained exposure to high concentrations; infants and patients > 40 years are at greater risk; susceptibility is also associated with mutations in the 12S ribosomal RNA gene. Cochlear damage is common. High-frequency hearing loss, tinnitus, vertigo and ataxia occur. Vestibular damage, tinnitus, and deafness occur commonly. The elderly and in patients with renal impairment are at increased risk.
Neuromuscular blockade Aminoglycosides Capreomycin
Rare. Potentiated by anaesthesia, muscle relaxants, and myasthenia gravis. Partial neuromuscular blockade has been reported with high doses. Respiratory paralysis may follow rapid intravenous infusion.
Arthritis Pyrazinamide Ethambutol Arthralgia Rifabutin Isoniazid Pyrazinamide Fluoroquinolones PAS
Acute gout may be precipitated by inhibition of uric acid excretion. It is rare except in patients with pre-existing gout. Reduced renal clearance of uric acid uncommonly precipitates gout after prolonged administration.
Common (1–2%). The incidence is increased with higher doses. A rheumatic syndrome occurs rarely. Very common (up to 40%). More frequent with daily than with intermittent doses. It is usually mild and self-limiting. It may be related to elevated uric acid and the incidence is reduced in patients taking rifampicin concomitantly. Uncommon. It may be related to hyperuricaemia. May occur as part of a hypersenstivity reaction.
Tendinitis Fluoroquinolones
Rare. Tendon rupture has been reported.
Blood dyscrasias Rifampicin Rifabutin
Thrombocytopenia, neutropenia, and haemolytic anaemia occur rarely (<0.1%) and may be associated with a ‘flu-like’ syndrome. Common (> 1%). Leucopenia, neutropenia, thrombocytopenia, and anaemia are reported. (Continued)
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APPENDICES
Table A2.22
Selected side effects of antituberculosis agents—(cont’d)
Isoniazid Pyrazinamide Fluoroquinolones Ethambutol Streptomycin Cycloserine PAS Linezolid Capreomycin Clarithromycin Coagulopathy Rifampicin PAS
Thrombocytopenia, neutropenia, haemolytic anaemia, sideroblastic anaemia (pyridoxine responsive), and aplastic anaemia are reported rarely. Rarely, sideroblastic anaemia, and thrombocytopenia. Rare; leucopenia. Rare; thrombocytopenia. Rare; agranulocytosis and aplastic anaemia. Megaloblastic anaemia has been reported. Leucopenia, agranulocytosis, thrombocytopenia, and eosinophilia have been reported. Coombs positive haemolytic anaemia may develop in patients with G6PD deficiency. Myelosuppression is common with prolonged use; anaemia (reported in 12–80% of MDR-TB patients in small series), neutropenia, leucopenia, pancytopenia, and thrombocytopenia have been reported. Leucopenia, leucocytosis, eosinophilia, and (rarely) thrombocytopenia have been reported. Leucopenia and thrombocytopenia are reported uncommonly.
Rare. Postnatal haemorrhages (probably related to reduced vitamin K levels) have been reported in mother and infant when rifampicin is administered during the last few days of pregnancy. Hypoprothrombinaemia has been reported.
Lactic acidosis Linezolid
Linezolid inhibits mitochondrial protein synthesis in a dose- and-time-related manner; several cases of lactic acidosis have been reported.
Heart failure Cycloserine
Reported with high doses.
QTc interval prolongation Fluoroquinolones Clarithromycin
Uncommon. Reported in association with gatifloxacin and moxifloxacin. Rarely, arrhythmias occur. Ventricular tachycardia and torsades de pointes have also been reported.
Hypertension Fluoroquinolones
Uncommon.
Peripheral oedema Fluoroquinolones
Uncommon.
Vasodilation/flushing Pyrazinamide Isoniazid Fluoroquinolones
Very common; in up to 30% of patients within 30 min of ingestion. The symptoms are transitory, not associated with harmful effects, and tolerance usually develops after repeated doses. Rare. May be related to ingestion of food or beverages with high monoamine concentrations (such as cheese and wine). Rare.
Vasculitis Isoniazid Fluoroquinolones
Rare. Rare.
‘Flu-like’ syndrome Rifampicin Rifabutin PAS
Uncommon. More likely with intermittent doses (0.4–0.7% when 600 mg is used twice weekly). Uncommon (<1%). Lo¨ffler’s syndrome, an infectious mononucleosis- or lymphoma-like syndrome, has been reported.
Drug-induced lupus Isoniazid Rifampicin, rifabutin
With prolonged therapy, 20% develop antinuclear antibodies. The clinical syndrome necessitating drug discontinuation develops uncommonly (in <1%). Rare. Malaise, myalgia, arthritis, and peripheral oedema in association with positive antinuclear antibody have been reported. Increased risk may be related to concurrent use of a microsomal enzyme inhibitor such as clarithromycin or ciprofloxacin.
Anaphylaxis Fluoroquinolones Rifampicin Clarithromycin
Rare. Less severe allergic reactions (localized periorbital or perioral oedema, swelling of tongue, dizziness, palpitations, urticaria, bronchoconstriction) also occur. Rare. Rare.
Anaphylactoid reaction Ethambutol
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Rare.
APPENDIX
Tuberculosis drug information
Vaginitis Fluoroquinolones
2
Reported commonly. May be related to moniliasis.
Endocrine effects Rifampicin
Rare. In patients with compromised adrenal function; adrenocortical insufficiency may be precipitated by rifampicin-induced induction of cortisol metabolism. Gynaecomastia is reported rarely. Rare. Gynaecomastia, alopecia, impotence, amenorrhoea, and hypothyroidism, or goitre, have been described. The development of hypothyroidism/goitre is relatively common. The incidence is higher in patients taking ethionamide concomitantly, and with prolonged treatment. Thyroid function normalizes after cessation of the drug.
Isoniazid Ethionamide PAS Dysglycaemia Pyrazinamide Ethionamide Fluoroquinolones
Increases adipose uptake of dextrose thus lowering blood sugar; may complicate glycaemic control in diabetics. May cause hypoglycaemia. Diabetes may be difficult to control on initiation of ethionamide. Abnormal glucose homeostasis. Hyper- or hypoglycaemia was reported in 1.1%, 0.2%, 0.3%, and 0.3% of elderly patients prescribed gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin respectively. Hypoglycaemia has been reported. Hypoglycaemia has been reported uncommonly.
PAS Clarithromycin Dyslipidaemia Fluoroquinolones
Rare.
Body fluid discoloration Rifampicin, rifabutin
a b c
Universal. Reddish-orange to reddish-brown discoloration of urine, tears, saliva, sweat, and sputum should be expected. The use of soft contact lenses should be avoided as they may become stained.
There is considerable overlap in the toxicity profiles of rifampicin and rifapentine; most of the side effects of rifampicin can be considered to apply to rifapentine. Ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Adverse events reported for cycloserine can be considered to apply to terizidone too.
Table A2.23 Selected drug–drug interactions involving rifampicin Anaesthetics
Inhalational hydrocarbons (e.g. halothane; except isoflurane) Ropivacaine, alfentanil, morphine, codeine
Anticoagulants
Warfarin
Anticonvulsants
Phenytoin, lamotrigine, valproic acid
Antidiabetic agents
Sulphonylureas, biguanides, rosiglitazone
Antihistamines Anti-infectives
Fexofenadine Protease inhibitors (PI)a
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)a Antibacterials
Induction of anaesthetic metabolism may increase the risk of hepatotoxicity. Enhanced clearance of anaesthetic agent; increased doses generally required. Enhanced warfarin metabolism may lead to markedly reduced anticoagulant effectiveness; rifampicin withdrawal can precipitate bleeding in patients established on anticoagulants; prothrombin time monitoring is indicated and warfarin dose increases of two to three times may be required. Induction of anticonvulsant metabolism may result in an increased frequency of seizures. Monitoring of anticonvulsant concentrations, with dose adjustments as necessary, is advised. Enhanced metabolism of tolbutamide, chlorpropamide, glyburide, glimepiride, repaglinide, biguanides and rosiglitazone may result in reduced effectiveness. Intensified blood glucose monitoring advised; dose adjustments may be necessary. Enhanced metabolism may reduce antihistame effect. Dramatic reductions in protease inhibitor levels (including ritonavir-boosted protease inhibitors) result in subtherapeutic levels; ritonavir levels less affected (#35%). Addition of extra ritonavir to PI regimens can counteract rifampicin’s induction but the approach is not adequately evaluated and may be associated with an increased risk of hepatotoxicity.b Combination should be avoided if possible. Reduced concentrations of efavirenz (20–25%) and nevirapine (30–50%); clinical importance not established. Significantly reduced levels of clarithromycin, erythromycin, doxycycline, trimethoprim and sulfamethoxazole may result; alternate antibiotics should be considered. Combination with chloramphenicol has potential for higher risk of aplastic anaemia and reduced chloramphenicol concentrations; avoid combination. (Continued)
967
APPENDICES
Table A2.23
Selected drug–drug interactions involving rifampicin—(cont’d) Antifungals
Antimalarials Antimycobacterials
Bronchodilators
Theophylline, aminophylline, oxtriphylline
Cardiovascular drugs
Digoxin, digitoxin Quinidine Amiodarone, quinidine Mexiletine, tocainide
Hormone therapy
Verapamil, nifedipine, diltiazem, felodipine, nisoldipine, amlodipine, propranolol, metoprolol, carvedilol, enalapril, losartan, disopyramide, tocainide, propafenone Oral contraceptives Tamoxifen Levothyroxine
Hypolipidaemics
Simvastatin, fluvastatin, lovastatin
Immunosuppressives
Ciclosporin, tacrolimus
Corticosteroids
Narcotics
Methadone
Psychotropic agents
Nortriptyline, amitriptyline
Miscellaneous
Sertraline Bupropion, haloperidol, risperidone, quetiapine, benzodiazepines, buspirone, clomipramine, clozapine, zolpidem, zopiclone Antacids Alcohol Bone marrow depressants Ondansetron Sulfasalazine Vitamin D
Metabolism of azole antifungals is enhanced; increased fluconazole doses may be required. Ketoconazole, itraconazole and voriconazole should be avoided when possible as more substantial reductions occur. Atovaquone, mefloquine and quinine concentrations may be significantly reduced; alternative agents should be considered. Increased risk of hepatotoxicity with isoniazid. High rates of hepatotoxicity in healthy individuals treated for latent TB infection with pyrazinamide and rifampicin. Concentrations of dapsone may be substantially reduced. Clofazimine may retard rifampicin absorption. Induction of microsomal enzymes by rifampicin may cause concentration reductions requiring dose adjustments. Enhanced elimination may result in subtherapeutic concentrations of digoxin. Digoxin concentration monitoring recommended. Quinidine concentration monitoring advised; may require increased dose. Increased antiarrhythmic metabolism; avoid combination (or monitor quinidine levels if possible). Clearance is increased; monitor dysrhythmia control; dose adjustment may be required. Enhanced elimination of cardiovascular agent. Clinical monitoring recommended. May require dose adjustment or use of an alternative agent. Enhanced elimination may result in inadequate protection against conception. Substantially reduced tamoxifen concentrations; may require alternate therapy or a rifampicin-sparing regimen. TSH serum concentrations should be monitored and the levothyroxine dose increased if necessary. Monitoring of hypolipidaemic effect is advised as increased doses of, or substitution of, hypolipidaemic agent may be required. Substantially reduced immunosuppressive concentrations. Combination best avoided. Dose adjustment and monitoring required. Enhanced metabolism of corticosteroids may reduce efficacy or precipitate adrenal insufficiency. Corticosteroid doses may need to be increased two to three times. Monitor clinically. Narcotic withdrawal precipitated by use of rifampicin in up to 70%; two or three times the usual dose may be required. Concentration monitoring of the tricyclic antidepressant is advised. Increased doses or use of an alternative agent may be required. Serotonin reuptake inhibitor withdrawal may be precipitated. Bupropion concentrations may be reduced. Increased doses or use of an alternative psychotropic agent may be required. Clinical monitoring is recommended. Absorption of rifampicin may be reduced; avoid coadministration. Increased risk of hepatotoxicity. Concurrent use of rifampicin may enhance leucopenic and/or thrombocytopenic effects; close monitoring is advised. Enhanced metabolism of ondansetron may result in reduced concentrations. Sulfasalazine concentrations reduced. Reduced 25-hydroxyvitamin D and 1alpha 25-dihydroxyvitamin D
Rifampicin is a potent inducer of several important enzymes and drug transporters affecting the disposition of drugs including cytochrome P450 (CYP) 2B6, CYP2C8, CYP2C9, and CYP3A4, phase II enzymes (e.g. such as UDP-glucuronosyltransferases, sulphonyltransferases and glutathione-S-transferases), and transmembrane protein drug transporters (e.g. p-glycoprotein). The effect is maximal after a few days of repeated doses and lasts for about 2 weeks following cessation of rifampicin. Rifapentine has similar actions but is less potent. a Refer to Chapter 60. b Several studies have reported raised hepatic transaminase levels or hepatitis in a substantial proportion of patients receiving cotreatment with protease inhibitor-based antiretroviral (ARV) regimens with added ritonavir (up to 400 mg twice daily) and anti-TB drug regimens including rifampicin, isoniazid, and pyrazinamide. Potential confounding factors include hepatitis B or hepatitis C virus infection, advanced HIV infection and disseminated TB. However, studies in healthy volunteers receiving rifampicin with increased doses of protease inhibitors have reported high rates of hepatitis.
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APPENDIX
2
Tuberculosis drug information
Table A2.24 Selected drug–drug interactions involving rifabutin Anti-infectives
Protease inhibitors Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Antibacterials Antifungals
Immunosuppressives
Isoniazid Ciclosporin, tacrolimus
Narcotics
Methadone
a
Reduced protease inhibitor concentrations and increased rifabutin concentrations with risk of uveitis. Dose adjustments required.a Rifabutin concentrations may be reduced; increased dose of rifabutin is recommended.a Raised rifabutin concentrations (and increased risk of uveitis and neutropenia) when CYP3A4 inhibitors such as clarithromycin or ciprofloxacin are administered concurrently. Azoles such as fluconazole inhibit rifabutin’s metabolism, increasing the risk of uveitis and neutropenia. Potential for increased frequency and severity of haematological reactions. Less potent reductions in immunosuppressive concentrations than with rifampicin; monitoring advised. Unlike combination with rifampicin, methadone withdrawal is infrequent.
Refer to Chapter 60.
Table A2.25 Drug–drug interactions associated with isoniazid, pyrazinamide, ethambutol, and aminoglycosides Isoniazid Alcohol Antacids
Anticonvulsants
Antidiabetic agents Anti-gout agents
Corticosteroids
Pyrazinamide
Increased risk of hepatotoxicity. Isoniazid metabolism enhanced. Aluminium-containing antacids may reduce isoniazid absorption.
Ethambutol
Absorption of ethambutol may be reduced; avoid coadministration.
Isoniazid may inhibit phenytoin, carbamazepine and diazepam metabolism.a Increased risk of hepatotoxicity with carbamazepine.b Valproate toxicity may be increased. Antagonizes hypoglycaemic effect of insulin. Dose adjustment of anti-gout agent may be necessary as pyrazinamide inhibits uric acid clearance. Prednisolone enhances renal elimination of isoniazid.
Didanosine
Absorption of ethambutol may be reduced; avoid coadministration.
Disulfiram Diuretics
Increased risk of disulfiram-induced psychosis.
Enflurane Levodopa Nephrotoxic and ototoxic agentsc
Enhanced defluorination; significance unknown. Risk of flushing, palpitations, hypertension.
Additive potential for increased uric acid concentrations.
Additive potential for increased uric acid concentrations.
Protease inhibitors
Enhanced nephrotoxicity.
Enhanced risk of nephrotoxicity and ototoxicity. Increased risk of neuromuscular blockade; avoid combination.
Neuromuscular blocking agents
Neurotoxic medications Paracetamol
Aminoglycosides
Increased risk of CNS effects, e.g. cycloserine, ethionamide. Increased risk of hepatotoxicity; avoid large doses of paracetamol. Potentially increased risk of hepatotoxicity.d
Increased risk of neurotoxicity.
Potentially increased risk of hepatotoxicity.d (Continued)
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APPENDICES
Table A2.25
Drug–drug interactions associated with isoniazid, pyrazinamide, ethambutol, and aminoglycosides—(cont’d) Isoniazid
Pyrazinamide
Rifampicin
Increased risk of hepatotoxicity
High rates of hepatotoxicity in healthy individuals treated for latent TB infection.
Theophylline, aminophylline, oxtriphylline Vitamin B6
Inhibition of bronchodilator metabolism.
Warfarin
Ethambutol
Aminoglycosides
Antagonism of gamma-aminobutyric acid (GABA) formation by isoniazid may lead to neurotoxicity. Decreased hepatic metabolism of warfarin might necessitate dose adjustment.
a
When rifampicin and isoniazid are given together the overall effect is usually to decrease the concentrations of drugs such as phenytoin and diazepam. Increased formation of intermediate metabolites of isoniazid, when given with carbamazepine, may confer a greater risk of hepatotoxicity. c For example, aminoglycosides, capreomycin, colistin, polymyxin B, vancomycin. d Several studies have reported raised hepatic transaminase levels or hepatitis in a substantial proportion of patients receiving co-treatment with protease inhibitor-based antiretroviral regimens with added ritonavir (up to 400 mg twice daily) and antitubercular drug regimens including rifampicin, isoniazid and pyrazinamide. Potential confounding factors include hepatitis B or hepatitis C virus infection, advanced HIV infection and disseminated tuberculosis. However, a study in healthy volunteers receiving rifampicin, saquinavir and ritonavir reported high rates of hepatitis. b
Table A2.26 Drug–drug interactions of ethionamide, PAS, fluoroquinolones, cycloserine, and capreomycin Ethionamide Alcohol
PAS
Fluoroquinolones
Psychotic reactions have been reported.
Bronchodilators such as theophylline Didanosineb
Absorption of digoxin reduced by approximately 20%. Impaired absorption of PAS; avoid concurrent administration. Potentially increased risk of hepatotoxicity. Inhibited acetylation of isoniazid may lead to increased concentrations.
Diphenhydramine
Ethionamide Isoniazid
Minerals
Substantially reduced absorption of fluoroquinolonesb Clearance is reduced leading to increased bronchodilator concentrations. Absorption of fluoroquinolones may be reduced; avoid coadministration. Gatifloxacin increases digoxin concentrations.
May reduce fluoroquinolone absorptionb
Nephrotoxic and ototoxic agentsa
Neurotoxic medications
Phenytoin
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Capreomycin
Increased risk of seizures.
Antacids
Digoxin
Cycloserine
Enhanced risk of nephrotoxicity and ototoxicity. Increased risk of CNS effects when used with isoniazid or cycloserine.
Increased risk of CNS effects when used with isoniazid or ethionamide. Hepatic metabolism of phenytoin is inhibited; monitoring of phenytoin concentrations is advised.
APPENDIX
Tuberculosis drug information
Probenecid
Competitive excretion; PAS levels increased 2–4
Warfarin
Enhanced hypoprothrombinaemic effect; dose adjustment of anticoagulant may be required.
2
Inhibition of tubular secretion of fluoroquinolones may result in substantially increased plasma concentrations. Increased anticoagulation may occur. The prothrombin time should be monitored.
a
For example, aminoglycosides, capreomycin, colistin, polymyxin B, vancomycin. Divalent cations markedly reduce the absorption of fluoroquinolones. The interaction has been associated with failure of antibiotic therapy. Fluoroquinolones should not be administered within 2 hours of a dose of antacids containing aluminium, calcium or magnesium. Coadministration with sucralfate, the chewable tablet form of didanosine, iron, magnesium, calcium or zinc (or vitamin or dietary supplements containing a significant amount of these cations) should be avoided.
b
SOURCES OF INFORMATION Blumberg HM, Burman WJ, Chaisson RE, et al.; American Thoracic Society, Centers for Disease Control and Prevention; Infectious Diseases Society. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of
America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167(4):603–662. Sweetman SC (ed.). Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005. USP DI Volume 1, Drug Information for the Health Care Professional, 26th edn. Thomson Micromedex, 2006. World Health Organization. Guidelines for the Programmatic Management of Drug-resistant
Tuberculosis (WHO/HTM/TB/2006.361). Geneva: World Health Organization, 2006. World Health Organization. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children (WHO/HTM/TB/ 2006.371; WHO/FCH/CAH/2006.7). Geneva: World Health Organization, 2006.
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APPENDIX
3
Web sources of information on tuberculosis and global organizations supporting tuberculosis control Ernesto Jaramillo
The Stop TB strategy is used here as the framework to present the most useful and relevant websites on TB control by 2007.
STRENGTHENING BASIC DIRECTLY OBSERVED TREATMENT, SHORT COURSE (DOTS) AND TUBERCULOSIS CONTROL IN GENERAL http://www.msh.org/ Management Sciences for Health is a US-based public health technical agency that works on different aspects of TB control. http://www.doctorswithoutborders.org/news/tuberculosis/ Doctors without Borders or Me´decins Sans Frontie`res is an independent humanitarian technical agency that provides medical care, including TB diagnosis and treatment, and advocates for improving global TB control policies. http://www.kncvtbc.nl/ KNCV-Tuberculosis Foundation is a Dutch technical agency working in TB control nationally and internationally. http://www.worldlungfoundation.org/ World Lung Foundation works in partnership with organizations throughout the world working in lung health. http://www.equi-tb.org.uk/ Equity-TB promotes the implementation of pro-poor strategies, which enhance care and support for TB among the poorest. http://www.iuatld.org/ The International Union against Tuberculosis and Lung Disease (the Union) works to prevent and control lung diseases including TB. http://www.path.org/ PATH is an international non-profit organization supporting TB control efforts. http://www.stoptb.org/ The Stop TB Partnership comprises a network of more then 500 organizations working together to achieve the goal of world free. It operates through a Secretariat and seven working groups listed below in this appendix. http://www.damienfoundation.org The Damien Foundation promotes sustainable, accessible and high-quality TB control programmes. http://www.who.int World Health Organization is the UN leading agency in global public health policy and technical assistance.
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ADDRESS TUBERCULOSIS/HUMAN IMMUNODEFICIENCY VIRUS (HIV), MULTIDRUG-RESISTANT TUBERCULOSIS AND OTHER CHALLENGES IMPLEMENT COLLABORATIVE TUBERCULOSIS/HIV ACTIVITIES http://www.tbhiv-create.org/ CREATE is a consortium of organizations implementing research studies to assess the impact of new approaches for controlling TB/acquired immunodeficiency syndrome (AIDS). http://www.unaids.org/en/ UNAIDS brings together the efforts and resources of 10 UN system organizations to the global AIDS response. http://www.aidsinfonyc.org/tag/ Treatment Action Group is an independent AIDS research and policy think tank advocating for better tools for preventing and treating AIDS, including TB. http://www.hdnet.org/v2/home/ Health and Development Networks facilitates information, dialogue and advocacy approaches on HIV and TB control.
PREVENT AND CONTROL MULTIDRUG-RESISTANT TUBERCULOSIS http://www.pih.org Partners in Health delivers healthcare and training and advocates and conducts research in MDR-TB control. http://www.wma.net/e/ The World Medical Association has the only web-based training course on MDR-TB based on WHO guidelines. http://icn.org The International Council of Nurses has a global TB/MDR-TB project to train nurses on MDR-TB management. http://www.lillymdr-tb.com/ The Lilly MDR-TB Partnership is a public–private health initiative promoting capacity building in MDR-TB management. http://www.ihf-fih.org The International Hospital Federation (IHF) has a TB and MDR-TB-control training manual for hospital managers. http://www.mdr-tb
APPENDIX
Tuberculosis and global organizations supporting tuberculosis control
The State Agency of Tuberculosis and Lung Diseases of Latvia houses the first WHO Collaborating Centre for Research and Training in Management of Multidrug-Resistant Tuberculosis.
CONTRIBUTE TO HEALTH SYSTEM STRENGTHENING http://ntiindia.kar.nic.in/ The National Tuberculosis Institute of Bangalore, India, is a WHO Collaborating Centre for TB research and training. http://www.urc-chs.com/ University Research Corporation helps government and private sector clients to design, operate and evaluate programmes that address health, social and educational needs, including TB. http://www.ghwa.org/ The Global Health Workforce Alliance is a partnership working on solutions to the healthcare workforce crisis. http://hs2020.org/ Health systems 20/20 is USAID’s global health project, mostly focused in Africa, addressing health system barriers to accessing health services. http://www.hsanet.org/ Health Systems Action Network is a global network working to strengthen health systems. http://www.idpintl.org/ International Development Projects (IDP) works to strengthen DOTS and public health services in developing countries.
EMPOWER PEOPLE WITH TUBERCULOSIS AND COMMUNITIES ADVOCACY, COMMUNICATION AND SOCIAL MOBILIZATION http://www.results.org/ RESULTS is a non-profit grassroots advocacy organization working to create political will for TB control globally. http://www.tbalert.org/ TB Alert is a UK-based charity, focused on patient advocacy and public awareness of TB globally. http://www.weforum.org/en/initiatives/globalhealth/index.htm The Global Health Initiative engages businesses in public– private partnerships to tackle HIV/AIDS, TB, malaria and health systems. http://www.afroglobal.org/ Afro Global Alliance Initiative is a non-profit and non-governmental organization forum working to support efforts to improve public health in Africa, including TB control programmes. http://www.soros.org/initiatives/health The Open Society Institute’s Public Health Program aims to promote health policies, including TB, based on social inclusion, human rights, justice and scientific evidence.
COMMUNITY PARTICIPATION IN TUBERCULOSIS CARE http://www.ifrc.org/ The International Federation of Red Cross Societies implements TB-patient-support programmes aimed at the most vulnerable.
3
PATIENTS’ CHARTER FOR TUBERCULOSIS CARE http://www.worldcarecouncil.org/ The World Care Council is a new non-government organization mobilizing to turn approved recommendations for the standards of care into practice. http://www.tbsurvivalproject.org, This advocacy website designed and managed by Paul Thorn engages MDR-TB and TB patients worldwide, providing information and patient resources.
ENABLE AND PROMOTE RESEARCH http://www.nitd.novartis.com/ Novartis Institute for Tropical Diseases is a public–private partnership dedicated to finding new drugs for diseases such as TB. http://www.gatesfoundation.org/ The Bill and Melinda Gates Foundation is a major donor supporting the development of innovative approaches to preventing, diagnosing and treating TB. http://www.jata.or.jp/ The Japanese Research Institute of Tuberculosis works in basic, clinical and epidemiological TB research. http://www.trc-chennai.org/ The Tuberculosis Research Centre of Chennai does clinical and operational research on TB. http://www.doe-mbi.ucla.edu/TB/ The TB Structural Genomics Consortium is a network of international institutions working in structural genomics of mycobacteria. http://www.aeras.org/ The Aeras Global TB Vaccine Foundation works in the development of new TB vaccines. http://www.finddiagnostics.org/ The Foundation for Innovative New Diagnostics develops, compares, evaluates and promotes uptake of new diagnostic approaches to infectious diseases. http://www.tballiance.org The TB Alliance is a not-for-profit partnership working in the development of new anti-TB drugs.
OTHER SOURCES http://www.cdcnpin.org/scripts/subscribe.asp#journal The TB-Related News and Journal Items Weekly Update is an electronic mailing list managed by the US Centers for Disease Control and Prevention (CDC), compiling abstracts of TB-related articles published in peer-reviewed journals, lay media reports on TB, timetable of scientific events and even vacancy notes published by organizations working in TB control. http://www.scidev.net/ms/tuberculosis/ This is a hub for news on research and policy in TB control, managed by Science and Development Network.
ACKNOWLEDGEMENT Many thanks to Ms Rachel Green, intern at the WHO Stop TB Department during the 2007 summer, for combing the web to collect and produce the first shortlist of 95 websites on which this appendix is based.
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Keertan Dheda and Alimuddin I Zumla
It is now widely acknowledged that, in addition to scaling up the directly observed treatment, short course (DOTS) strategy, investment in research and development (R&D) of new tools to fight TB is urgently needed if the disease, including drug-resistant and human immunodeficiency virus (HIV)/TB coinfection, is to be eliminated. However, TB R&D, relative to other diseases, is grossly underfunded. For example, the US National Institutes of Health (NIH) spent more on R&D of anthrax and smallpox (individually) than it did on TB in 2005. The Treatment Action Group, a New York-based activist think tank that works to strengthen research, policy and programmes that can effectively address HIV/acquired immunodeficiency syndrome (AIDS) and related issues, estimates that, to lay a sound scientific foundation for the elimination of TB, at least $2 billion needs to be spent annually on R&D compared with the current $393 million.1 Moreover, to achieve the goals set forth in The Global Plan to Stop TB,2 there is a need to draw up a comprehensive global TB R&D agenda covering key areas of need, i.e. basic science, operational and behavioural research, and new tools to fight TB (drugs, diagnostics and vaccines). There is also a need to drive progress and prevent duplication for global coordination and tracking of TB R&D funding (not done at present) and to support policies that strengthen healthcare systems. These activities should be coordinated at international, national and funding agency level. Donors should and are supporting public–private product development partnerships to facilitate the development of new tools to fight TB. Thus, not only should funding for TB research increase drastically but funding activities should be annually updated and coordinated to cover the entire spectrum of activities required for TB elimination. Other aspects of TB research funding deserve mention. Recently there has been a move, by some funding agencies, towards supporting a few single well-established, investigator-led multinational consortia, rather than individual investigators performing well-defined hypothesis-driven projects. The advantages of this strategy include the undertaking of adequately powered studies by scientists from different disciplines and countries and including private–public partnerships. It is likely, however, that both approaches are needed if innovative solutions to tackle the TB pandemic are to be found. Kaufmann and Parida3 have recently reviewed the dynamics and merits of ‘push’ (funding based on a proposed research plan) and ‘pull’ (agencies promising a secure market and fixed purchase price agreed in advance) research programmes (see Fig. A4.1). Traditional push strategies for the development of new drugs, diagnostics and vaccines may be insufficient and pull strategies including
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incentives such as tax reduction for companies, a tiered price system (for developed vs poor countries) and synergy between private companies and the public sector may be required. All stakeholders, including government agencies, ministries and TB activists, should be incorporated into the planning of research projects. Large-scale funding is required for setting up research and recruitment infrastructure and capacity, which is lacking in highburden countries, to evaluate new tools to fight TB (drugs, vaccines and diagnostics). Finally, an important aspect raised in Treatment Action Group’s (TAG) report on R&D funding deserves mention. International and community advocacy must be supported by funding agencies to raise the political profile of TB internationally and
Blockbuster
Profit
4
Tuberculosis research funding
Preclinical
Clinical
Market
TB
Time
Investment
APPENDIX
Decrease investment (Push programmes)
Increase profit (Pull programmes)
Push programmes R&D tax credits Publicprivate partnership
Pull programmes Two-price system Market guarantee mechanism Tax credits on sales
Reduce cost
Increase revenues
Fig. A4.1 Research development costs of new tools (vaccines, diagnostics and drugs) are high. Moreover, despite considerable financial investment, the success of newly developed interventions are not guaranteed and neither are profits to companies to cover their development costs. These factors have hindered the development of new interventions over the past several decades. Thus conventional ‘push’ mechanisms to decrease development costs must be in synergy with ‘pull’ mechanisms that will drive commercial development and public–private partnership. Kaufmann SH, Parida SK. Changing funding patterns in tuberculosis. Nat Med 2007;13:299–303.
APPENDIX
4
Tuberculosis research funding
within wealthy nations. The effect of this strategy is illustrated by the galvanizing of political commitment by HIV activists in the 1980s, which facilitated the investment of $30 billion by the NIH in HIV research over the past two and a half decades. In Table A4.1, courtesy of TAG, are listed the key R&D funding agencies in 2005–2006 who contributed $400 million towards TB-related research activities. Approximately 70% came Table A4.1 Top 40 funders of tuberculosis R&D reported to the Treatment Action Group as of October 2006 Rank
Donor
Total (in $)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
NIAID/NIH Gates Foundation Medical Research Council (UK) Other institutes and centres/NIH Centers for Disease Control Company X Wellcome Trust NHLBI/NIH European Commission 6th Framework Otsuka Institut Pasteur AstraZeneca USAID Inserm TB Research Center (ICMR), India Ministry of Science and Technology, India Netherlands Ministry of Foreign Affairs (DGIS) Max Planck Institute Canadian Institute of Health Research Novartis Department for International Development (DFID) Russian TB Institutesa Rockefeller Foundation Ellison Medical Foundation Global Fund to Fight AIDS, Tuberculosis and Malariab Research Institute for TB, Japan Anti-TB Association Sequellac Brazil (in aggregate) Food and Drug Administration Company Y Swedish International Development Agency Development Cooperation of Ireland Ministry of Public Health, TB cluster, Thailand Netherlands Organization for Scientific Research (NWO) Swiss Agency for Development and Cooperation KNCV Tuberculosis Foundation Danish International Development Agency (Danida) All India Institute of Medical Sciences Ministry of Foreign Affairs, France Eli Lilly Foundation TOTAL
120,273,000 57,411,457 30,887,839 20,334,300 19,903,000 18,640,160 18,081,359 17,117,000 13,322,711 12,300,000 8,472,800 8,000,000 6,694,000 5,721,560 5,313,133 3,168,488 3,168,488 2,500,000 2,376,098 2,255,193 2,008,832
22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
a
1,930,343 1,750,000 1,650,000 1,648,083 1,487,961 1,400,000 755,587 651,231 500,000 486,599 360,000 287,050 199,716 195,099 170,066 170,344 154,821 127,092 113,660 392,713,089
Aggregate spending of four Russian Federation TB institutes. Global Fund Figures estimated based on their reported activities. c Sequella spent $3.5 million; $2.1 million from NIH not counted since. Reproduced with permission from the TAG. b
Round 1 Round 2
TB activities to date
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Planning 3.0M
TB/HIV VAX
Sequella 25.0M
DX Drugs
CREATE 44.6M Aeras 82.9M
TDR 10.0M FIND 23.3M TB Alliance 25.0M
TB Alliance 104.0M Accelerator 40.0M
Fig. A4.2 Summary of the Gates Foundation grant packages previously allocated and in evolution. Funding by the Gates Foundation, and other agencies, has led to the formation of non-profit-making entities such as Aeras, FIND, TB Alliance, TB-Vac, CREATE, TDR, EDCTP and WHO MDR-TB, which have provided linkages and collaborative mechanisms for specific research agendas and facilitated the involvement of private companies and scientists from other disciplines.
from the public sector (including international development agencies from the USA and European Union (e.g. FP5, FP6 and FP7 programmes), 20% from philanthropic private foundations (the largest being the Gates Foundation, which had an endowment of $29.2 billion by the end of 2005; see Fig. A4.2), 11% from industry and < 1% from multilateral agencies such as the Global Fund.1 The NIH sponsored almost 40% of all TB research reported ($158 million or 0.55% of the NIH budget, approximately 52 cents per US resident).1 A total of $400 million was invested in TB research in 2005 (30% on drugs, 24% on basic science, 18% on vaccines, 13% on operational research, 11% on applied/preclinical/infrastructure/unspecified and 4% on diagnostics). A detailed breakdown of donors that supported basic science, operational, drug-related, vaccine-related and diagnostic-related research is shown in Fig. A4.3.
CONCLUSIONS It is clear that current funding for TB research is inadequate for development of new tools required to control TB, as specified by The Global Plan to Stop TB. Moreover, given the lag phase of basic research in translating into effective interventions, the importance of specific components such as drugs, diagnostics and vaccine research, and the importance of operational and societal research, there needs to be a ‘global register’ and coordinated effort between agencies, thus facilitating the structured and balanced support of different components of TB research. It is likely that innovative pull in addition to the traditional push factors will be required to achieve the ambitious targets set by The Global Plan to Stop TB and the Millennium Development Goals. Finally it must be underscored that these strategies must be implemented in parallel with existing efforts to improve capacity (laboratory and clinical) and DOTS and Bacillus Calmette–Gue´rin (BCG) coverage in developing countries, and global strategic efforts to ensure financial sustainability of developing country economies.
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APPENDICES Max Planck 1.1% India MoST 0.5% CIHR 1.3% NWO 0.2% Other NIH ICs 1.7% Brazil 0.04% Gates Foundation 2.8% EC 6th Framework 4.4% Wellcome Trust 7.6%
MRC 9.6%
A
NIAID 54.5%
NHLBI 16.2%
India MoST 3.0% Company Y 3.0% Sequella 4.9%
CDC 0.2% Inserm 0.1% CIHR 0.1% All India Institute 0.02%
USAID 5.2%
DFID 5.6%
B
Gates Foundation 41.5%
NIAID 36.5%
Fig. A4.3 Donors contributing to different components of TB research. (A) Basic science, (B) diagnostics.
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(Continued)
APPENDIX
Tuberculosis research funding
4
Inserm 0.5% FDA 0.4% Sequella 0.5% CIHR 0.4% India MoST 0.6% DC Ireland 0.3% Rockefeller Foundation 1.5% All India Institute 0.1% Novartis 2.9% Other NIH ICs 0.1% EC 6th Framework 2.2% DFID 0.03% NL MoFA (DGIS) 2.3% USAID 3.2% NIAID 33.6%
Wellcome Trust 4.4%
AstraZeneca 7.7%
Gates Foundation 8.5%
CDC 9.2% Company X 16.6%
C
Otsuka 10.3%
India MoST 1.1% CDC 1.4% Max Planck 2.2% Ellison Foundation 2.4%
Inserm 1.1% CIHR 0.3% Other NIH ICs 0.3% FDA 0.3% Danida 0.2%
Wellcome Trust 5.7%
Gates Foundation 41.2%
EC 6th Framework 9.4%
D
NIAID 34.5%
Fig. A4.3—(cont’d) (C) TB drugs, (D) TB vaccines. Reproduced with permission from TAG. (A) Funders of TB basic science research (total ¼ $93,661,494); (B) funders of TB diagnostic research and development ($16,449,619); (C) funders of TB drug-related research ($119,766,935); (D) funders of TB vaccines ($69,611,048)
REFERENCES
2. Global Plan to Stop TB, 2006–2015. Available at URL: http://www.stoptb.org/globalplan. 3. Kaufmann SH, Parida SK. Changing funding patterns in tuberculosis. Nat Med 2007;13:299–303.
1. Freuer C. Tuberculosis Research and Development: A Critical Analysis. Syed J, Harrington M, Huff B (eds). Treatment Action Group, 2006. Available at URL: http://www.aidsinfonyc.org/tag/tbhiv/tbrandd2.html
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Epilogue John M Grange, H Simon Schaaf, and Alimuddin I Zumla
The history of TB is one of scientific, medical, social, and political failure. Although modern short-course treatment for TB is among the most effective and inexpensive of treatments for life-threatening diseases, TB remains one of the leading causes of morbidity and mortality world-wide. When the World Health Organization (WHO) declared TB a global emergency in 1993, the initial response from the international community was slow and inadequate. However, the ensuing resurgence of TB, which continues to kill nearly 2 million people each year, the emergence of multidrug- and extensively drug-resistant TB, and the devastating effect of the dual TB and human immunodeficiency (HIV)/acquired immunodeficiency (AIDS) epidemic on control programmes in Africa is forcing the international community to unite in a more synchronized and effective way. A renaissance of TB research and development activity in many fields, including the impact of the HIV/AIDS pandemic, in adults and children has occurred in the past decade.
KEEPING PACE WITH INCREASING KNOWLEDGE ON TUBERCULOSIS This comprehensive clinical reference book provides a detailed review of the enormous forward strides that have been taken over the past decade in the understanding and management of TB, a disease that has plagued the human race since the dawn of recorded history. It has engaged a wide spectrum of TB health workers, medical practitioners of many specialties, epidemiologists, microbiologists, immunologists, pathologists, social scientists, and basic science researchers from all over the world who in a collaborative and concerted strategic effort have put together an up-to-date clinical treatise on a killer disease which still, despite effective therapy, has a devastating effect on the human race. A vast amount of new information on all aspects of this disease has been generated over the past decade and much of it is summarized and presented in clear terms by experts in their own field in this book. This effort illustrates the changing global attitude which now recognizes the seriousness of the TB epidemic and the enormous amount of effort currently going on at individual, local, regional, national, and international levels. With increasing, though still inadequate, amounts of funding being made available for research on TB, particularly new drugs, diagnostics, and vaccines, there is now the glimmer of hope that we have been looking for and it may be right to say that the tide can now be turned against TB if the appropriate resources can be made available and sustained. A vast amount of work is still required to eventually control this disease and we as
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the scientific community must not rest on our laurels until it is under control globally.
LEARNING FROM THE PAST The announcement of the discovery of the tubercle bacillus by Robert Koch on the evening of 24 March 1882 led to an unprecedented wave of research by the medical community. As time went on, the long and determined struggle of Calmette and Gue´rin led to the development of the BCG vaccine, powerful anti-TB agents were discovered, and therapeutic regimens which could have led to the global control of the disease if adequate resources had been available for TB control programmes were developed. Complacency on the part of governments and the western donor agencies, and the advent of the HIV/AIDS epidemic and drug-resistant TB, has led to nearly 2 million people dying of TB every year. Today there are more cases of TB in the world than at any previous time in history. It is a tragic fact that, despite the vast amount of dedicated work over many decades by some of the brightest minds in the biomedical world, our goal of eradicating or even controlling this, ‘the Captain of all of these Men of Death’, remains stubbornly elusive. To understand the situation today, and to make real progress in the elimination of TB, we need to take a very broad look at the basis of the changing trends in the behaviour of the disease in communities world-wide and the attitudes of the various communities to the disease in their midst. In this respect, the American historian Arthur Schlesinger remarked that history reminds us ‘of the limits of our passing perspectives’ and that, quoting Winston Churchill, ‘the longer you can look back, the further you can look forward.’ A century ago, the American public health physician John B. Huber wrote, ‘The tubercle bacillus is an index by inversion of the real progress of the human race. By it the claim of civilization to dominate human life may fairly be judged. Tuberculosis will decrease with the substantial advance of civilization, and the disease will as surely increase as civilization retrogrades.’1 In John Huber’s days, TB was the cause of one in seven deaths of young adults. Today, it is the cause of one in seven deaths of young adults. The only difference is the distribution of the disease: once the scourge of Europe and the New World, it is now very much an affliction of the resource-poor regions, where 95% of cases, and 98% of deaths due to it, occur. The scandal is that TB is the cause of one in four preventable deaths of young adults. ‘If preventable, why not prevented?’ This question, posed by the British Monarch Edward VII on his visit to a TB sanatorium early in the twentieth century, challenges and haunts us at the beginning of the twenty-first century.
Epilogue
THE CRITICAL YEARS One of the crucial periods in the long history of this disease, in many ways a disastrous period from which we have learnt much, occurred in Europe and the New World between 1950 and 1990. Paradoxically, this was the time when highly effective anti-TB therapy was introduced and subsequently, as the result of the tireless efforts of pioneers in Europe, USA, and Japan, schedules for treatment and prevention of TB were fine-tuned. In 1994, Sir John Crofton, a highly respected British pioneer of anti-TB therapy, wrote, ‘It is a sad reflection on society’s incompetence that, more than thirty years after the methods for cure and prevention were evolved and before the advent of the HIV pandemic, there were already more patients with active tuberculosis in the world than there had been in the 1950s.’2 In what sense has society been incompetent? Without doubt, the greatest enemy of TB control has been complacency. This was particularly evident between the 1980s and 1990s among those who were best placed to organize and implement effective preventive and curative measures. Sadly, TB has always been predominantly regarded a disease of the poor, the displaced, and the marginalized; people who the wealthy and established population would like to forget. As early as 1908, Leonard Williams was scathing of the rampant indolence and backsliding in the campaign against TB and he wrote, ‘The crusade against consumption may be said to have degenerated into a pious opinion that the bacillus resembles the socialist in being a very wicked and obtrusive person whose existence it is well that people of refinement should forget.’3 One cause of complacency has been the false trust in the eventual ability of scientific progress, such as the introduction of antiTB therapy and BCG vaccination, to lead to the conquest of TB in a country. An examination of the trends in notified TB in the industrially developed nations during the twentieth century illustrates the fallacy of this assumption. In all such nations the notification rate of TB had been in steep decline well before ‘scientific’ control measures were introduced. Clearly something else had been having an effect in the pre-chemotherapy days. According to many, this ‘something else’ was not any specific public health measure or measures but a general increase in living standards, with improved overall health, nutrition, ventilation, natural and artificial lighting, and less overcrowding. This concept, known as the McKeown thesis,4 tends to accentuate attitudes of complacency and to the view that, as the resource-poor nations develop economically, the decline in the prevalence of TB will be an inevitable natural consequence. This attitude has been termed the ‘Luddite trap’, so-named after Ned Ludd, a nihilist who resisted innovation and mechanization in the Industrial Revolution.5,6 The alternative view is that positive and beneficial changes in public health do not occur spontaneously and predictably alongside socioeconomic improvement but are the result of enormous effort and innovation and numerous specific initiatives, often requiring a considerable struggle by dedicated people in the face of apathy, indolence, and dogma and ‘some of the most formidable political, economic and cultural forces imaginable’.7
DECLINING INTEREST IN TUBERCULOSIS IN THE USA AND EUROPE As a result of complacency and a false sense of security, interest in TB almost disappeared in Europe and the USA during the period
between 1960 and the early 1990s; TB was considered a disease of poverty-ridden developing countries and not a threat to western countries, even though there were clear warning signs that the emerging HIV/AIDS pandemic could well cause a devastating reversal in the decline of the disease. Funding for research dwindled to a mere trickle and charities turned their attention to other causes. In the UK, the Medical Research Council’s TB units, which had done so much to perfect the cure for this disease, were closed in the mid-1980s, even though cases of HIV-related TB had by then been reported in the UK. Peter Davies, a leading TB physician in the UK, has stated, ‘If one wished to find a symbol of the way the developed world has turned its back on the problems of disease in the developing world, which has seen little change in the incidence of disease among its people, then this closure would perhaps be the most poignant.’8 Of course, with attention diverted away from it, the inevitable happened. Tuberculosis returned, as described in 1991 in a classic paper by Lee Reichman with the very appropriate title ‘The U-shaped curve of concern’.9 In fact it only appeared to return, as in truth it had never gone away. As implied in the above quotation from Peter Davies, the developing world had seen little change in disease incidence. Sadly, the only place that it had been absent from was the conscience of those in a position to help. By the 1980s this disease could no longer be ignored by those who had previously thought that they were safe from its ravages.
RESURGENCE OF INTEREST IN TUBERCULOSIS The abrupt reversal in interest in TB in the USA and Europe that occurred in the early 1990s took its rise from American newspaper articles describing the spread of the disease from the ethnic minorities, the homeless, the drug addicts, the prisoners, and others whom most people chose to ignore, to white middle-class Americans who had considered themselves ‘above’ such an affliction. This caused fears for personal safety, and frightened people to call for action and, indeed to their very great credit, the New York authorities mounted a massive and costly campaign against this disease in their city and reversed the trends. The wave of interest and concern spread beyond the USA and the WHO re-established its TB programme.10 In 1992 the anniversary date of Robert Koch’s announcement of his discovery of the tubercle bacillus, 24 March, was declared World Tuberculosis Day. Subsequently in 1993 an historic conference entitled Tuberculosis – Back to the Future was held at the London School of Hygiene and Tropical Medicine,11 where the WHO took the unprecedented step of declaring TB a global emergency. In the following years the WHO developed its Global Plan to Stop Tuberculosis, engaged in intensive advocacy for adoption of its five-point DOTS strategy, and established the Global Alliance for TB Drug Development. Also, with the United Nations, the WHO initiated the Advocacy Forum for Massive Effort against Diseases of Poverty and was a foremost protagonist of the United Nations Millennium Development Goals. The impact of these initiatives, particularly the WHO DOTS strategy, is difficult to quantify as we have no idea what would have happened had they not occurred, but it is clear that, where applied rigorously, the DOTS strategy makes a definite positive impact on the incidence of TB.
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BACK TO THE FUTURE – THE ‘NEW TUBERCULOSIS’: HIV COINFECTION AND MULTIDRUG-RESISTANT TUBERCULOSIS Sadly, though, the world has been slow to adopt the DOTS strategy and the significant gains made in some regions that have adopted it have been largely offset by serious problems in others, notably those with a high HIV/AIDS burden. The title of the 1993 London conference, Back to the Future, was chosen to stress that we are not returning to the problems of a former era, but are faced with new challenges calling for new solutions.11 Two great contemporary challenges to TB control, described in detail in this book, are the deadly synergy between TB and HIV disease and the emergence of mutants of the tubercle bacillus resistant to many or most of the anti-TB drugs. There are fears of the emergence of TB forms that, with our present armamentarium of drugs, will be untreatable. Novel forms of treatment are urgently required; to improve patient compliance by shortening the duration of chemotherapy, to deal with drug-resistant TB, and to improve treatment outcomes of newly diagnosed TB in HIV-infected individuals.
TUBERCULOSIS ANYWHERE IS TUBERCULOSIS EVERYWHERE: GLOBAL TUBERCULOSIS IS A LOCAL PROBLEM It is now realized that, far from being restricted to the poor and the marginalized, TB is a global problem from which no community or individual is safe. Nobody is safe until all are safe or, in the words of Don Enarson, ‘tuberculosis will not be eliminated anywhere until it is eliminated everywhere.’12 In this age, notably since the collapse of communism, we hear much about ‘globalization’, which has been defined as ‘a process of closer interaction of human activity, with spatial, temporal and cognitive dimensions’. It might be hoped that this process would embrace a global approach to all the major problems, including health-related ones affecting the human race. In practice, it appears to do little more than embrace the concept of a ‘free market’ – free, that is, from control of governments but not from multinational corporations – which was supposed to lead to global prosperity. In practice, it has led to a widening of the gap between rich and poor nations and between rich and poor within nations. The health sector has suffered particularly badly, with pharmaceutical giants focusing on cures for the ‘lifestyle diseases’ of the wealthy nations. The ‘Inverse Care Law’, formulated by Tudor Hart in 1971,13 states that ‘the availability of good medical care tends to vary inversely with the need for it in the population served’. Tudor Hart added that this law operates particularly in situations in which medical care is market-based; in his words, ‘a primitive and historically outdated social form’. Sadly, this primitive social form is so widespread today. Also, sadly, so much of modern medical thinking is charged with the notion that the only things that matter are those that can be quantified. This attitude has been termed ‘scientism’, defined as an approach to medical practice that regards the scientific understanding of the disease as the only relevant issue, whilst ignoring any other factors.14 While in no way denigrating the enormous contributions made by basic research, particularly in recent years at the molecular level, the words of Sir Douglas Black, a past President of the Royal College of Physicians of London, should encourage a wider and more balanced approach – ‘evidence-based biomedicine is but one facet of the whole complex structure of
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modern medicine and not without its limitations in addressing major public health challenges.’15 Encouragingly, the narrow and dogmatic belief systems of scientism are being seriously challenged from many angles. A most welcome and positive trend in the global approach to TB and other serious and widespread public health problems is the increasing involvement of workers from many disciplines.16 While doubtless adding to the complexity of the subject, complexity can be viewed positively as an incentive to developing novel ways of working together. The term ‘political ecology’ has been given to the interdisciplinary study of geographical, social, economic, anthropological, cultural, and environmental factors that affect the behaviour of disease.17 With multiple barriers that stand in the way of effective control of TB, an interdisciplinary approach – integrating the quantitative assessment of the effectiveness of control strategies and the qualitative assessment of their effect on the ability of patients to access and complete treatment – is needed to develop effective, flexible context-oriented and patient-centred approaches.18 A key part of this process is to assess the structures of care and support available for patients and to identify the shortfalls, over and above those mentioned in international policy documents, in the management of control at national and local levels. An interdisciplinary approach will ensure simultaneous consideration of the social, economic, and environmental dimensions of disease, since questions about access to health-care, recourse to treatment, and delivery of care, including the determination of their respective costs and other factors, are fundamental to effective control.
DIFFICULTY IN MANAGING COINFECTION WITH HIV The current WHO-recommended strategy for TB control, DOTS, has certainly helped improve TB control in large highly populated areas of the world.19 The progress to date does, however, show that DOTS alone is not sufficient to achieve the 2015 targets set by the Millennium Development Goals and the Stop TB Partnership. In areas where people are at high risk of coinfection with HIV and Mycobacterium tuberculosis, there is a pressing need to identify ways to jointly treat the two diseases, which include the identification of optimum regimens and timing of treatment of coinfected individuals. On a wider scope, there is an urgent need to identify the best methods for ensuring proper diagnosis and delivery of treatment to coinfected people in resource-poor countries, which is highly dependent on the quality of the existing health services. The development of an operational research framework, integrating qualitative and quantitative methods, will help policymakers to understand the complex nature of the social aspects, health services-related factors, and policy context of the disease. This knowledge will, in turn, make TB control programmes more responsive and reflective of local health systems and social structural constraints and resources, ultimately permitting adjustment of international policies to local realities, for efficient and effective disease control worldwide.
TUBERCULOSIS ELIMINATION: WHAT’S TO STOP US? This is the title of a challenging paper by Lee Reichman, who stresses the undeniable fact that non-compliance with therapy is a major barrier to TB control but emphasizes that this is not so much the patients who do not comply, but the providers of healthcare at
Epilogue
the local, national, and international levels.20 Reichman remarked that ‘if any of these parties did what they should do, things might be different. Especially if they were to show the wholly justified outrage for which the situation cries out.’ The overwhelming tragedy is that the poor peoples of the world are, so frequently, unable to help themselves.21 They do not merely suffer from monetary poverty but also from human poverty as they lack the education and physical resources that would empower them to achieve, for themselves and their families, an acceptable standard of health and well-being.22 Poverty-stricken and marginalized peoples, including members of ethnic minority communities in industrially developed nations, have had few advocates in the wealthier sections of the community and often have serious difficulties in accessing healthcare, despite this being in principle free at the point of delivery. Prevalent gender-related issues and irrational stigma often deny women access to adequate healthcare. In this context, the WHO has stated that ‘Since there is a cure for tuberculosis – a cure that is not being fully used – tuberculosis is no longer a medical epidemic, but an epidemic of injustice’.23 The wealthy nations have a moral duty to press for the creation of a more just, equitable, and healthy global society. We are reminded of the words of King Solomon – ‘Along the way of justice there is life.’ The additional burden faced by the poor in many regions is conflict. The closely interwoven link between disease, conflict, and poverty is the true ‘axis of evil’. By the end of the twentieth century the neglect of TB of the 1980s had been replaced by an enormous increase in interest and action but financial and human resources were woefully inadequate. The new millennium was seen by many as being the focal point for a new beginning and a revolution in human affairs. There were, for example, calls to mark the new millennium by cancellation of the massive debts stifling economic growth in many resource-poor nations. The first meeting of the Advocacy Forum for Massive Effort against Diseases of Poverty, sponsored by the WHO and UNAIDS, was held in October 2000, in the Swiss city of Winterthur. The statement issued by the Forum was impressive: This year – at the start of a new millennium – a movement is building that has the power to break the vicious cycle of poverty and disease. For the first time in history, the international community has the financial means, the medications, and the know-how to take a stand against a small number of diseases that cause tremendous suffering and economic loss. This massive effort against the diseases of poverty, which unites partners in unique ways, is moving the world from words to action – action that can facilitate sustainable development, stimulate economic growth, ensure greater global public health security and, most importantly, save human lives.
There is no doubting the sincerity of those uttering these words at the dawn of the third millennium but, through no fault of their own, these worthy aims have not been realized. Far from ushering an epoch of peace, harmony, and prosperity, the first decade of the new millennium has been one of horror and disaster. The pledges of help made in the year 2000 have not been kept. Instead, one blessed with a fertile yet macabre imagination might well consider that the Four Horsemen of the Apocalypse have been unleashed, especially the fourth – the sickly pale horse whose rider’s name was Death. In the same year, 2000, a spokesman for Me´decins Sans Frontie`res issued a dire warning, ‘It is only a matter of time before multidrug-resistant tuberculosis . . . becomes a daily reality worldwide. The cost of the epidemic to the world will be counted in billions of pounds and may become unmanageable.’
WORKING TOGETHER TO CONTROL TUBERCULOSIS There is no doubt that the WHO has made a great and conscientious effort to take on the massive problem of TB control. Numerous religious institutions, specific charities, such as the UK charity TB Alert, and non-governmental organizations have provided great support to the poorer sections of the community and communities themselves have taken very effective steps to help themselves. To take just one of many examples, a Zambian organization called Bwafwano, meaning ‘helping one another’, founded by a group, now around 150, of local village ladies who support patients, supervise their treatment, and attend to daily needs is a glowing example. In the words of the Bwafwano team, their mood has swung from being saddened yet determined to care sensitively for the dying to excitement at being able to help people live. These international, national, and local research and control initiatives have been very encouraging but, as usual, they have been plagued by inadequate resources. Globally TB research remains grossly underfunded despite a recent boost in research and development funding. The usual funders of medical and scientific research were until recently out of touch with reality, only providing minuscule funding which was allocated restrictively so that its overall impact was limited and made no headway towards achieving improved TB management. Fortunately, over the past 7 years there has been a wind of change in the funding of infectious diseases research, particularly TB, malaria, and HIV/AIDS. The European Commission and the Gates Foundation have generously committed large resources for individual researchers, research organizations, and private– public partnerships to develop new tools for the campaign against TB, focusing on new diagnostics, drugs, and therapeutic regimens to shorten the course of chemotherapy, and the development of novel vaccines. The Gates Foundation has established the not-forprofit Global Alliance (for new drugs), Foundation for Innovative New Diagnostics (FIND) for coordinating work on newer diagnostics, and the Aeras Foundation for researching into TB vaccines. While such major funding efforts focused on supporting western researchers are important, the operational and implementation research which governs effective delivery of TB care has been neglected. Disappointingly so far, promising initiatives supported by several European countries such as the European Developing Country Clinical Trials Partnership (EDCTP) have not yet made any significant impacts. Once they have established administrative structures, they may well play a key role in facilitating clinical trials research in TB, HIV, and malaria in developing countries.
SUPPORTING OPERATIONAL, PROGRAMMATIC, AND IMPLEMENTATION RESEARCH Realizing the glaring omission of operational and implementation research from the international funding agenda, the WHO and the STOP TB Partnership have now included research into their main agenda and have formed the TB Research Movement.24 The establishment of this movement has been mandated by the STOP TB Partnership Board and the WHO TB advisory body, the Scientific and Technical Advisory Group (STAG). The need to enable and promote research as a key element of the WHO’s
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new STOP TB strategy is the ultimate call for research funding agencies to provide the greatly needed resources to carry out the research.
FUTURE DIRECTIONS TOWARDS TUBERCULOSIS CONTROL The TB fraternity has thankfully unified in stating its strategy, although funding agencies in the UK need to catch up with their USA and EC counterparts. Importantly, it is now also up to governments of developing countries to fully commit resources to TB control, and for donors to provide catalytic financial aid. The new Stop TB Strategy and the Global Plan with its important developments at regional levels, of which several have been outlined in this book, present an ideal opportunity to unite in turning the tide against TB. The 2006 report of the WHO–STOP TB partnership Global Plan to Stop TB clearly sets out the detailed strategies that need to be implemented over the 10-year period 2006-2015.24 Globally it seems feasible that it will be possible to meet the UN Millennium Development Goal target to halve prevalence and death rates of TB from the 1990 levels by the year 2015. In Africa and Eastern Europe, HIV and the escalating problem of drug resistance, as well as wider societal and health system issues, require more intensive action.25 Collaboration with HIV programmes is essential. Implementation of the Global Plan to Stop TB with existing tools will
REFERENCES 1. Huber JB. Civilization and tuberculosis. Br J Tuberc 1907;1:158–168. 2. Crofton J. Foreword. In: Davies PDO (ed.). Clinical Tuberculosis. London: Chapman and Hall Medical, 1994: xv–xvi. 3. Williams L. The worship of Moloch. Br J Tuberc 1908;2:56–62. 4. McKeown T, Record RG. Reasons for the decline in mortality in England and Wales in the nineteenth century. Popul Stud 1962;16:94–122. 5. Farmer P, Nardell E. Nihilism and pragmatism in tuberculosis control. Am J Public Health 1998;88:1014–1015. 6. Grange JM, Gandy M, Farmer P, et al. Historical declines in tuberculosis: nature, nurture and the biosocial model. Int J Tuberc Lung Dis 2001;5:208–212. 7. Chapman S, Lupton D. The Fight for Public Health. London: BMJ Publishing Group, 1994.
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cost an estimated US$56 billion and will save 14 million lives over the next 10 years. The sustained and increased investment in development of new tools for TB control (new drugs, diagnostics, and vaccines), the recent focus on operational, implementation, and programmatic health systems research with the current multidisciplinary approach will eventually result in the coveted prize – the control of TB world-wide. Total elimination of this disease will not occur and diligent surveillance will be constantly required. In 1999, two editors of this book (AZ and JG) wrote, It may well be the case that the ultimate answer to the global emergency of tuberculosis lies in a revolution of human conduct and a replacement of the present world order with one based more equitably on natural justice. It is not beyond the bounds of possibility that a very serious threat from a major epidemic, such as that of multidrug-resistant tuberculosis, and that of associated HIV/ AIDS might be the trigger event for such a peaceful revolution. The alternative is too awful to contemplate.22
Apart from adding ‘extensively drug-resistant TB’, we still adhere to this view. The many authors of this reference work have clearly described the road forward for the conquest of the ‘white death’. Only the human race (particularly those in political and economic power) can decide whether to follow this road. Scientists and clinicians have already demonstrated that they will enthusiastically continue with their commitments to get rid of one of the most lethal infectious diseases in human history.
8. Davies PDO. Preface. In: Davies PDO (ed.). Clinical Tuberculosis. London: Chapman and Hall Medical, 1994: xvii–xix. 9. Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991;144:741–742. 10. Kochi A. The global tuberculosis situation and the new control strategy of the World Health Organization. Tubercle 1991;72:1–6. 11. Porter JDH, McAdam KPWJ. Tuberculosis—Back to the Future. Chichester: Wiley, 1994. 12. Enarson DA. Strategies for the fight against tuberculosis. Pneumologie 1994;48:140–143. 13. Hart TJ. The inverse care law. Lancet 1971;1:405– 412. 14. Leggett JM. Medical scientism: good practice or fatal error? J R Soc Med 1997;90:97–101. 15. Black D. The limitations of evidence. J R Coll Phys Lond 1998;32:23–26. 16. Porter JDH, Grange JM (eds). Tuberculosis—An Interdisciplinary Perspective. London: Imperial College Press, 1999. 17. Mayer JD. Geography, ecology and emerging infectious diseases. Soc Sci Med 2000;50:937–952.
18. Lienhardt C, Rustomjee R. Improving TB control: an interdisciplinary approach. Lancet 2006;367:949– 950. 19. Sharma S, Liu JJ. Progress in DOTS in global control. Lancet 2006;367:951–952. 20. Reichman LB. Tuberculosis elimination—what’s to stop us? Int J Tuberc Lung Dis 1997;1:3–11. 21. Grange JM, Zumla A. Tuberculosis and the povertydisease cycle. J R Soc Med 1999;92:105–107. 22. Zumla A, Grange JM. The ‘global emergency’ of tuberculosis. Proc R Coll Physicians Edinb 1999;29:104–115. 23. World Health Organization. TB—a Global Emergency. WHO Report on the TB Epidemic. Geneva: World Health Organization, 1994. 24. Stop TB Partnership. The global plan to stop TB 2006-2015. [online]. Accessed 10 March 2006. Available at URL:http://www.stoptb.org/globalplan 25. Zumla A, Gandy M. Politics, science and the ‘new’ tuberculosis In: Gandy M, Zumla A (eds). The Return of the White Plague: Global Poverty and the ‘New’ Tuberculosis. London: Verso, 2003: 237–242.
Index
A Abacavir, 624, 625, 641 adverse effects, 697 skin rash in children, 633 rifampicin interaction, 623 Abdomen, acute in children, 433, 434 Abdominal pain, 425, 426, 438, 461, 511, 512 childhood gastrointestinal tuberculosis, 433, 434 clofazimine adverse effect, 680 drug-induced hepatotoxicity, 681 Abdominal plain radiographs, 223 gastrointestinal tuberculosis, 426, 434 male genital tuberculosis, 452 Abdominal tuberculosis, 382–383 case reports, 835–836 children, 154, 155, 432–436, 533, 835–836 clinical examination, 157 epidemiology, 432 multidrug resistant disease, 533 radiology, 269, 271, 275–276, 277, 278, 279 clinical presentation, 382, 383, 398, 520 diagnosis, 383 dissemination, 520 HIV coinfection, 383, 525 imaging, 223, 269, 271, 275–276, 277, 278, 279, 301–302 hepatosplenic/gallbladder involvement, 304–305 lymphadenopathy, 303–304 pancreatic involvement, 305 surgical treatment, 520–521 see also Gastrointestinal tuberculosis Aboriginal people, 13, 790 Abscess irrigation, nosocomial transmission risk, 581 Absolute concentration method, 175, 542 Access to healthcare, 662, 665, 749, 800, 926, 942 direct/indirect costs (impoverishing effects), 912 gender disparities, 756, 757, 888, 913, 981 migrants, 893, 894, 895, 898 poor people, 908, 981 research approaches, 755, 756 Access to laboratory services, 669 AccuProbe, 173 nontuberculous mycobacteria identification, 63 Acetazolamide, 418 Acetylator status, isoniazid metabolism, 52, 610 children, 629 side effects, 677 Achalasia, 257 Acid-fast bacilli, 46, 173, 205, 206, 219 detection ascites fluid, 428, 434, 461 breast tuberculosis, 473 cerebral tuberculomas, 405 cerebrospinal fluid, meningitis diagnosis, 384, 404, 415 conjunctival tuberculosis, 478 DOTS programme implementation, 669 ear tuberculosis, 463 female genital tuberculosis, 458 HIV–tuberculosis coinfection, 526, 655 immune reconstitution inflammatory syndrome, 697 International Standards for Tuberculosis Care, 650 laboratory safety, 742 neonatal specimens, 574 new methods, 231
ocular tuberculosis, 482 ovarian tuberculosis, 513 parathyroid tuberculosis, 508 pericardial fluid, 355 pleural effusion fluid, 344, 345 pregnant patients, 575 prostate tuberculosis, 451, 452 quality assurance programmes, 739 renal tuberculosis, 439 urine, genitourinary tuberculosis diagnosis, 441 see also Sputum smear microscopy; Ziehl–Neelsen staining Acid-fast staining, 48, 57, 171 Acromegaly, 504 Acylated trehaloses, 48 Adaptive immune response, 75, 143 Addisonian crisis, 388, 509 Addison’s disease see Adrenal insufficiency Addresins, 83 Adenosine deaminase assay, 222 abdominal tuberculosis, 383 ascites fluid, 428, 434, 461, 520 isoenzymes (ADA1/ADA2), 222, 345 meningitis, 404 pericarditis, 356, 382 pleural effusions, 344–345, 369, 381 Adenovirus vaccine vectors, 111, 753 Adherence, 553, 639, 655, 676, 751, 943, 980–981 children, 535, 628, 634–635 isoniazid prophylaxis, 636 clinical trials, 917 defaulter follow-up, 934 DOTS programme implementation, 671–672 drug resistance prevention, 553 factors influencing, 654, 672–673 gender differences, 889–890 HIV–tuberculosis coinfected individuals, 753 antituberculous–antiretroviral drug concurrent treatment, 655 importance for TB control, 934 incentives, 905, 943 interventions for improvement, 654 latent tuberculosis treatment, 636, 777–778 multidrug resistant tuberculosis treatment, 535, 643, 646, 656 operational issues, 668–675 patient education, 596, 598 patient support, 598, 640, 643, 671, 672, 754, 930, 934, 943 patient-centred approach, 596 poverty-related problems, 605 Stop TB strategy implementation, 943 tuberculosis care standards, 649, 652, 653–654 vertical transmission infuence, 573 workplace tuberculosis management, 906 Adhesins, 76 Adhesion molecules, 83–84 Adhesions, 127 intestinal obstruction in children, 434 Adjuvanted protein subunit vaccines, 753 Adrenal biopsy, 509 Adrenal insufficiency, 126, 508, 509, 521 treatment, 509 Adrenal steroids, tuberculosis susceptibility influence, 91–92
Adrenal tuberculosis, 388, 505, 508–510, 521 clinical presentation, 508, 509 differential diagnosis, 508–509 epidemiology, 508 imaging, 252, 306 children, 269 investigations, 509 management, 509–510 pathology, 509 tissue destruction, 126 Adrenaline (epinephrine), anaphylactic reactions management, 677 Adult respiratory distress syndrome immune reconstitution inflammatory syndrome, 339 miliary tuberculosis, 240 Adult-type progressive tuberculosis see Postprimary tuberculosis Advocacy community healthcare programmes, 665 DOTS programme implementation, 668, 669 nurses’ role, 711 workplace healthcare programme establishment, 905 Advocacy, communication and social mobilization (ACSM) national TB control programmes, 799 Stop TB Strategy implementation, 945, 949 Advocacy Forum for Massive Effort against Diseases of Poverty, 979, 981 Aeras Global TB Vaccine Foundation, 229 AERAS–402 vaccine, 107, 111 clinical studies, 111 preclinical studies, 111 Afghanistan, 19, 40, 886 Africa, 13, 21, 22, 23, 147, 160, 166, 227, 228, 229, 328, 332, 342, 494, 515, 528, 756, 951 childhood tuberculosis, 40, 41 community involvement in tuberculosis control programmes, 663, 664 epidemiology, 19 current status, 940 extensively drug-resistant tuberculosis, 943 extrapulmonary tuberculosis, 377, 378 Global Plan to Stop TB targets, 951, 952, 954 HIV–tuberculosis coinfection, 41, 96, 524, 927 Millenium Development Goals, 24, 25 musculoskeletal tuberculosis, 494, 495 Mycobacterium bovis tuberculosis, 150 National TB Programmes development, 933 private health facilities, 603, 604 workplace tuberculosis, 902 Ag85A, 48 AERAS–402 vaccine, 111 MVA85A vaccine, 108 Ag85B, 48, 753 AERAS–402 vaccine, 111 rBCG30 vaccine, 110 vaccine studies, 112 Ag85C, 48 see also Lipoarabinomannan Agar-based media, 172, 219 drug susceptibility testing, 219 Agglutination serotyping, 48, 49 Air centrifuge, 8 Air disinfection, 9 Air encephalography, 285, 417–418
983
INDEX Air extraction cabinets, 742–743 Air filters, 553, 902 Air-space disease, imaging in children, 268 Air-travel-linked outbreaks, 584, 590–591 contact tracing, 773 Airborne infection isolation (respiratory isolation), 708 Airborne transmission, 8–9, 13, 17, 129, 323, 333, 788 animal experiments, 9–10 extensively drug-resistant tuberculosis, 553 healthcare setting control strategies, 702 human-to-animal, 150 infecting dose, 142 particle size considerations, 9 transmission-based infection precautions, 702 workplace, 905 zoonotic tuberculosis, 147 Airway compression/obstruction expansile pneumonia, 369, 370 imaging, 299–300 children, 262, 272 postprimary tuberculosis, 247, 249 immune reconstitution inflammatory syndrome, 698 laryngeal tuberculosis, 373 lymph node disease, 144 pre-chemotherapy studies, 140 retropharyngeal abscess, 374 spinal tuberculosis, 374 case report, 868 strictures, 299–300 surgical treatment, 517 Airway disease, 361, 364–368 bronchoscopy, 365–366 clinical presentation, 364 complications, 368 imaging, 240 chest radiography, 364–365 computed tomography, 365 medical management, 366–367 adjuvant corticosteroids, 628 surgical management, 367–368 unilateral hyperinflation, 364–365 see also Airway compression/obstruction Alaska, 3 Alcohol abuse, 18, 166, 401, 515, 589, 611, 771, 781, 944 antituberculous chemotherapy adverse effects, 676, 681 with liver disease, 642 peripheral neuropathy, 684 Allergic drug reactions, 677 management, 677, 679 prevention, 679 Allopatric hosts, 55 Alma Alta Declaration, 660 Alpha1-antitrypsin deficiency, 61 16a-bromoepiandrosterone (HE–2000), 92 Alveolar proteinosis, 61 Amenorrhoea, 164, 457, 459 pituitary tuberculosis, 504 Amikacin, 613, 958 adverse effects, 965 acute renal failure, 682 ototoxicity, 685 peripheral neuropathy, 684 Buruli ulcer (Mycobacterium ulcerans infection), 72 central nervous system penetration, 545, 557 clinical efficacy, 613 cross resistance, 555, 556 kanamycin, 613, 644 early bactericidal activity, 613 extensively drug-resistant tuberculosis, 20, 555, 556 multidrug resistant tuberculosis, 408, 613 meningitis, 408 Mycobacterium abscessus pulmonary disease, 71 Mycobacterium avium complex skin infections, 71 Mycobacterium chelonae pulmonary disease, 71 Mycobacterium kansasii disease, 70 with renal failure, 564 resistance, 539, 540, 551, 553, 613, 644, 757 susceptibility testing, 543 nontuberculous mycobacteria, 66 Aminoglycosides, 612–613 adverse effects, 678, 965 gastrointestinal upset, 680
984
nephrotoxicity, 467, 677 ototoxicity, 467, 576, 645, 677, 685, 686 renal impairment, 557 risk to foetus, 576 vestibular toxicity, 467, 685, 686 contraindications in pregnancy, 645 with renal function impairment, 447, 455 drug interactions, 969–970 extensively drug-resistant tuberculosis, 555, 556 multidrug resistant tuberculosis, 408, 467, 543, 644, 656 children, 534 renal excretion, 455 Amoxicillin/clavulanic acid, 615, 958 adverse effects, depression/psychosis, 686 AMPLICOR MTB Test, 197, 198, 200, 201 clinical evaluation, 199 guidelines for use, 199 Amplified MTD Test, 197, 198 Amprenavir, ritonavir interaction, 620 Amyloidosis, 127, 142 renal failure, 440 Anal tuberculosis, 426 Anaphylactic drug reactions, 677, 966 management, 677, 679 prevention, 679 Anaphylactoid drug reactions, 966 Anda-TB test, 189, 191 Aneurysms, tuberculous, 307 Animal hosts, 787 control strategies, 793 Ankle joint tuberculosis, case report, 866 Antacids, 680 drug interactions, 680 rifampicin, 687 Antibodies, 75 new detection methods, 233–234 serological assays, 179, 189, 190 Antibody competition assay, tuberculous meningitis diagnosis, 405 Antigen 85 complex, 48, 233 see also Ag85A; Ag85B; Ag85C Antigen presentation, 78, 79–80, 119 CD1 molecules, 77, 80 MHC Class I molecules, 78, 79–80 segregated antigens, 80 MHC Class II molecules, 78, 79 Antigen presenting cells, 75, 76 granuloma formation, 117 Antigen processing, 119 macrophages/dendritic cells, 77–78 Antigen-capture ELISA, serological diagnostic methods, 223 Antigen-specific IgG assays, meningitis diagnosis, 405 Antigens, mycobacterial, 47–48 detection methods diagnostic tests, 326 mycobacterial identification, 174 new methods, 233–234 distribution, 48 for serological tests, 189 Antihistamines, 677, 679 Antiretroviral therapy, 24, 528, 529, 655, 674, 807, 809, 951 adverse effects, 578, 697 children, 633–634 hepatotoxicity, 676 peripheral neuropathy, 684 antituberculous drug concurrent treatment, 618, 633, 655, 809 adverse effects, 856–857 case reports, 883–885 latent infection/prophylaxis, 784, 808 pregnant patients, 578 second-line drugs, 645 antituberculous drug fixed-dose combinations, 753 antituberculous drug interactions, 447, 528, 557, 633, 641, 645, 655, 809, 917 case report, 856–857 fluoroquinolones, 618–619 management recommendations, 624–625 mechanisms, 618–619 research approaches, 625 rifampicin, 455, 481, 687, 782
rifamycins, 618, 624–625, 676 second-line drugs, 555 benefits in tuberculosis patients, 618 case reports, 883–885 CD4 T cell counts as eligibility criteria, 809 children, 42, 632, 633–634, 753 tuberculosis clinical presentation, 155 extensively drug-resistant tuberculosis concomitant treatment, 557 host response to Mycobacterium tuberculosis, 100 immune reconstitution inflammatory syndrome see Immune reconstitution inflammatory syndrome International Standards for Tuberculosis Care, 655 management approaches, 604–605 pregnant women, 320–321, 578, 810–811 research priorities, 751, 752–753 timing of initiation, 528, 641, 655, 695, 699, 752, 809–810 children, 633, 634, 635 tuberculosis imaging findings, 254–256 tuberculosis management algorithms collaborative treatment services, 321 for individuals on therapy, 318–319, 320 pregnant women, 320–321 tuberculosis development within 6 months of starting treatment, 319, 320 tuberculosis risk attenuation, 784 Antituberculous chemotherapy, 608–616, 638–646, 958–971 adherence see Adherence adjunctive corticosteroids see Corticosteroids adrenal tuberculosis, 509–510 adverse effects, 676–688, 697, 963–967 anaphylaxis/allergy, 677, 679, 966 body fluids discolouration, 686–687, 967 bone/joint pains, 680, 965 central nervous system toxicity, 410, 687, 964–965 children, 633–634 depression, 686 dermatological, 679–680, 964 factors influencing, 676–677 gastrointestinal upset, 680–681, 963 haematological, 683, 965 hepatotoxicity, 410, 681–682, 964 hypothyroidism, 687 influenza-like syndrome, 687, 966 injection-related, 687 major, 676, 677 management, 677 minor, 676, 677 peripheral neuropathy, 684, 965 psychosis, 686 renal failure, 682–683, 964 respiratory/shock syndrome, 687 seizures, 684–685 vestibulo-cochlear toxicity, 685–686, 965 visual impairment, 683–684, 965 airway disease, 366–367 antiretroviral drug concurrent treatment see Antiretroviral therapy antiretroviral drug interactions see Antiretroviral therapy arthritis, 502 Bacillus Calmette-Gue´rin (BCG) adverse events, 764, 766 disseminated disease (BCG-osis), 768 breast tuberculosis, 474 breastfeeding, 641–642 broncho-oesophageal fistula, 372 Buruli ulcer (Mycobacterium ulcerans infection), 72 cancer patients, 565 central nervous system tuberculosis, 407–408 central nervous sytem penetration, 545 children see Childhood tuberculosis clinical trials see Clinical trials continuation phase, 627, 628, 638, 639–640, 652, 653, 740 cutaneous tuberculosis, 491–492 dose recomendations (WHO), 653 DOTS programme implementation, 670–671 drug supply see Drug supply duration of treatment, 553, 557, 608, 638, 653, 751 clinical trials of new agents, 917 early bactericidal activity, 608, 638
INDEX elderly people, 565 empyema, 347, 369 endocrine gland effects, 505 expansile pneumonia, 370 extensively drug-resistant tuberculosis, 555–557 core drug selection guidelines, 556–557 extrapulmonary tuberculosis, 379, 528, 628, 630–631, 639, 670–671 female genital tuberculosis, 461 first-line drugs (drug-susceptible tuberculosis), 543, 639 WHO essential drugs, 609 fixed dose combinations, 639, 652–653, 670, 751, 943 side effects management, 687–688 gastrointestinal tuberculosis, 430, 435–436 genitourinary tuberculosis, 447 Group classification, 544 healthcare facility infection control, 706 historical aspects, 4–5, 926, 930–931 developed countries, 932 developing countries, 932–933 HIV–coinfected individuals see HIV–tuberculosis coinfection immunosuppressive agent interactions, 563 initial phase, 627, 628, 638, 639, 652, 653 International Standards for Tuberculosis Care, 649, 652–653, 654, 655, 656 with liver impairment, 642, 645 lymphadenitis, 394, 398, 630–631 male genital tuberculosis, 455 meningitis, tuberculous, 385, 407–408, 417, 545, 628, 630 miliary tuberculosis, 628, 630 monitoring response, 598, 654, 672 multidrug resistant tuberculosis see Multidrug resistant tuberculosis national TB control programmes, 795, 797 new drugs, 615–615, 751 nontuberculous mycobacterial infections, 65, 70, 71, 72 ocular tuberculosis, 478, 482–483 pancreatic tuberculosis, 511 paradoxical reaction, 689 patient support, 639 pericardial effusions, 357 pericarditis, tuberculous, 357–358, 382 pituitary tuberculosis, 506 pleural tuberculosis, 347, 369, 381 pregnant women, 576, 578, 641, 810 principles, 638–639 prophylaxis, 25, 330, 635–636, 780–784, 807–808, 810 monitoring, 782, 783 regimens, 781–782, 783 resource-constrained countries, 783 target groups, 780–781, 783 TB control strategies, 783–784 pulmonary tuberculosis, 338, 526–528, 628–630, 639 with renal impairment, 563, 564, 642 research, 746, 753, 945–946 outcome optimization, 750 resistance prevention, 553, 608–609, 638 reticuloendothelial system tuberculosis, 395, 399 second-line drugs, 535, 544, 555, 632, 641, 642, 643, 656, 674, 944 with hepatic failure, 645 length of parenteral administration, 731 number of drugs, 730–731 optimal regimen, 732, 733 with renal failure, 645, 646 resistance, 553 teratogenicity, 576 WHO reserve drugs, 609 spinal tuberculosis, 385, 467, 500, 519, 631 sterilizing activity, 608, 638, 639 Stop TB Strategy implementation, 943, 945–946 treatment regimens, 553, 627–628 new cases (WHO recommendations), 639–640, 653 precautions, 609 previously treated cases (WHO recommendations), 640–641 standard regimen, 608–609 terminology/coding, 628 tumour necrosis factor a antagonist-treated patients, 570
vertical transmission prevention, 573 workplace tuberculosis, 906 Aortic aneurysms, 307 Aortic disease imaging, 307 Aortic pseudoaneurysm, surgical treatment, 521 Aortoenteric fistula, 521 Apoptosis caseating granulomas, 85 macrophages, 82 Mycobacterium tuberculosis killing, 84 with HIV coinfection, 103 Arabinogalactan, 48, 49, 53 Arabinosyl transferase, 53 Arachnoiditis, case report, 863 Archaeological record, 1, 2 Argentina, 553 Arrhythmias, cardiac, 359 drug-induced, 966 Arthralgia, 333 drug-induced, 965 Arthritis, drug-induced, 965 Arthritis, tuberculous, 126, 252, 385, 501 clinical presentation, 501 imaging, 308–309, 501–502 children, 293, 294 Phemister triad, 252, 308, 501 treatment, 502 Ascites, 301–303, 383 adenosine deaminase assay, 222 constrictive pericarditis, 382 cytology/microscopy, 209, 210, 221 fluid examination, 428, 434, 461 gastrointestinal tuberculosis, 426, 427, 428, 434 children, 269, 278, 433, 434 imaging, 269, 278 immune reconstitution inflammatory syndrome, 697 peritoneal tuberculosis, 165, 461, 520 sample processing, 209 specimen collection, 217, 461 ultrasonography, 223 Ascites praecox, 382 Asia, 19, 227, 228, 332, 756, 940, 951 community involvement in tuberculosis control programmes, 663, 664 extensively drug-resistant tuberculosis, 552 Asian/South Indian variant, 53 Aspergilloma, 124, 250, 339 imaging, 300 management, 339 Aspergillosis, 207 Aspiration, 371, 372 Aspirin, 680 Assisted living facility outbreaks, 584–585 Asthma, 650 corticosteroids use, risk of tuberculosis, 566 Ataxia, drug-induced, 685, 686 Atazanavir, ritonavir interaction, 622 Atlantoaxial instability, 495 Atovaquone, rifampicin interaction, 624 Atrial fibrillation, 353, 359 Attenuation indicator lipid, 49, 50 Atypical mycobacteria see Nontuberculous mycobacteria Audit global tuberculosis control strategies, 789 Good Clinical Practice, 921 health care services, 789 sputum smear microsocpy protocols, 704 Augmentin, nontuberculous mycobacteria susceptibility testing, 66 Auramine-O staining, 171, 218 Australia, 3, 61 Autofluorescence fine needle aspiration samples, 212 see also Fluorescence microscopy Autoimmune disease, 386 Autoimmune haemolytic anaemia, 395 Automobile-related outbreaks (‘hotboxing’), 584, 590 Avicenna (Ibn Sina), 129 Axillary lymph node involvement BCG lymphadenitis, 391 breast tuberculosis, 471, 472 Azithromycin Mycobacterium avium complex
disseminated infection, 72 pulmonary disease, 70 susceptibility, 65 Mycobacterium kansasii pulmonary disease, 71 Mycobacterium marinum infection, 72 nontuberculous mycobacteria susceptibility testing, 66 Azole antifungal agents, 619, 620 rifabutin interactions, 624 rifampicin interactions, 623 Azoospermia, obstructive, 451
B B7-H1/B7-DC/PD-1, 82 B7-H2/ICOS, 82 Bacillus Calmette-Gue´rin (BCG), 18, 25, 107, 155, 759–768, 795, 978 adverse effects, 391, 394, 488, 495, 764 chemotherapy strains, 768 children, 395, 577 classification, 765 diagnosis, 764 diagnostic/management algorithm, 766 HIV infected individuals, 577, 763–764 immune reconstitution syndrome, 768 local/cutaneous, 484, 486, 764–765 management, 764 osteitis, 495, 767, 768 pulmonary disease, 767, 768 regional see Bacillus Calmette-Gue´rin (BCG) adenitis systemic disease, 767–768 tuberculids, 488 see also Bacillus Calmette-Gue´rin (BCG) disseminated disease (BCG-osis) BCG Pasteur, 759, 760, 761 cerebral tuberculosis prevention, 384, 411 contraindication with HIV infection, 706–707, 708 neonates, 577 daughter strains, 50, 55 development, 50 efficacy, 5, 6, 55, 107, 112, 735, 753, 761–762 HIV–infected individuals, 763 influence of background Th2 response, 93 meningitis protection, 384 nontuberculous mycobacterial disease, 391 variability in level of protection, 46, 49, 735, 761–762 genetics, 760–761 healthcare worker vaccination, 706, 904 historical aspects, 5, 759–760 immune response, 112, 729, 761 ‘improved’ strain, 753 intravesical instillation, 768 male genital tuberculosis induction, 450, 451 urinary tract infection induction, 446 M cell transport, 432 neonatal vaccination, 577 following maternal tuberculosis exposure, 576 Nocard strain, 50, 759, 760 normal reaction, 764 pyrazinamide resistance, 612 safety, 735 HIV–infected children, 113 tuberculin skin test cross-reactivity, 40, 133 false positive result, 181, 182, 458 vaccination programmes, 5, 762 vaccination recommendations, 735 Bacillus Calmette-Gue´rin (BCG) adenitis, 391, 765–766 HIV–infected children, 391 immune reconstitution inflammatory syndrome, 391, 394 Bacillus Calmette-Gue´rin (BCG) disseminated disease (BCG-osis), 767–768 with congenital cellular immune deficiency, 763 cutaneous lesions, 768 diagnosis, 764, 767 HIV infected individuals, 763 children, 394 management, 764, 767–768 lymphadenitis, 394 Bacillus Calmette-Gue´rin with RD1 (BCG::RD1), 56 BACTEC, 212, 473, 730 Bactec, 460, 170, 172, 173, 175, 219, 542
985
INDEX Bacteraemia, mycobacterial, 121 Badgers (Meles meles), bovine tuberculosis spead, 147 Bangladesh, 19 community involvement in tuberculosis control programmes, 663, 664 internal migration, 897 Barium contrast studies, 223 Barium enema gastrointestinal tuberculosis, 301, 426–427 Stierlin’s sign, 427 string sign, 427 Barium meal, gastrointestinal tuberculosis, 426 Barium swallow, tracheobroncho-oesophageal fistula, 371 Bars/pubs, outbreaks in social networks, 584, 589 Bartonella henselae, 208 bcg locus, 718 BDPProbeTec ET Mycobacterium tuberculosis Complex Direct Detection Assay, 198, 201 Beijing strains, 30, 32, 55, 56, 88–89, 169, 401, 587 molecular epidemiological studies, 34, 35 phenolic glycolipid production, 401 Spreading Index (SI), 55 Biochemical markers, 729 cerebrospinal fluid, 221 effusion fluid, 221–222 research priorities, 752 Biological safety cabinets, 742, 743 Bird fancier’s disease, 208 Birth weight, 575, 810 Bison, Mycobacterium bovis hosts, 147 Bladder fibrosis, 441 Bladder tuberculosis, 438, 439, 445–446, 521 imaging investigations, 306, 441 surgical treatment, 448 Blastomyces dermatitides, 207 Bleach method, sputum sample preparation, 171–172, 218, 231, 650, 739 Blinding, clinical trial design, 916–917 Blood dyscrasia, drug-induced, 683, 965–966 Blood specimen collection, 218 Blood vessel involvement imaging, 307 wall destruction, 126 Bloodhound eNose, 234 Boarding school outbreaks, 589 Body fluids discolouration, drug-induced, 686–687, 967 Bone grafting, spinal tuberculosis surgery, 520 Bone marrow biopsy, 399 Bone marrow lesions, 399 children, 394, 395 Bone pain, antituberculous drug side effects, 680 Bone scintigraphy, spinal tuberculosis, 497 Bone tuberculosis see Osteoarticular tuberculosis Bone/joint infection, nontuberculous mycobacteria, 68–69 treatment, 71–72 Botswana, 540 Bovine tuberculosis, 146 developed countries, 147 developing countries, 147 disease course, 146 eradication programmes, 146, 147, 151 historical aspects, 4, 146, 151 non-visibly lesioned (NVL) animals, 146 zoonotic importance, 146 Bowel obstruction, 127, 253, 382 surgical management, 430 Bracing spinal tuberculosis, 500 tuberculous arthritis, 502 Brain abscess, 251, 521 children, 271, 286, 288, 413, 422 imaging, 271, 286, 288, 313 Brain, space-occupying lesions, 127 Brazil, 12, 19, 227 Breast abscess, 470, 472 biopsy, 473, 474 Breast fibrosis, 126 Breast tuberculosis, 387, 469–474 age at presentation, 470 axillary lymph node involvement, 471, 472 biopsy, 474
986
carcinoma differentiation, 474 classification, 469, 470 clinical features, 470 diagnosis, 472–473 fine needle aspiration cytology, 473 microbiological culture, 473 polymerase chain reaction-based methods, 473 radiological investigations, 472–473 histopathology, 474 historical aspects, 469 HIV coinfection, 472 Indian literature, 469 in males, 470 medical treatment, 474 multidrug resistant tuberculosis, 474 pathogenesis, 471 primary, 469 secondary, 469 surgical treatment, 474 see also Mastitis, tuberculous Breastfeeding, 572, 577 antituberculous chemotherapy, 641–642 multidrug resistant tuberculosis, 645 breast tuberculosis, 471 HIV–infected women, 577–578 Breath tests, 224, 233–234 Breathlessness, 165, 335, 343 elderly patients, 565 pericardial effusions, 352 pericarditis, 381 pleural effusions, 381 children, 368 Bronchial artery embolization, 338, 339, 374 Bronchial aspirates, 217 Bronchial obstruction/stenosis, 120, 262 imaging, 297 see also Airway compression/obstruction Bronchial rupture, 121 Bronchial washings/brushings, 209 cytopathology, 210 processing, 209 Bronchiectasis, 124, 126, 242, 650 children HIV–infected, 161 indications for lung resection, 368 pre-chemotherapy studies, 141 Mycobacterium avium complex disease, 66 treatment, 70 nontuberculous mycobacterial infection, 61 body habitus association in postmenopausal women, 61, 66 imaging findings, 256, 257 postprimary tuberculosis, 242, 244, 246, 249 Bronchoalveolar lavage, 209, 217 cytopathology, 210 neonates, 574 specimen processing, 209 Bronchogenic carcinoma imaging, 300 tuberculosis patients, 564 Bronchogram, childhood airway disease, 365 Broncholithiasis, 247, 250 imaging, 300 Broncho-oesophageal fistula, 120, 382 children, 371–372 management, 372 ventilation problems, 372 Bronchopleural fistula, 242, 250, 381, 517 imaging, 246, 247, 299 surgical treatment, 517 Bronchopneumonia, tuberculous, 120, 121 Bronchoscopy broncho-oesophageal fistula, 371 caseating material removal, 365, 366, 367 childhood airway disease, 365 findings, 365–366 indications, 365 presurgical assessment, 367 expansile pneumonia, 370, 371 haemoptysis in children, 374 infection transmission risk, 581, 702, 706 lung resection, 517
preoperative evaluation, 517 lymph node enucleation, 371 transbronchial biopsy, 521 organ transplant patients with tuberculosis, 567 Bronx box, 53–54, 220 Broth-based drug susceptibility testing, 175, 219, 231, 542 Buffalo, Mycobacterium bovis hosts, 147 Bugie, Elizabeth, 4 Bursitis, tuberculous, 495, 496, 501, 502 imaging, 309 Buruli ulcer, 46, 55 clinical presentation, 69 diagnosis, 69 epidemiology, 61 treatment, 72 Busacca nodules, 478 Butcher’s warts, 148 Butter, bovine tuberculous transmission, 148 Byrd outbreak, 130
C 11
C-choline positron emission tomography, 314 C-reactive protein, 497, 511 antituberculous chemotherapy response, 528 C-type lectins, 76 variants, tuberculosis susceptibility, 89, 90 CA125, 458, 461, 512 Calcification, pulmonary, 120, 130, 137 children, pre-chemotherapy studies, 138–139 Calcitriol (1,25-dihydroxy vitamin D3), 90, 752 immune response to mycobacteria, 718 Calmette, Albert, 5, 759 Calmodulin, 77 Calmodulin-dependent protein kinase (CaMKII), 77, 79 Calymmatobacterium granulomatis, 208 Cambodia, 19 Canada, 148 nontuberculous mycobacteria, 60 Capreomycin, 613, 959 adverse effects, 678, 964, 965, 966 acute renal failure, 682 gastrointestinal upset, 680 nephrotoxicity, 613 ototoxicity, 685 peripheral neuropathy, 684 central nervous system penetration, 545, 557 clinical efficacy, 613 drug interactions, 970–971 extensively drug-resistant tuberculosis, 20, 555, 556 mode of action, 52 multidrug resistant tuberculosis, 408, 545, 613, 644, 656 children, 534 male genital tuberculosis, 455 nontuberculous mycobacteria resistance, 65 pregnant/breastfeeding women, 645 with renal failure, 564 resistance, 539, 540, 551, 757 cross resistance, 613 mutations, 52, 552 Cardiac catheterization, constrictive pericarditis, 354, 356 Cardiac tamponade, 352, 355, 359, 381 Care principles, 649 Care standards health facility management, 596 see also International Standards for Tuberculosis Care Case definition, 316 childhood tuberculosis, 143–144, 162, 363 extrapulmonary tuberculosis, 377 HIV–tuberculosis coinfection, 528 Case finding, 169, 228 active, 338, 339, 595, 931 children, 656 control strategy principles, 789 current limitations, 746, 749 DOTS programmes, 909, 934 implementation, 669–670 gender disparities, 888 HIV–coinfected individuals, 807 International Standards for Tuberculosis Care, 656 national TB control programmes, 795, 796, 801 new diagnostic methods, 230
INDEX passive, 595 research approaches, 755, 756 Stop TB strategy implementation, 942 workplace tuberculosis, 906 see also Contact tracing and management Case reproduction number, 132, 164, 788 Case-fatality rate, 17 Case-report forms, 918 Caseating granulomas adrenal tuberculosis, 509 epididymal tuberculosis, 452 hepatosplenic tuberculosis, 304 ovarian tuberculosis, 513 pancreatic tuberculosis, 511 renal tuberculosis, 444, 445 Cat scratch disease, 208 Catalase, 12 Catalase-peroxidase, 48 Cavernostomy, 516 Cavitating lung disease, 11, 57, 131, 729 childhood tuberculosis, 144, 268, 868 adult-type disease, 144, 362 antituberculous chemotherapy, 628 case study, 868 pre-chemotherapy era, 140 clinical presentation, 165 diabetic patients, 561, 562 imaging, 242, 243, 245, 253, 254, 268, 297, 298, 868 Mycobacterium tuberculosis strain differences, 12 postprimary (reactivation) tuberculosis, 122–123, 242, 243, 245 primary tuberculosis, 241 progressive primary tuberculosis, 241 CCL2 (MCP-1) variants, tuberculosis susceptibility, 88 CCL18 variants, tuberculosis susceptibility, 89 CCR5, HIV-1 cellular entry, 102 CD1, 75 antigen presentation, 77, 80 CD1-restricted T-lymphocytes, 75 function, 82–83 CD4, HIV-1 cellular entry, 102 CD4 T cells, 13, 75, 79 activation, 82 Bacillus Calmette-Gue´rin (BCG) response, 112 cytokine production, 80 effusion fluid cytomorphology, 210 function, 82 granulomas, 98, 118, 130 HIV infection, 124 tuberculosis coinfection, 97, 98–99, 103 immune response to mycobacteria, 378, 761 MHC Class II molecule interactions, 79 pleural effusions, 342, 343 vaccine development studies, 112 CD8 T cells, 75 activation, 82 Bacillus Calmette-Gue´rin (BCG) response, 112 CD1 antigen presentation, 80 cytolytic function, 82 MHC Class I molecule interactions, 79 tuberculosis immune response, 378 vaccine development studies, 112 CD14, 76 CD28, 82 CD40, 99 CD40 ligand, 99 CD80, 76, 82 CD86, 76, 82 CD161, 83 CDC control guidelines, 11 Cefoxitin Mycobacterium abscessus pulmonary disease, 71 Mycobacterium avium complex skin infections, 71 Mycobacterium fortuitum pulmonary disease, 71 nontuberculous mycobacteria susceptibility testing, 66 Cell membrane, 48 Cell wall permeability, 49 structure, 48–49 Cell-mediated immune response, 13, 75, 143, 515 lung cavitation, 11 pregnant patients, 575 Cellular migration, 83–84
Central nervous system tuberculosis, 384–385, 401–411 case studies, 831–834, 858–861 children, 271–274, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 413–422, 858–861 complications, 410–411 epidemiology, 401 extensively drug-resistant tuberculosis, 557 HIV coinfected individuals, 402–403, 526 HIV infection-related risk, 401 host genetic susceptibility, 401 imaging, 250–251, 271–274, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 309–311, 526, 858–861 parenchymal tuberculosis, 311–313 target sign, 313 tuberculous abscess, 313 management, 407–408 antituberculous chemotherapy, 407–408 drug-resistant tuberculosis, 408–409 mycobacterial genotype influences, 401 neuro-ophthalmological findings, 480–481 paradoxical reactions, 379 pathology/pathogenesis, 406–407 prevention, 411 response to treatment, 410–411 see also Intracranial tuberculomas; Meningitis, tuberculous Cerebral infarction, 410 imaging, 311 Cerebral tuberculomas see Intracranial tuberculomas Cerebritis, 251 Cerebrospinal fluid acid-fast bacilli detection, 221, 384, 404, 415 adenosine deaminase assay, 222, 404 antituberculous drug penetration, 379, 417, 545 ethambutol, 630 pyrazinamide, 630 rifampicin, 408, 630 streptomycin, 630 biochemical markers, 221 cerebral tuberculoma investigations, 402 cytology samples, 209 cytomorphology, 210 molecular analytic methods, 404, 416 neonates, 574 specimens collection, 217 processing, 210 tuberculosteric acid detection, 405 tuberculous meningitis investigations, 402 biomarkers, 404, 405 children, 415 microscopy, 404, 415 nucleic acid amplification techniques, 404, 416 response to treatment, 410 Cervical lymphadenopathy, 68, 131, 165, 380, 397, 464–465, 521 case studies, 821, 823–825, 835–836 cervical spinal tuberculosis, 495 children, 326–327, 380, 391, 823–825, 835–836 differential diagnosis, 393 clinical presentation, 380 diagnosis, 465 histopathology, 207 immune reconstitution inflammatory syndrome, 690 Mycobacterium bovis tuberculosis, 150 nontuberculous mycobacterial infection, 67–68, 327 treatment, 71 staging, 465 zoonotic tuberculosis, 148–149, 151 lupus vulgaris (scrofuloderma), 149 Cervical spinal tuberculosis, 495, 496, 497, 520 case study, 862 surgical treatment, 520 Cervical tuberculosis, 458, 459 clinical presentation, 459–460 differential diagnosis, 460 Cervicovaginal (Pap) smears, 209 Cetrimide decontamination, 232 CFP-10, 56, 79, 108, 776 interferon-g-based diagnostic assays, 185, 221, 345 serological detection, 189, 192
Chancre, primary tuberculous, 459, 486 differential diagnosis, 492 Cheese, bovine tuberculous transmission, 148 Chemokines, 83–84 tuberculosis susceptibility genes, 88–89 Chemotherapy see Antituberculous chemotherapy Chest pain, 165 pericardial effusions, 352 pericarditis, 381 Chest radiographs, 164, 223, 649 availability in resource-constrained settings, 317 breast tuberculosis, 472 childhood tuberculosis, 158, 159, 326, 362–363 adult-type disease, 142 airway compression/bronchial narrowing, 272, 273, 364, 365 allergic consolidation (epituberculosis), 141 bronchopneumonic consolidation, 141 care standards, 652 caseating consolidation, 141 classification of intrathoracic disease, 361, 362 frontal, high-kilovolt radiographs, 364, 365 HIV coinfection, 328 lymph node disease, 140, 141, 262, 264, 265, 267, 361, 364 multidrug resistant tuberculosis, 533 parenchymal disease, 268, 269, 270 pericardial disease, 274 pleural disease, 274 pre-chemotherapy studies, 136, 138, 140, 141, 142 primary tuberculosis, 239 screening, 324 unilateral hyperinflation, 364–365 children, normal appearances, 263 as clinical trial endpoint, 113 contact tracing, 772, 773 cutaneous tuberculosis, 490 diabetes mellitus with tuberculosis, 561 diagnosis of tuberculosis, 227, 316, 326, 336–337 algorithms, 316, 317 following positive tuberculin skin test, 184 immigrant screening, 733, 734 sensitivity, 651 elderly people, 565 expansile pneumonia, 369–370 extrapulmonary tuberculosis, 651 female genital tuberculosis, 458 gastrointestinal tuberculosis, 426, 434 Ghon focus, 138 healthcare worker pre-employment screening, 706 HIV–tuberculosis coinfection, 328, 336, 337, 526, 655 latent infection diagnosis, 808 immune reconstitution inflammatory syndrome, 697 International Standards for Tuberculosis Care, 651, 652 laryngeal tuberculosis, 464 male genital tuberculosis, 452 meningitis, tuberculous, 404–405, 415 miliary tuberculosis, 239, 386 multidrug resistant tuberculosis contact tracing, 536, 537 Mycobacterium avium complex pulmonary disease, 66, 67 Mycobacterium kansasii pulmonary disease, 66, 68 neonates, 574 nontuberculous mycobacteria pulmonary disease, 69 fibrocavitary disease, 256–257 nontuberculous mycobacteria-induced hypersensitivitylike lung disease, 258 ocular tuberculosis, 482 organ transplant patients with tuberculosis, 567 parathyroid tuberculosis, 508 pericarditis, tuberculous, 241, 356, 382 constriction, 353, 354 effusions, 352, 353 pituitary tuberculosis, 506 pleural effusions, 240, 344, 381 Pneumocystis jiroveci pneumonia, 160, 161 postprimary (reactivation) tuberculosis, 242, 245, 336 airway abnormalities, 247 primary (Ghon) complex, 136 primary tuberculosis, 237–238, 239, 336 cavitation, 241 parenchymal opacities, 239, 240 prison inmates, 586
987
INDEX Chest radiographs (Continued) pulmonary calcification, 120 renal failure patients with tuberculosis, 563 spinal tuberculosis, 497 thyroid gland tuberculosis, 467 tumour necrosis factor a antagonist pretreatment assessment, 569 Chest wall tuberculosis, children, 374 Childcare facility outbreaks, 584, 589 Childhood tuberculosis, 131, 154–162, 362, 515 abdominal see Abdominal tuberculosis active disease risk, 75, 323 adherence, 628, 634–635 adjuvant corticosteroids, 628 adult-type (secondary) see Postprimary tuberculosis airway disease see Airway disease antituberculous chemotherapy, 627–636, 670 administraton, 635 adverse effects, 635, 677 congenital tuberculosis, 577 dosages, 670 extrapulmonary tuberculosis, 630–631 first-line drug dosages, 627–628, 629–630 multidrug resistant tuberculosis, 534–535, 631–632 pharmacokinetics/pharmacodynamics, 628, 629–630, 633 prophylaxis, 330, 606, 635–636, 781 re-treatment cases, 631 second-line drugs, 632 Stop TB strategy implementation, 943 treatment regimens, 627–628 at-risk age periods, 41, 136, 154, 155, 324 broncho-oesophageal fistula, 371–372 case definitions, 143–144, 162, 363 cellular immune response, 155 central nervous system see Central nervous system tuberculosis cervical lymphadenopathy, 326–327, 380, 391, 393, 823–825, 835–836 chest radiographs see Chest radiographs chest wall tuberculosis, 375 chylothorax, 373 clinical examination, 157–158 clinical presentation, 156–157, 324 intrathoracic manifestations, 361–363 cold abscess formation see Cold abscess formation congenital tuberculosis see Congenital tuberculosis contact tracing (acive case finding), 40, 41, 134, 136, 144, 154, 155, 324, 606, 656, 781 investigations/management, 773, 775, 776 control programme impact assessment, 727–728 definition, 38 diagnosis, 154, 155–156, 216, 218, 229, 327, 362–363, 729, 753 active disease, 326–329 algorithm, 329, 753 bacteriological confirmation, 159, 362 care standards, 652 with HIV infection, 159, 160 scoring systems, 159 stratification according to resource availability, 323 symptom-based, 326–327 WHO guidelines, 155 DOTS programme implementation, 670 empyema, 368, 369 epidemiology, 38–42, 154, 771–772 age-related risk, 154–155 global burden of disease, 40 HIV coinfection, 160 information sources, 39–40, 42 population at risk, 40 sentinel event indicator of trends, 38, 40, 42 expansile pneumonia see Pneumonia, expansile extrapulmonary see Extrapulmonary tuberculosis fine needle aspiration biopsy, 211 follow-up, 635 gastrointestinal tuberculosis see Gastrointestinal tuberculosis haemoptysis, 374 HIV coinfection, 41, 42, 144, 154, 155, 156, 158, 159, 324, 363, 536, 656 Bacillus Calmette-Gue´rin (BCG) protective efficacy, 763
988
safety, 763–764 case study, 867 disseminated BCG disease (BCG-osis), 767–768 disseminated tuberculosis, 386 drug toxicities, 633–634 ear involvement, 387, 463 epidemiology, 41, 42, 324 gastrointestinal involvement, 435 immune reconstitution inflammatory syndrome, 380, 634, 695 long-term care facility outbreaks, 585 management, 325, 632–633 prognosis, 363 progression risk, 144, 324 testing, 161, 162, 533 timing of antiretroviral therapy initiation, 633, 634, 635 tuberculosis diagnosis, 159, 160, 328 tuberculous lymphadenitis, 393–394 tuberculous meningitis, 413, 416 hospital-based treatment, 603 host–pathogen balance, 142 immune response, 85, 143, 155, 324 index of suspicion in high-risk areas, 154 International Standards for Tuberculosis Care, 42, 652, 656 laryngeal tuberculosis, 373–374 latent infection, 144, 782 lymphadenitis see Lymphadenitis, tuberculous lymphobronchial tuberculosis, 364 meningitis see Meningitis, tuberculous multidrug resistant tuberculosis see Multidrug resistant tuberculosis musculoskeletal system see Musculoskeletal tuberculosis; Osteoarticular tuberculosis ocular, 476–483 eyelid, 477 oesophageal perforation, 372–373 osteomyelitis, 502 pericarditis, 351, 355 effusions, 274, 361, 382 phrenic nerve involvement, 373 pleural effusions see Pleural effusions pneumonia, 533 pre-chemotherapy natural history, 133–144, 323 adult-type disease, 141–142 allergic lung consolidation (epituberculosis), 141 bronchopneumonic lung consolidation, 141 caseating lung consolidation, 141 clinical ‘time-table’ of pathology, 136–138, 143, 787 exposure to infection, 133–134, 136 haematogenous spread, 142 intrathoracic manifestations, 138–140 lymph node disease, 140, 141 morbidity, 136 mortality, 136 pleural disease, 141 summaries of original studies, 134, 135, 137, 139 prevention, 330 Bacillus Calmette-Gue´rin (BCG) vaccinaion, 762 in resource-limited settings, 324, 325 primary tuberculosis see Primary tuberculosis prognosis, 363 radiology, 158, 159, 262–295, 362–363, 858–869 intrathoracic disease classification, 361, 362 research priorities, 753 reticuloendothelial system, 394–395 retropharyngeal abscess, 374 screening (in resource-limited settings), 324–325 algorithm, 325 spinal see Spinal tuberculosis sputum specimen collection, 209, 217, 326, 328, 362, 650, 652 transitions, 38–39, 40, 323 disease to cure, 42 disease to death, 41–42 exposure to infection, 41, 133–134, 136, 323 infection to disease, 41, 136–137, 323, 324 treatment, 161–162 complicated intrathoracic and upper airway disease, 364–375 disseminated disease, 331 flow diagram, 329–330 guidelines, 330
management algorithms, 323–331 principles, 329 rationale, 330 sputum-smear negative disease, 330–331 sputum-smear positive disease, 331 tuberculin skin test, 158 see also Infants; Pulmonary tuberculosis Children HIV infection see HIV infection immune system maturation, 155, 324 normal chest radiograph, 263 Chile, 23 China, 19, 22, 23, 25, 164, 596, 940 childhood tuberculosis, 40 internal migration, 897 multidrug resistant tuberculosis, 539, 551, 642, 943 Chloride, cerebrospinal fluid, 221 Choroidal tubercles, 476, 481 HIV coinfected patients, 481 Choroidal tuberculosis (posterior uveitis), 478–479 differential diagnosis, 479 serpiginous choroiditis, 479 Chronic obstructive pulmonary disease, 335, 336 corticosteroids use, risk of tuberculosis, 566 nontuberculous mycobacterial infection, 61, 67 Chylothorax, 380 children, 373 Chylous ascites/chyluria, 380 Chylous peritonitis, 434 Ciprofloxacin, 615, 959 childhood tuberculosis, 634 clinical efficacy, 615 cross resistance, 555 drug susceptibility testing, 730 multidrug resistant tuberculosis, 644 prophylaxis in contacts, 536 nontuberculous mycobacteria susceptibility testing, 66 resistance, 553 Civil society organizations, 660, 662 Clarithromycin, 615, 959 adverse effects, 963, 964, 965, 966, 967 clinical efficacy, 615 cytochrome P450 inhibition, 619 drug interactions efavirenz, 645 nevirapine, 645 rifabutin, 624 rifampicin, 624 ritonavir, 645 male genital tuberculosis, multidrug resistant, 455 Mycobacterium avium complex infection, 65, 70, 72 Mycobacterium kansasii infection, 70, 71 Mycobacterium marinum infection, 72 nontuberculous mycobacteria susceptibility testing, 66 Clavulanic acid, 615 Clinic cards, 599, 602 HIV–infected patients, 605 Clinical diagnosis, 316 Clinical governance, global tuberculosis control strategies, 789 Clinical trial protocol, 917–918 administrative aspects/logistics, 918 budget, 919 design details, 918 ethical issues, 918 Good Clinical Practice, 921 Institutional Review Boards/Independent Ethics Committees review, 920 investigators’ responsibilities, 920 objectives, 918 rationale for study, 918 reporting/dissemination, 918 sponsors’ responsibilities, 920 timeline, 918–919 Clinical trials, 916–923 adherence, 917 administrative arrangements, 922 blinding, 916–917 budget, 922 control groups, 916, 918 data collection methods, 918 data management/analysis, 923 design, 916–917
INDEX non-inferiority, 917 sample size calculation, 918 sponsors’ responsibilities, 920 superiority, 917 trial population, 918 in developing countries, 757 drug delivery, 917 ethical issues, 757, 918 historical aspects, 917 inclusion/exclusion criteria, 916, 918 infrastructure requirements, 751 Investigator’s Brochure, 921, 922 management/coordination, 921–922 monitoring, 921, 922 site visitis, 922 outcome measures, 918 patient recruitment, 918 randomization, 916, 917, 918 Standard Operating Procedures (SOPs), 921, 922 statistical analysis, 918 supervision, 922 committees, 923 terminology, 916 see also Good clinical practice (GCP) Clinics, 596, 603 drug-resistant tuberculosis management, 605 infection control, 598 risk classification, 703 inner city care of working patients, 606 management issues, 598 non-attender follow-up, 599, 605 nurse-run, 711 patient monitoring, 598 patient referral, 596, 598 record-keeping, 599 staff training, 598 see also Healthcare settings CLIP, 79 Clofazimine, 52, 615, 959 adverse effects, 678, 963, 964 abdominal pain, 680 Clubbing, finger, 161, 165 Co-stimulatory molecules, 75, 79 dendritic cells, 76, 77 Co-stimulatory pathways, T cell activation, 82 Coagulopathy, drug-induced, 966 Coccidioides immitis, 207 Cochlear damage, antituberculous drug-induced, 685 see also Ototoxicity Cold abscess formation cervical lymphadenopathy, 380, 465 children, 374, 380 chest wall, 868 liver, 394 lymphadenitis, 380, 392 spleen, 394 HIV–tuberculosis coinfection, 526 musculoskeletal tuberculosis, 495 orbital tuberculosis, 479 paraosseous, 307 seminal vesicle tuberculosis, 450, 451 spinal tuberculosis, 495, 496, 497 surgical drainage, 501 Collaborative tuberculosis/HIV activities, 804–811, 942, 943, 980, 982 HIV infection antiretroviral therapy, 809 cotrimoxazole prophylaxis, 809 patient care/support, 809 prevention, 808–809 testing and counselling, 808 injecting drug users, 810 integration of programmes, 674, 754, 805–806 coordinating bodies, 806 implementation, 806 joint planning, 806–807 monitoring/evaluation systems, 807 national TB control programmes, 798, 804, 805 prison inmates, 810 recommended activities, 806 record keeping, 807 refugees, 810 surveillance, 806
tuberculosis case finding, 807 infection control, 808 preventive therapy, 807–808 WHO ProTEST initiative, 804–805 women of reproductive age, 810–811 Collagen vascular disease, 566 Collapse, lung/lobar, childhood tuberculosis airway obstruction, 364 imaging, 268 pre-chemotherapy studies, 141 Colonic tuberculosis, 382, 424, 426 children, 433 clinical presentation, 426 strictures, 427 Colonoscopy, 224 gastrointestinal tuberculosis, 427–428, 434 Colony morphology, 49, 50, 219 Colorimetric methods, 730 drug susceptibility testing, 176 Common cold, 9 Communicable disease theory historical aspects, 786 ‘web of causation’, 787–788 agent, 787 environment, 788 host, 787–788 transmission, 788, 792–793 Communities, definition, 662 Community participation, 660–666 at country level, 663–664 core elements, 664, 665 advocacy, 665 budgeting/financing, 666 capacity building, 665 evaluation, 666 monitoring, 666 policy guidance, 665 quality assurance, 666 social mobilization, 665 training plans, 665 DOTS programme implementation, 670, 672 operational partnership establishment, 662 partnership approach, 662–663, 666 rights-based approach, 664 social justice, 664 Stop TB Strategy implementation, 944, 945 terminology, 661 tuberculosis control programmes, 913 case study using storekeepers, 914 national programmes, 799 Community volunteers, 663 DOTS programme implementation, 670 Complement, 75, 76 Complement receptors, 75–76 Compliance see Adherence Computed tomography, 224, 297–300 abdominal tuberculosis, 269, 278, 279, 303 adrenal tuberculosis, 509, 510 airway disease, 365 arthritis, tuberculous, 308, 502 ascites, 302, 303 brain parenchymal infection, 251 breast tuberculosis, 473 cerebral infarction, 311 childhood tuberculosis, 269, 274, 278, 279, 291, 292, 297, 365, 368, 421 airway compression/bronchial narrowing, 272, 273 airway, presurgical assessment, 367 central nervous system, 271, 273, 274, 280, 281, 282, 283, 284, 285, 286, 290, 414, 416 hepatic, 395 intrathoracic cold abscess, 374 lymphadenopathy, 262, 266, 267, 268, 297, 298 parenchymal lung disease, 270, 271, 297 chyothorax, 373 corticosteroid treatment-related tuberculosis, 566 empyema, 347 expansile pneumonia, 370 extrapulmonary tuberculosis, 671 gastrointestinal tuberculosis, 253, 301, 302, 303, 427 omental/small bowel mesentery involvement, 303 genitourinary tuberculosis, 441
hepatosplenic tuberculosis, 304, 395 HIV–tuberculosis coinfection, 254, 526 hydrocephalus, 384, 404, 414, 417 immune reconstitution inflammatory syndrome, 697 laryngeal tuberculosis, 373 male genital tuberculosis, 452 mediastinal lymphadenopathy, 380, 398 meningitis, tuberculous, 271, 273, 274, 280, 281, 282, 283, 284, 285, 286, 290, 310, 311, 384, 404, 414, 415, 416 miliary tuberculosis, 239, 269, 299 myocarditis, tuberculous, 359 nontuberculous mycobacterial pulmonary disease, 66, 67, 68, 69 oesophageal-mediastinal fistula, 251 orbital tuberculosis, 479 organ transplant patients with tuberculosis, 567 ovarian tuberculosis, 512 pancreatic tuberculosis, 305, 511 parathyroid tuberculosis, 508 pericardial constriction, 353, 354 pericardial effusions, 352 pericarditis, tuberculous, 274, 352, 356, 382 peritoneal tuberculosis, 303, 461 pituitary tuberculosis, 506 pleural effusions, 299, 368, 381 pleural tuberculosis, 274, 344 postprimary (reactivation) tuberculosis, 245, 297–299 airway abnormalities, 247 primary tuberculosis, 238, 297 prostate tuberculosis, 306 radiculomyelitis, tuberculous, 313 Rasmussen aneurysm, 250–251, 300 renal tuberculosis, 252, 305, 452 retropharyngeal abscess, 374, 466 skull, bone tuberculosis, 467 spinal tuberculosis, 291, 292, 307, 385, 497, 519 thyroid tuberculosis, 507 tuberculomas, 280, 300 intracranial, 312, 313, 406, 421 tuberculosis complications, 300 see also High resolution computed tomography Confidentiality, 655, 905, 934 clinical trial data, 918 Confusion, antituberculous drug-induced, 687 Congenital transmission, 572 Congenital tuberculosis, 127, 328, 388, 572 antituberculous chemotherapy, 577 case report, 850–851 clinical presentation, 577 definition, 572 maternal history, 573 Congregate settings, 333 air-travel-linked outbreaks, 584, 590–591 assisted living situations, 584–585 childcare facilities, 589 confined locations, 581–592 contact tracing, 773 extensively drug-resistant tuberculosis, 553, 554 healthcare facilities, 581–584 homelessness shelters, 587–588 infection control plans, 944 military installations, 587 multidrug resistant tuberculosis, 547 outbreaks with HIV infection, 536 prisons, 585–587 schools, 588–589 social network-linked outbreaks (bars/pubs), 589–590 Stop TB Strategy implementation, 944 tuberculosis infection risk, 10, 11, 808 worksites, 588 Conjunctival biopsy/smears, 478 Conjunctival tuberculosis, 477–478 Consent see Informed consent Consolidation, pulmonary expansile pneumonia, 369 imaging findings, 253, 254 HIV–tuberculosis coinfection, 254 postprimary (reactivation) tuberculosis, 242 progressive primary tuberculosis, 241 Contact tracing and management, 130, 155, 323, 606–607, 771–778 active, 361
989
INDEX Contact tracing and management (Continued) air-travel-related exposure, 590 antituberculous drug prophylaxis, 536, 781 bar/pub outbreaks (social network-linked outbreaks), 589–590 children, 40, 41, 134, 136, 144, 154, 155, 324, 606 multidrug resistant tuberculosis, 532, 533, 535, 536, 607 concentric circle approach, 772, 774 contact medical evaluation, 775–776 contact priority ranking, 773–775 control strategy principles, 789 decision to initiate investigation, 772 definitions, 772 evaluation of procedures, 777 field investigation, 773 field visits to contacts, 775 high-prevalence countries, 776 immigrant workers (case study), 896 index case assessment, 772 interview, 773 International Standards for Tuberculosis Care, 656 investigation plan, 773 low-prevalence countries, 772–776 military installation outbreaks, 587 objectives, 772 optimization, 777–778 prison inmates, 586 school outbreaks, 588 tuberculin skin testing, 185, 220 worksite outbreaks, 588 see also Case finding Contact transmission, infection control strategies, 702 Contraceptive pills, rifampicin interactions, 687 Control groups, clinical trial design, 916, 918 Control strategies, 15, 19, 22–24, 132, 164, 377, 734–735, 940, 942 animal reservoirs, 793 care standards, 789 see also International Standards for Tuberculosis Care community involvement, 660, 661, 913 see also Community participation coordination of HIV and TB care programmes, 674, 754 DOTS see DOTS (Directly Observed Treatment, Short-Course) drug resistance prevention, 740 elimination goals, 24–25 extensively drug-resistant tuberculosis, 553–554, 558 financial resources, 791 future perspectives, 937, 955 gender issues, 890 global approaches, 786–793, 980, 981 healthcare facility infection control plans, 703 historical aspects, 786, 938 Styblo model development/implementation, 932–933 human resources, 791 immigrants/refugees, cost-effectiveness, 733–735 indicators for monitoring, 946 interdisciplinary approaches, 980 laboratory services requirements, 740–741 latent disease treatment (prophylactic chemotherapy), 783–784 limitations of current approaches, 791–792 multidrug resistant tuberculosis, 547 new strategies, 740 organization of services, 791 patient involvement, 913 political/administrative commitment, 668–669 poverty issues, 908, 909 principles, 788–789 public health measures, 789–790 quality assurance, 789 research approaches, 754–755, 790–791 statistics/modelling, 790 surveillance, 789–790 Web information sources, 972–973 workplace tuberculosis, 904–905 see also National TB control programmes Controversies, 727–735 Convulsions see Seizures Cord factors, 49 Corneal tuberculosis, 478
990
Corticosteroid treatment-related tuberculosis, 566 Corticosteroids, 166, 256, 259, 752 adrenal insufficiency (Addison’s disease), 509 anaphylactic drug reaction management, 677 childhood tuberculosis, 418, 422, 435–436, 628, 630 airway disease, 366 multidrug resistant disease, 535 extrapulmonary tuberculosis, 671 gastrointestinal tuberculosis, 435–436 HIV–tuberculosis coinfection, 104, 529 immune reconstitution inflammatory syndrome, 528, 697 intracranial tuberculomas, 385, 422 meningitis, tuberculous, 379, 385, 409–410, 418, 630 ocular tuberculosis, 478, 479, 480, 481, 482 pericardial constriction, 358 pericardial effusions, 357–358 pericarditis, tuberculous, 379, 382 pleural tuberculosis, 347, 369 respiratory failure, tuberculous, 379 rifampicin interactions, 455, 630 Cortisol–cortisone shuttle dysregulation, 92 Cost-effectiveness control strategies in immigrants/refugees, 733–735 DOTS strategy, 954 Global Plan to Stop TB, 954 HIV–tuberculosis coinfection treatment, 753 nucleic acid amplification tests, 201 Cost-recovery schemes, 801 Cotrimoxazole, 655 adverse effects, 697 skin rash in children, 633 long-term availability, 605 nontuberculous mycobacteria susceptibility testing, 66 pleural tuberculosis, 347 Pneumocystis jiroveci pneumonia (children), 160 prophylaxis, 529, 655, 807, 809 adverse effects, 676 case report, 880–881 children, 632, 753 reseach priorities, 755 rifampicin interactions, 624 Cough, 165, 166, 316, 333, 334, 335, 362, 553, 788, 888 childhood tuberculosis, 154, 155–156, 157 infants, pre-chemotherapy studies, 141 multidrug resistant tuberculosis, 533 symptom-based diagnosis, 326 HIV–tuberculosis coinfection, 525, 807 International Standards for Tuberculosis Care, 650 management approach, 339 Mycobacterium tuberculosis transmission, 11, 123, 129 human-to-animal, 150 pericarditis, tuberculous, 352, 381 pleural tuberculous, 343, 381 Cough aerosol-sampling, 11 Cough hygiene in healthcare settings, 706, 904 CR1, 75, 76 CR3, 75, 76 CR4, 75, 76 Cranial nerve involvement, 384, 401–402 imaging, 311 intracranial tuberculomas, 480–481 pathogenesis, 406 tuberculous meningitis, 413, 480 CRISPAs (clustered regularly interspaced short palindromic repeats), 51–52 Crofton, John, 930, 931, 979 Crohn’s disease, 52, 90, 239, 301, 303, 512, 520 gastrointestinal tuberculosis differentiation, 426, 427, 428, 429–430 children, 435, 438 histopathology, 207 Cross resistance, 555, 556, 613, 644 Crowded conditions see Congregate settings Cryptococcal infection, 207, 623, 689, 695 Cryptogenic organizing pneumonia, 566 CTLA-4 (CD152), 82 Cuba, 23, 540 Culture filtrate proteins (CFPs), 47, 48 Culture media, 47, 172, 212, 219, 231 liquid, 172, 219 nontuberculous mycobacteria, 62, 65 solid, 172, 219 TK medium, 174, 219
Culture, mycobacterial see Microbiological culture Cutaneous drug reactions, 679–680 drug challenge/reintroduction, 679, 680 management, 679 prevention, 679–680 see also Skin rash Cutaneous tuberculosis see Dermatological tuberculosis Cutis miliaris disseminata, 386, 387 CXCR4, HIV–1 cellular entry, 102 Cycloserine, 614, 960 adverse effects, 535, 557, 614, 678, 964, 965, 966 depression/psychosis, 686 neurotoxicity, 614 peripheral neuropathy, 684 seizures, 685 central nervous system penetration, 545, 557 clinical efficacy, 614 drug interactions, 970–971 extensively drug-resistant tuberculosis, 555, 556 mode of action, 52, 614 multidrug resistant tuberculosis, 643 children, 534, 535 male genital tuberculosis, 455 meningitis, 408 pharmacology/pharmacokinetics, 614 resistance-determining gene mutations, 52, 552 teratogenicity risk, 576 Cyclosporin, drug interactions, 563 rifampicin, 455 streptomycin, 447 Cystic fibrosis, nontuberculous mycobacterial infections, 61, 66, 256 Cystourethrography, 452 Cytochrome P450s inducers exposure, drug-induced hepatotoxicity risk, 681 role in drug interactions, 619, 620, 630, 633 rifabutin, 623 rifampicin, 611 rifamycins, 528, 623 Cytokine therapy, 546, 752 Cytokines antiinflammatory, 82 dendritic cell production, 80–81 macrophage activation, 718 role of adjuvant immunomodulatory therapy, 752 macrophage production, 80–81, 718 Th1 cells, 82 tuberculosis susceptibility genes, 88–89 Cytology, 205 fluid samples, 209–210 processing, 209 pleural effusions diagnosis, 345 specimens, 209 tuberculosis diagnosis, 209–214 Cytomegalovirus, 689, 695, 698
D D ureC-lloþ, 753 Dactylitis, tuberculous, 494, 502 imaging findings, 252 Dapsone, 52 rifampicin interaction, 624 Dark Ages, 2 Data collection clinical trials, 918 management/coordination, 922 Stop TB Strategy implementation, 943 see also Record-keeping; Reporting systems Data management/analysis, clinical trials, 923 DC-SIGN, 76 HIV–tuberculosis coinfection effects, 98 variants, tuberculosis susceptibility, 90 Declaration of Helsinki, 920 Deer, Mycobacterium bovis hosts, 147 Defensins, 84 Dehydroepiandrosterone, 92 Delayed type hypersensitivity, 13, 136 HIV–tuberculosis coinfection, 97 immune reconstitution inflammatory syndrome, 697, 699 lung cavitation, 11
INDEX Mycobacterium tuberculosis strain differences, 12 nontuberculous mycobacteria infections, 60 paradoxical reaction, 689 pathogenesis, 119 primary tuberculosis, 119, 124 tuberculous pleurisy, 124, 378, 381 Deletions, 35, 54 Deligotyping, 32 Demeclocycline, 410 Democratic Republic of Congo, 19 Dendritic cells, 75, 76, 82 antigen processing, 77–79 children, 85 cytokine production, 80–81 granuloma formation, 117 HIV–tuberculosis coinfection impact, 98 maturation, 76 Toll-like receptors signalling, 77 Mycobacterium tuberculosis uptake, 75, 76 receptors, 76 phagosomes, 77–79 Denmark, 148, 167, 886, 888 Depression, antituberculous drug-induced, 686 Dermatological drug side effects see Cutaneous drug reactions Dermatological tuberculosis, 386–387, 484–493 BCG adverse effects, 768 case reports, 839–840 classification, 484–485 diagnosis, 485–486, 489–490 differential diagnosis, 491, 492 haematogenous, 488 historical aspects, 484 neonatal tuberculosis, 573, 574 pathogenesis, 485–486 primary, 486–487 secondary from endogenous source, 487–488 treatment, 491 children, 491–492 tuberculids, 488 Dexamethasone, tuberculous meningitis adjunctive treatment, 379, 409, 418, 529 Diabetes insipidus, 504 Diabetes mellitus, 256, 333, 386, 401, 611, 773 antituberculous drug adverse effects, 676 renal failure, 683 case histories, 814 rifampicin use, 611 tuberculosis, 560–562 clinical features, 560 differential diagnosis, 561 epidemiology, 560 glycaemic control, 560, 561 investigations, 561 management, 561–562 physical examination, 560–561 prognosis, 562 tuberculosis risk, 166, 560, 771, 944 Diagnosis, 164 available tests, 169, 170, 217 biochemical markers see Biochemical markers care standards, 649 see also International Standards for Tuberculosis Care chest radiographs see Chest radiographs children see Childhood tuberculosis current problems, 228–229 developed versus developing countries, 216, 227 effusion fluid examination, 221–222 facilities, 227, 228, 595, 603 health system levels, 230–231 laboratory system requirements, 738 histopathological, 205–206 historical aspects, 4 imaging, 223–224 immune-based see Immune-based diagnostic tests microbiological culture see Microbiological culture new methods, 227–234, 730 antibody response detection, 233–234 microscopy, 231 molecular methods, 232–233 mycobacteria growth detection, 231–232 prioritization, 230–231 product development partnerships (PDP), 229–230
nucleic acid amplification tests see Nucleic acid amplification tests ordering tests, 216–225 poverty-related barriers, 912 improving access to services, 913 protocols in healthcare settings, 706 audit, 704–705 research priorities, 746, 747, 748–750, 753 sputum smear microscopy see Sputum smear microsocpy Stop TB Strategy implementation, 945–946 unresolved issues, 729–730 see also Diagnostic algorithms Diagnostic algorithms, 316–322, 740, 746 BCG adverse events, 766 childhood tuberculosis, 329, 652, 753 multidrug resistant disease, 533 extrapulmonary tuberculosis, 317 DOTS programme implementation, 671 HIV–tuberculosis coinfection, 316, 317–318, 319 one-stop methods, 913, 914 pulmonary tuberculosis, 316–317, 669 sputum smear microscopy, 316, 317, 651 Dialysis patients, 440, 563 antituberculous chemotherapy, 564 tuberculosis, 562 Didanosine adverse effects, 557 fluoroquinolone interactions, 619, 645 Diffusion weighted imaging, meningitis, 271, 274, 290 Digital rectal examination, prostate tuberculosis, 450 Dignity of individuals community healthcare programmes, 665 patient-centred health service provision, 662 Direct repeat (DR) chromosomal region, 30, 52, 103 Direct variable repeat (DVR), 30 Disability grants, 605 Disseminated nontuberculous mycobacterial infection, 69 diagnosis, 69 treatment, 72 Disseminated tuberculosis, 131, 385–386 children, 155, 386, 627 pre-chemotherapy studies, 136, 140, 141, 142 reticuloendothelial system involvement, 394 treatment guidelines, 330, 331 clinical presentation, 386 corticosteroid treatment-related, 566 definition, 385 diagnosis, 386 HIV–tuberculosis coinfection, 97, 166, 386 clinical presentation, 525 immune reconstitution inflammatory syndrome risk, 695 primary disease, 333 renal tuberculosis, 445 see also Miliary tuberculosis Dissemination, 121–122, 130–131, 136, 237, 333, 385–386, 515 abdominal tuberculosis, 520 breast tuberculosis, 471 childhood tuberculosis, pre-chemotherapy studies, 142 endobronchial, 245, 254 extrapulmonary tuberculosis pathogenesis, 377, 378 gastrointestinal tuberculosis, 432 musculoskeletal tuberculosis, 495 Mycobacterium tuberculosis strain differences, 12 postprimary (reactivation) tuberculosis, 242 zoonotic tuberculosis, 149 DNA vaccines, 753 Domagk, Gerhardt, 4 Dormancy, mycobacterial, 56, 143, 608, 719, 728, 729, 753, 787 DOT (directly observed treatment), 347, 917, 934 advantages, 654 HIV–tuberculosis coinfected individuals, 527, 641, 753, 804 injecting drug users, 810 latent tuberculosis treatment (prophylaxis), 776, 777 migrant patients, 897, 898, 899 outcome evaluation, 654 pregnanct patients, 576 prison inmates, 587
DOTS (Directly Observed Treatment , Short-Course), 22, 25, 164, 228, 338, 639, 640, 649, 654, 661, 727, 740, 746, 757, 791, 890, 930–938, 940, 943, 950, 951, 979, 980 adaptation to emergence of drug resistance, 934 to emergence of HIV epidemic, 933–934 case detection, 22, 669, 909 children, 330, 379, 533, 535, 627, 630, 633, 635, 670 clinic-based services, 596, 598 community involvement, 672 cost-effectiveness, 954 delivery system, 668 extensively drug-resistant tuberculosis, 555 global tuberculosis control strategies, 789 laboratory service requirements, 739, 740 multidrug resistant tuberculosis, 533, 535, 644, 646, 656, 944, 946 national TB control programmes, 795, 797, 799 patient support aspects, 598 political/administrative commitment, 668–669 programme evaluation, 22–23, 673 programme implementation, 668–675, 933 adherence, 671–672 antituberculous drug regimens, 670–671 case finding, 669 case referral mechanisms, 670 drug supply, 673 extrapulmonary tuberculosis, 670–671 monitoring response to treatment, 672 private sector involvement, 674 sputum microscopy services, 669–670 supervision/monitoring, 673 progress against 2005 targets, 934–935 publicity/promotion, 934 reporting system, 657 Stop TB Strategy, 23–24 expansion, 24, 942–943, 946, 949, 950 workplace healthcare programmes, 904, 905 DOTS supporters, 555, 639, 934 elderly tuberculosis patients, 565 International Standards for Tuberculosis Care, 653 private doctors, 604 working patients, 606, 906 DOTS-Plus, 535, 555, 757, 934, 950 multidrug resistant tuberculosis, 543 Double negative T cells, 80 Double-balloon enteroscopy, gastrointestinal tuberculosis, 428 Doxycycline Mycobacterium chelonae pulmonary disease, 71 Mycobacterium fortuitum pulmonary disease, 71 Mycobacterium marinum infection, 72 nontuberculous mycobacteria susceptibility testing, 66 Droplet nuclei, 8, 9, 13, 129, 130, 333, 581, 788 exposure risk, 130 healthcare setting control strategies, 702 transmission-based infection precautions, 702 tuberculosis transmission, 8, 9, 123, 129 Drowned lung (liquefaction necrosis), 268 see also Pneumonia, expansile Drug adverse effects clinical trials, 916 Good Clinical Practice, investigators’ responsibilities, 920 post-marketing surveillance, 916 see also Antituberculous chemotherapy Drug interactions, 641, 963, 967–971 antiretroviral–antituberculous drug see Antiretroviral therapy HIV–infected patients, 618–625 mechanisms, 618–619 absorption, 618–619 cytochrome P450s induction, 619, 620 cytosolic enzymes, 619–620 mixed inhibitor/inducer drugs, 620 P-glycoprotein induction, 619 prediction rule limitations, 620 research priorities, 625, 751, 752–753 Drug resistance, 164, 174, 638, 927, 980 ‘amplifier effect’, 553 Beijing lineage, 55 Bronx box detection method, 53–54, 220
991
INDEX Drug resistance (Continued) cross-resistance/class-resistance, 553, 555, 611, 613 DOTS strategy adaptation, 934 due to errors in tuberculosis management, 649, 655 follow-up testing, 741 International Standards for Tuberculosis Care, 655 management in children, 631 mechanisms, 552 molecular epidemiological studies, 34–35 mutations, 52–53, 552–553 plasmid transfer (infectious drug resistance), 54 prevention, 553, 608–609, 649, 740 TB control programme strategies, 740 primary (new drug resistance), 532, 552 second-line drugs, 553 secondary (acquired), 532–533, 552 Stop TB Strategy implementation, 943–944 surveillance, 739 see also Extensively drug-resistant tuberculosis; Multidrug resistant tuberculosis Drug supply, 599, 655, 668, 800 DOTS programme implementation, 673, 942 national TB control programmes, 797, 799 second-line drugs, 605 Stop TB Strategy implementation, 943 workplace tuberculosis control, 906 Drug susceptibility testing, 219, 227, 230, 540, 542, 739, 740 absolute concentration method, 175, 542 colorimetric methods, 176, 232 contact tracing, 773 conventional (phenotypic) testing, 174–175, 542 direct/indirect testing, 175 extensively drug-resistant tuberculosis, 551, 554, 556 International Standards for Tuberculosis Care, 655, 656 laboratory services networks, 791 requirements, 738, 740, 742 safety, 742, 743 line probe assays (strip tests), 201–202, 219–220 microbiological culture, 174–175, 219, 232, 739 rapid liquid culture media, 175, 219, 231, 542 microscopic observation of drug susceptibility (MODS) assay, 174, 176–177, 219, 232, 408 molecular methods, 175–176, 219, 233, 542 molecular beacons, 202 multidrug resistant tuberculosis, 534, 542–543, 545, 641, 642, 644, 656, 730, 740 contacts, 536 follow-up, 741 nontuberculous mycobacteria, 65–66 limitations, 70 phage-based assays, 176, 219, 220, 232 previously treated cases, 640 childhood tuberculosis, 631 proportion method, 175, 219, 542, 543 pyrazinamide, 175, 219 quality assessment, 743 resistant ratio method, 175, 542, 543 rifampicin, 408 second-line drugs, 542–543, 730 Stop TB strategy implementation, 942–943 Dubos Tween albumin broth, 172 Duodenal tuberculosis, 301, 382, 425, 520 clinical presentation, 425 Dusts exposure, 902 Dysglycaemia, drug-induced, 967 Dyslipidaemia, drug-induced, 967 Dyspnoea see Breathlessness
E Eales’ disease, 479–480 Ear discharge, neonatal tuberculosis, 573, 574 Ear tuberculosis, 387, 463 complications, 463 treatment, 463 Early bactericidal activity, 608, 638 amikacin, 613 drug resistance prevention, 608 fluoroquinolones, 615 isoniazid, 608, 610 rifabutin, 611
992
Eastern Europe, 23, 228, 951 epidemiology, 21–22 current status, 940 extensively drug-resistant tuberculosis, 540, 552 gender disparities in tuberculosis, 886–887 Global Plan to Stop TB targets, 951, 952, 954 Millenium Development Goals, 24, 25 multidrug resistant tuberculosis, 539 Eastern Mediterranean Region, 951 Echocardiography tuberculous myocarditis, 359 tuberculous pericarditis, 356, 382 constriction, 353 effusions, 352, 353 Ecology of mycobacteria, 45–46 Education employers, 606 International Standards for Tuberculosis Care, 657 laboratory staff, 741 patients, 595, 596, 598 public/community, 791 EEA1 (early endosomal autoantigen 1), 79 Efavirenz, 641 adverse effects, 557 skin rash in children, 633 contraindications infants, 634 pregnant patients, 578, 634, 641, 810–811 drug interactions, 557 clarithromycin, 645 rifampicin, 619, 620–621, 633, 752, 810 rifamycins, 620, 624 fixed-dose combinations, 753 variability in pharmacokinetics, 620 Effusion fluid adenosine deaminase assay, 222 biochemical markers, 221–222 cytomorphology, 210 interferon-g release assays, 222 lysozyme, 223 microscopy, 221 specimen collection, 209, 217 specimen processing, 209 Egypt, 150 Ehrlich, Paul, 4, 46 eis (enhanced intracellular survival), 56 Elderly people, 565, 788 active tuberculosis risk, 75, 565 antituberculous chemotherapy, 565 adverse effects, 677 hepatotoxicity risk, 681 extrapulmonary tuberculosis, 377 investigations, 565 long-term care facility outbreaks, 585 spinal tuberculosis, 385 tuberculin skin test, 182 false-negative tests, 181 tuberculosis clinical presentation, 335, 565 Electrocardiogram, tuberculous pericarditis, 356 acute, 352, 354 constriction, 353 effusions, 352, 354 ELISA, 169 gastrointestinal tuberculosis diagnosis, 428 HIV diagnosis, 221 interferon-g-based diagnostic assays, 186, 221, 777 lipoarabinomannan diagnostic assay, 174 serological diagnostic methods, 185, 191, 192, 223, 730 ELISPOT, 730 interferon-g-based diagnostic assays, 185, 221, 777, 781 tuberculous meningitis diagnosis, 405 Elks Mycobacterium bovis hosts, 147 tuberculosis transmission, 147, 148 embA, 612 mutations, 53 embB, 612 mutations, 53 embC mutation, 53 Emergency Plan for AIDS Relief, 806 Emphysema, 242
Employment, 606 see also Workplace healthcare programmes; Workplace tuberculosis Employment sector definition, 901 role in tuberculosis control, 904–905 Empyema, 124, 127, 342, 381 children, 368, 369, 381 pre-chemotherapy studies, 141 clinical presentation, 343 imaging, 247, 299 management, 347, 369 surgical, 347, 516, 517–519 pathogenesis, 343 Empyema necesitans, 247 Encephalitis, 406 Endobronchial dissemination, 245, 254 Endocrine disorders, drug-induced, 505, 967 Endocrine gland tuberculosis, 504–513 Endogenous re-infection see Postprimary tuberculosis Endometrial samples, pregnant patients, 575 Endometrial tuberculosis, 458, 459 Endomyocardial biopsy, tuberculous pericarditis, 356 Endoscopic enucleation, childhood tracheobronchial complications, 367 Endoscopic retrograde cholangiopancreatography, 511 Endoscopic ultrasound fine needle aspiration guidance, gastrointestinal tuberculosis, 429 pancreatic tuberculosis, 511 Enforced treatment, extensively drug-resistant tuberculosis, 557 Enoyl acyl carrier protein, 53 Environmental factors, 166, 771, 788 confined locations, 581 contact tracing investigations, 773 developed countries, 166–167 developing countries, 166 healthcare facility infection control strategies, 904 extensively drug-resistant tuberculosis, 553 tuberculosis susceptibility, 91–93, 130, 136 Environmental mycobacteria see Nontuberculous mycobacteria Epic guidelines, 702 Epidemic, tuberculosis, 17, 107 current status, 935, 940, 941, 979 global data, 21 historical aspects, 3, 13 recent resurgence in Europe/North America, 11, 12, 167 Stop TB Strategy impact, 940 Epidemiology, 17–25, 515, 771, 788, 909, 978 adrenal tuberculosis, 508 annual rates of infection, 727–728 antituberculous chemotherapy impact, 164 antituberculous drug side effects, 677, 679, 681, 682, 683, 684, 685, 686 central nervous system tuberculosis, 401 childhood tuberculosis, 38–42, 154 abdominal, 432 age-related risk, 154–155 lymphadenitis, 391, 392 meningitis, 413 reticuloendothelial system, 394 current status, 935, 940, 941, 950, 978, 979 definitions, 38 diabetes mellitus-associated tuberculosis, 560 extensively drug-resistant tuberculosis, 540–541, 551–552, 943 extrapulmonary tuberculosis, 377, 378 female genital tuberculosis, 457 future projections, 955 gastrectomy patients with tuberculosis, 568 gastrointestinal tuberculosis, 424, 432 gender differences, 572, 886 genitourinary tuberculosis, 438 Global Plan to Stop TB estimated impact of planned activities, 951 regions, 950–951 historical aspects, 3, 13, 931 HIV–tuberculosis coinfection, 96, 100–101, 524, 806, 927, 979 immigration impact in developed countries, 167
INDEX immune reconstitution inflammatory syndrome, 689–690 malge genital tuberculosis, 450 malignant disease with tuberculosis, 564 molecular methods see Molecular epidemiology multidrug resistant tuberculosis, 539–542, 642, 940, 943 musculoskeletal tuberculosis, 494–495 national TB control programme surveillance/ monitoring activities, 799 nontuberculous mycobacterial infection, 60–61 geographic differences, 60 ocular tuberculosis, 476, 477 organ transplant patients with tuberculosis, 566–567 osteoarticular tuberculosis, 494 ovarian tuberculosis, 512 pancreatic tuberculosis, 510–511 parathyroid tuberculosis, 507 pericarditis, tuberculous, 351 pituitary tuberculosis, 504 pleural tuberculosis, 342 poverty–tuberculosis association, 908 prevalence, problems with estimation, 727–728 pulmonary tuberculosis, 332–333 recent outbreaks, 494, 927 renal failure patients with tuberculosis, 562 research approaches, 747, 756–757 spinal tuberculosis, 494, 519 statistics/modelling, 790 testicular tuberculosis, 511 thyroid tuberculosis, 506–507 trends, 21–22 global/regional, 19–20 tumour necrosis factor a antagonist-related tuberculosis risk, 569 zoonotic tuberculosis, 150 developed countries following eradication programmes, 149 developing countries, 150 Epididymal abscess, 452 tuberculous versus pyogenic, 452, 453 Epididymal tuberculosis, 450, 451, 511, 521 case report, 848–849 clinical presentation, 450 differential diagnosis, 451 fine needle aspiration, 451, 452 imaging, 306 pathology, 452–453 scrotal ultrasonography, 452 surgical treatment, 455 Epididymectomy, 455 Epididymo-orchitis, 306, 511 Epidural abscess, 307, 313 Epidural granulomas, 519 Epidural phlegmon, 313 Episomes, 54 Epituberculosis see Pneumonia, expansile Equity, community healthcare programmes, 665 Erythema induratum, 387 of Bazin, 485, 488, 490 differential diagnosis, 492 complicating BCG vaccination, 484 vulval tuberculosis, 459 Erythema nodosum, 333, 387, 488 clinical presentation, 488 Erythrocyte sedimentation rate, 221, 336 childhood multidrug resistant tuberculosis, 533 female genital tuberculosis, 458 male genital tuberculosis, 451–452 ovarian tuberculosis, 512 pancreatic tuberculosis, 511 spinal tuberculosis, 497 tuberculous arthritis, 502 ESAT-6, 5, 55, 56, 79, 88, 108, 753, 776 antigen-specific IgG assays, tuberculous meningitis diagnosis, 405 interferon-g-based diagnostic assays, 185, 221, 345 serological detection, 189, 192 vaccine studies, 112 EspA, 56 Established Market Economies, 951 Estonia, 21, 539, 540 extensively drug-resistant tuberculosis, 552
ESX-I locus, 56 Etanercept, 333, 569 HIV–tuberculosis coinfection, clinical trials, 723 tuberculosis risk, 569 ethA mutations, 53 Ethambutol, 608, 609, 612, 639, 640, 740, 960 adverse effects, 612, 678, 963, 964, 965, 966 children, 635 optic neuritis, 483, 535, 612, 629, 635, 676, 677, 683–684 peripheral neuropathy, 684 skin rash, 679 breast tuberculosis, 474 central nervous system penetration, 417, 545, 630 childhood tuberculosis, 330, 331, 435, 535, 628, 629, 630, 631, 632, 634 clinical efficacy, 612 disseminated BCG disease (BCG-osis), 768 drug interactions, 969–970 expansile pneumonia, 370 extensively drug-resistant tuberculosis, 555, 556 extrapulmonary tuberculosis, 379, 630 female genital tuberculosis, 461 gastrointestinal tuberculosis, 430, 435 genitourinary tuberculosis, 447 HIV–tuberculosis coinfection, 527, 632 International Standards for Tuberculosis Care, 652, 653 with liver function impairment, 642, 682 lymphadenitis, tuberculous, 394, 398 meningitis, tuberculous, 408, 410, 630 mode of action, 52, 53, 612 multidrug resistant tuberculosis, 535, 632, 643, 644 prophylaxis, 536, 782 Mycobacterium avium complex disseminated infection, 72 Mycobacterium bovis tuberculosis, 151 Mycobacterium kansasii infection, 70, 71 Mycobacterium marinum infection, 72 Mycobacterium xenopi infection, 71 nontuberculous mycobacteria susceptibility, 65 ocular tuberculosis, 482 ovarian tuberculosis, 513 pancreatic tuberculosis, 511 pericardial effusions, 357 pharmacokinetics, 612 children, 629 pregnanct women, 576, 641 renal excretion, 447, 455, 535, 682–683 renal failure patients precautions, 447 removal by haemodialysis, 564 resistance, 612, 655, 927 molecular determinants, 53 mutations, 52, 552 spinal tuberculosis, 500 standard treatment regimen, 543, 608–609 precautions, 609 susceptibility testing, 542, 730, 741 Ethical issues tuberculosis research, 757 vaccines development, 114 Ethionamide, 613–614, 960 adverse effects, 557, 614, 678, 963, 964, 965, 967 children, 535, 635 depression/psychosis, 686 hepatotoxicity, 614, 635, 645, 682 hypothyroidism, 687 peripheral neuropathy, 614, 684 biliary excretion, 447, 455 central nervous system penetration, 417, 545, 557 childhood tuberculosis, 417, 534, 535, 630, 631 clinical efficacy, 614 contraindication in pregnancy, 576, 645 drug interactions, 970–971 extensively drug-resistant tuberculosis, 555, 556 male genital tract tuberculosis, 455 meningitis, tuberculous, 385, 408, 417, 630 mode of action, 52, 53, 614 multidrug resistant tuberculosis, 408, 455, 534, 535, 643 neonatal prophylaxis following maternal tuberculosis exposure, 576 pharmacokinetics, 614 with renal function impairment, 455
resistance cross resistance, 614 mutations, 52, 552 Ethiopia, 19 Ethnic clustering, 87 Ethnic factors, 182, 925, 926 childhood tuberculosis mortality, pre-chemotherapy studies, 136 tuberculosis infection risk, 13, 130, 925 Etravirine, rifamycin interactions, 621 European Developing Country Clinical Trials Partnership (EDCTP), 981 Evolutionary aspects, 1, 2, 29, 46 iS6110 lineage studies, 51 molecular epidemiologial methods, 35 Mycobacterium tuberculosis complex, 54–55 Exposure to infection, 142, 323 contact tracing, 773–774 Extensively drug-resistant tuberculosis, 20, 174, 219, 539, 551–558, 642, 649, 740, 788, 937 children, 753 clinical predictors, 555 clinical presentation, 554 definition, 551 diagnosis, 551, 554 laboratory system requirements, 738 epidemiology, 540–541, 943 distribution, 551–552 molecular studies, 34 global strategic response, 558 health facility management, 605 HIV coinfection, 541, 551, 553, 555, 645 hospitalization, 557 immunotherapy, 718 infection control, 553–554 isolation of infectious cases, 705, 706 national TB control programmes, 800 origin, 552–553 outbreaks management, 790 prognosis, 551, 553 associated mortality, 545 cure rates, 557 research priorities, 558, 751, 753, 757 transmission, 553, 590 treatment, 555 antituberculous chemotherapy, 555–557 central nervous system tuberculosis, 557 concomitant HIV treatment, 557 duration, 557 enforced with involuntary detention, 557 extrapulmonary tuberculosis, 557 patient support, 555 surgery, 557 workplace healthcare, 904 External quality assessment, 739, 743 Extradural abscess, case study, 863 Extrapulmonary tuberculosis, 377–388, 515 adjuvant corticosteroid treatment, 671 antituberculous chemotherapy, 379, 528, 628, 630–631, 639, 670–671 case studies, 819–822, 823–825, 835–836 children, 154, 155, 324, 377–388, 533, 627, 628, 823–825, 835–836 clinical examination, 157 symptom-based diagnosis, 326–327 treatment, 379, 630–631 clinical presentation, 165, 166, 324, 380, 387–388, 525 corticosteroid treatment-related, 566 definitions, 377 diabetic patients, 560 diagnosis, 316, 317, 326–327, 671, 729 algorithm, 671 International Standards for Tuberculosis Care, 651 nucleic acid amplification tests, 199–200, 223 serological tests, 191–192 special investigations, 225 DOTS programme implementation, 670–671 epidemiology, 377, 378 extensively drug-resistant tuberculosis, 555, 557 gender differences, 888 HIV coinfection, 319, 334, 343, 377, 378–379, 555, 655 antiretroviral treatment algorithms, 320, 321 antituberculous chemotherapy, 528
993
INDEX Extrapulmonary tuberculosis (Continued) clinical features, 525 immune reconstitution inflammatory syndrome, 379, 380, 695 imaging findings, 251–252, 301 multidrug resistant tuberculosis, 533, 545 prognosis, 545 paradoxical reactions, 379 pathogenesis, 378 pregnant patients, 574 renal failure patients, 563 Exudates, 344 pericardial effusions, 355 pleural effusions, 369, 381 Eyelid tuberculosis, 477
F F15/LAM4/KZN strain, 169 18 F-fluoro–2-deoxy-D-glucose positron emission tomography (FDG-PET), 251, 313–314 breast tuberculosis, 473 Facial bone tuberculosis, 466–467 Facial nerve palsy, ear tuberculosis, 463 Failure to thrive, 154, 156, 157 multidrug resistant tuberculosis, 533 symptom-based tuberculosis diagnosis, 326 Fallopian tube tuberculosis, 383, 384, 458 imaging, 306 infertility, 460–461 obstruction, 127 Families community healthcare programmes, 665 role in health care provision, 662 Farmer’s lung, 208 Fas (CD95), 82 Fas-ligand-induced apoptosis, 82, 84 Fast ligation-mediated polymerase chain reaction, IS6110 genotyping, 30 FASTPlaque TB, 232, 326 FASTPlaque-Response, 232, 326 FASTPlaque-TB Rif, 176 FASTPlaque-tuberculosis-MDRi, 220 Fatigue, 164, 333, 334, 335, 495 childhood tuberculosis, 157 symptom-based diagnosis, 326 Fatty acid synthase I, 48, 51, 53 Fatty acid synthase II, 51 Fc g receptors, 76 Female genital tuberculosis, 383–384, 441, 457–461, 521 diagnosis, 457–458 hysterosalpingography, 458 laparoscopy, 458 microbiological culture/acid-fast bacilli detection, 458 polymerase chain reaction-based methods, 458 HIV coinfection, 458 imaging, 252, 306–307 incidence, 457 infertility, 460–461 management, 461 pathology, 458 peritoneal tuberculosis, 461 physical examination, 457 pregnant patients, 459 prevention, 457 symptoms, 457 treatment, 461 vertical transmission, 573 Femoral artery pseudoaneurysm, surgical treatment, 521 Fever, 164, 316, 328, 333, 334, 335, 343, 352, 381, 382, 386, 425, 426, 495, 511, 650 childhood tuberculosis, 156, 533 gastrointestinal, 433, 434 HIV–tuberculosis coinfection, 525, 807 immune reconstitution inflammatory syndrome, 690, 695, 697 pleural effusions, 368 Fibro-calcified nodules, 121 Fibrocavitary disease, nontuberculous mycobacterial infection, 256 Fibrosing mediastinitis, 250, 251, 398 imaging, 300
994
Fibrosis, 127 FIDELIS, 595 Financial aspects clinical trial management, 922 community healthcare programmes, 666 global control strategy funding, 791, 928, 946 Global Plan to Stop TB funding, 952–955, 982 planned activities, 950, 951 health care service reforms in developing countries, 800, 801 cost-recovery schemes, 801 joint tuberculosis/HIV resource mobilization, 806 migrant remitances, 892 national TB control programme funding, 797, 798, 800 patients’ financial burden, 800 research funding, 974–977, 981 Stop TB Strategy funding, 942, 950 implementation, 937 Fine needle aspiration, 209, 210–211 adrenal tuberculosis, 509 analgesia, 211 ancillary investigations, 214 BCG local/regional lesions, 765 breast tuberculosis, 473 cervical lymphadenopathy, 327, 465, 521 consent, 211 cutaneous tuberculosis, 489 cytomorphology, 212–214 epididymal tuberculosis, 451, 452 equipment, 211 extrapulmonary tuberculosis, 317, 651, 671 gastrointestinal tuberculosis, 429 immune reconstitution inflammatory syndrome, 697 liver abscess, 395 lymphadenitis, tuberculous, 380, 393, 397 diagnosis in children, 326 HIV coinfection, 526, 527 mycobacterial culture, 212 organ transplant patients, 567 pancreatic tuberculosis, 511 parathyroid tuberculosis, 508 pleural effusions, 381 renal failure patients, 563 reticuloendothelial system tuberculosis, 399 salivary gland tuberculosis, 466 slides preparation, 211, 212 staining, 212 spinal tuberculosis, 497 splenic lesions, 305, 395 technique, 210–211 bloody aspirate, 212 cysts, 211–212 procedure, 211 testicular tuberculosis, 512 thyroid tuberculosis, 467, 507 Finsen, Niels Ryberg, 484 Fish tank granuloma, 69 Fixed dose combinations, 639, 652–653, 670, 751 with antiretroviral drugs, 753 side effects management, 687–688 Stop TB strategy implementation, 943 Flexible bronchoscopy, 224 childhood airway disease, 365 endoscopic enucleation procedures, 367 laryngeal biopsy, 464 organ transplant patients, 567 transbronchial lymph node biopsy, 521 Flu-like symptoms, drug-induced, 687, 966 Fluconazole, rifampicin interaction, 623 Fludrocortisone adrenal insufficiency, 509 tuberculous meningitis, 410 Fluorescence microscopy, 231, 739, 746 quality assessment, 743 Fluorescence staining, 171, 651 Fluoroquinolones, 615, 674 adverse effects, 615, 963, 964, 965, 966, 967 children, 535 hepatotoxicity, 682
peripheral neuropathy, 615, 684 psychosis, 686 seizures, 685 childhood tuberculosis, 534, 535, 631, 634 clinical efficacy, 615 corneal tuberculosis, 478 drug interactions, 970–971 antiretroviral drugs, 618–619 didanosine, 645 early bactericidal activity, 608, 615 extensively drug-resistant tuberculosis, 20, 555, 556 mode of action, 615 multidrug resistant tuberculosis, 408, 534, 535, 545, 643, 645, 740 prophylaxis, 782 Mycobacterium chelonae pulmonary disease, 71 Mycobacterium fortuitum pulmonary disease, 71 Mycobacterium kansasii infection, 70 Mycobacterium xenopi pulmonary disease, 71 resistance, 539, 540, 552, 757 cross resistance, 555, 556 sputum smear status following empirical treatment, 651 tuberculous meningitis, 410 Follow-up management algorithms, 317 smear-negative pulmonary tuberculosis, 318 smear-positive pulmonary tuberculosis, 318 of sputum positive non-attenders, 669–670 of treatment defaulters, 934 Foot joint tuberculosis, case study, 866, 867 Foreign body granulomas, 208 renal tract, 445 Fos-amprenavir, ritonavir interaction, 622 Foundation for Innovative New Diagnostics (FIND), 230, 231, 232, 233, 234, 738, 749, 981 France, 150, 167 Frequency-pulsed electron-capture gas–liquid chromatography, tuberculosteric acid detection, 405 Fungal infection granulomatous mastitis, 474 histopathology, 207 ocular lesions, 479 urinary tract, 444 Furosemide, 418
G G-protein coupled transmembrane receptors, 83 Gallbladder tuberculosis, 426 imaging, 304–305 Galloping consumption, 245 gd T cells, 75, 378 CD1 molecule regulation, 80 function, 83 Gastrectomy patients, 166, 568 Gastric aspirates, 209, 326, 652 children, 217 multidrug resistant tuberculosis, 534 cytomorphology, 210 neonatal specimens, 574 specimen collection, 217 Gastric tuberculosis, 301, 382, 425, 520 children, 434 clinical presentation, 425 Gastritis, antituberculous drug side effects, 680 Gastrointestinal antituberculous drug side effects, 680–681, 963 complications, 680 management, 680 prevention, 681 Gastrointestinal tuberculosis, 377, 378, 424–430, 520 children, 432–436 differential diagnosis, 435 epidemiology, 432 pathology, 432–433 prognosis, 433 trial of therapy, 435 clinical presentation, 425–426, 433 Crohn’s disease differentiation, 426, 427, 428, 429–430, 435, 436 diagnosis, 426–427, 434–435 ascites fluid examination, 428
INDEX double-balloon enteroscopy, 428 endoscopic ultrasound-guided fine needle aspiration, 429 immunological tests, 428 laparoscopic findings, 428 magnetic resonance enteroclysis, 428–429 polymerase chain reaction-based tests, 428 epidemiology, 424 HIV coinfection, 424, 435, 525 hypertrophic forms, 301, 424, 433 imaging, 252–253, 301, 302, 426–427, 434 lymphadenopathy, 520–521 management, 430, 435–436 adjunctive corticosteroids, 435–436 DOTS programme implementation, 671 nutritional support, 435 pathogenesis, 424, 432 sites of involvement, 424–425 ulcerative forms, 301, 424, 432, 433, 434 ulcerohypertrophic forms, 301, 424, 433 Gatifloxacin, 615, 960 clinical trials, 917 duration of treatment, 751 glucose homeostasis impairment, 561–562 nontuberculous mycobacteria susceptibility testing, 66 Gaze palsy, 480 Gender-related differences, 886–890 access to health care, 913, 981 adherence, 889–890 case detection, 887 epidemiology, 20–21, 572, 886–887 extrapulmonary tuberculosis, 888 health-seeking behaviour, 888–889 poverty, measurement problems, 910 research approaches, 756, 890 sputum smear status, 888 tuberculosis infection risk, 18, 887–888 Gene–environment interactions, 87 Genetic factors, tuberculosis susceptibility, 87–91, 130, 136, 401, 787 cytokines/chemokines, 88–89 macrophage function, 90–91 Mycobacterium tuberculosis receptors, 89–90 Th1 pathway components, 87–88 Genetic markers, mutation rate assessment, 33 Genitourinary tuberculosis, 383–384, 438–448 clinical presentation, 383, 438 diagnosis, 383, 441–442 delay, 438 microbiology, 441–442 polymerase chain reaction-based methods, 441 epidemiology, 438 imaging, 252, 305–307, 441–444 keratinizing squamous metaplasia (leukoplakia), 446 lower urinary tract see Bladder tuberculosis; Ureteric tuberculosis Mycobacterium bovis infection, 150 pathogenesis, 438 pathology, 444–445 treatment, 447 DOTS programme implementation, 671 medical, 447 surgical, 448, 521 zoonotic, 149 Genome deletion analysis, 32 Mycobacterium avium paratuberculosis, 52 Mycobacterium bovis, 51 Mycobacterium leprae, 52 Mycobacterium tuberculosis, 51 regions of difference, 54–55 GenoType assays, 173 GenoType MTBC test, 201 GenoType MTBDR assay, 176, 201, 202, 233 Genotyping, data interpretation, 33 Gentamicin, ear tuberculosis, 463 Germany, 148, 150 Ghon complex (primary complex), 120, 130, 136, 361 lymphadenitis, 391–392 Ghon focus, 120, 121, 130, 136, 143, 144, 333, 361 children, pre-chemotherapy studies, 138, 141 with/without cavitation, 140
imaging, 297, 298 chest radiographs, 138, 237 Gibbus deformity, 252, 291, 307, 402, 495, 497, 499 Glasgow Coma Scale, 414 Global Alliance for TB drug development (GATB), 229–230, 615, 616, 917, 979, 981 Global DOTS Expansion Meeting, 805 Global DOTS Expansion Plan, 797, 933 Global Drug Facility, 798, 933, 942, 943 grants, 639 Global Fund to Fight AIDS, Tuberculosis and Malaria, 19, 744, 791, 798, 806, 909, 942 Global Partnership to Stop TB, 933 Global Plan to Stop TB, 23–24, 189, 558, 744, 757, 790, 792, 797, 802, 804, 904, 908, 936, 940, 949–955, 979, 982 2001–2005, 949–950 2006–2015, 754, 950 cost-effectiveness, 954 development, 949–950 evaluating implementaion, 955 funding, 950, 951, 952–955, 982 likelihood of achieving 2015 targets, 954 planned activities, 950–951 estimated epidemiological impact, 951 expected outcomes, 952, 953 planning to achieve targets, 951–953 Global TB Control, 946 Global Tuberculosis Initiative, 933 Glomerular filtration rate, 439 Glomerulonephritis, tuberculous, 440, 445 Glucose ascites fluid, 428 cerebrospinal fluid, 221 tuberculous meningitis, 402, 415 Glucose intolerance, 560 Glucuronosyl transferase, 619 Good Clinical Practice (GCP), 916, 919–920 clinical trial protocol content, 921 definition, 919 Investigator’s Brochure, 921 investigators’ responsibilities, 920 principles, 920 sponsors’ responsibilities/role, 920–921 audits, 921 Standard Operating Procedures (SOPs), 921 trial monitoring, 921 Good Laboratory Practice (GLP), 916, 919, 921 Gram staining, 171, 415 Granulocyte-macrophage colony-stimulating factor, immunotherapy, 721–722 Granuloma formation, 75, 84–85, 130, 378–379, 719 accumulation phase, 84, 99 antigen presenting cells, 117, 119 central caseous necrosis, 98, 119–120, 126, 205, 379 chest radiographs, 237 effector phase, 85 HIV–tuberculosis coinfection, 96, 97, 98, 99–100, 124, 205 antiretroviral therapy impact, 100 immune reconstitution inflammatory syndrome, 698 immunotherapy targeting, 719 initiation phase, 84, 99 Langerhans giant cells, 98 pathogenesis, 119 pericardial tuberculosis, 351, 352 pleural tuberculosis, 124 primaty tuberculosis, 119 renal tuberculosis, 438 resolution phase, 85 T cells, 118 tumour necrosis factor-a, 81 antagonist therapy, 723 Granuloma inguinale, histopathology, 208 Granulomas definition, 117 differential diagnosis bacterial infections, 207–208 foreign bodies, 208 fungal infection, 207 hypersensitivity pneumonitis, 208 parasite infection, 207 sarcoidosis, 206–207
fine needle aspiration biopsy, 213 histopathology, 205 imaging, 268 space-occupying effect, 127 Granulomatous angiitis, 121 Granulomatous artertitis, 121 Granulomatous endometriosis, 127 Granulomatous inflammation, 333 adrenal tuberculosis, 509 anterior uveitis, 478 cutaneous tuberculosis, 485 differential diagnosis malignant disease, 209 Wegener’s granulomatosis, 207 dissemination mechanisms, 121–122 histology, 205 HIV–tuberculosis coinfection, 124 meningitis, 406 pancreatic tuberculosis, 511 pituitary tuberculosis, 506 pleural tuberculosis, 342 secondary (adult-type) tuberculosis, 121 tuberculous mastitis, 474 Granulomatous lymphadenitis, 120, 122 Granulomatous mastitis, 474 Granulysin, 82, 83, 718 Greece, ancient, 1 Gue´rin, Camille, 5, 759 Gumma, tuberculous (metastatic tuberculous abscess), 488 differential diagnosis, 492 gyrA, 615 gyrB, 615
H HAART see Antiretroviral therapy Haematogenous spread see Dissemination Haematological antituberculous drug side effects, 683, 687, 965–966 management, 683 prevention, 683 Haematological malignancies, tuberculosis risk, 564 Haematology, 336 bone marrow disease, 395, 399 children, 395 diagnostic tests, 221 tuberculous arthritis, 502 Haematopoietic stem cell transplant patients, 256, 260, 564 Haematuria, 438 male genital tuberculosis, 450, 452 Haemodialysis patients, 333 hypercalcaemia, 441 Haemolytic anaemia, antituberculous drug-induced, 687 Haemophagocytic syndrome, 395 Haemoptysis, 121, 122, 142, 165, 333, 335, 338, 339 childhood tuberculosis, 374 management, 338 surgical, 517 postprimary (reactivation) tuberculosis, 242 Haemorrhage, 121, 126 gastrointestinal children, 433, 434 colonic lesions, 426 gastroduodenal lesions, 425 rectal lesions, 426 management, 338 massive, 338, 339 Haloperidol, 686 HE2000, 752 Health as human right, community healthcare programmes, 665 WHO definition, 661–662, 928 Health facility management, 595 ambulatory patient treatment, 596 care standards, 596 clinics, 596, 598 contacts management, 606–607 drug supplies, 599 drug-resistant tuberculosis, 605 HIV coinfected patients, 604–605 hospital-based treatment, 596, 603
995
INDEX Health facility management (Continued) infection control see Infection control, healthcare settings initial patient presentation, 595 laboratory specimen management, 603 microbiological monitoring, 599, 603 prison inmate services, 606 private treatment, 603–604 referral pathways, 595, 596, 603 services for mobile people, 606 Stop TB Strategy implementation, 944 Health posts see Clinics Health-seeking behaviour, gender differences, 888–889 Healthcare services, 662, 980 case management standards, 789 childhood tuberculosis epidemiological data, 40 clinical governance/audit, 789 clinical trials of care delivery, 917, 931 community involvement, 660 DOTS services, 668 employment sector services, 904 HIV/AIDS patient care, 809 tuberculosis/HIV collaborative activities, 805–806 improving delivery for poor people, 913–914 laboratory/diagnostic services, 746 system levels, 230–231 national TB control programmes, 795, 800 quality assurance, 789 reforms in developing countries, 800 cost-recovery schemes, 801 Stop TB Strategy implementation, 944–945 Healthcare workers, 663, 668 community exposure to TB, 584 DOTS programme implementation, 673, 674 education/training, 665, 704, 706, 709 HIV–infected, 707–708 immigrants, 706 latent disease prophylaxis, 781 national TB control programme staffing, 798 occupational TB infection, 581, 582, 583, 587, 595, 808, 901, 903 extensively drug-resistant tuberculosis, 553 multidrug resistant tuberculosis, 547 prevention see Infection control, healthcare settings sputum collection procedures, 603 risk of tuberculosis, 10, 901, 903 screening, 704, 706–707, 904 during employment, 707 pre-/on-emplyment, 706–707 staff-to-staff TB transmission, 584 vaccination, 904 Healthcentres see Clinics Hearing loss, antituberculous drug-induced see Ototoxicity Heart failure, 352, 359 drug-induced, 966 Helminth exposure, tuberculosis susceptibility influence, 92, 93 Henle–Koch postulates, 484, 786 HEPA (high-efficiency particulate air) filtration, 708, 904 Hepatitis, tuberculous, 382 Hepatobiliary tuberculosis, 253, 382, 392, 399, 426, 521 children, 394 clinical presentation, 426 imaging, 223, 304–305 Hepatomegaly/hepatosplenomegaly, 304, 399, 426 children, 394–395, 434 neonatal tuberculosis, 573, 577 Hepatotoxicity, drug-induced, 676, 677, 681–682, 964 antiretroviral drugs, 676 antituberculous drugs, 410, 681–682, 964 clinical presentation, 681 complications, 682 differential diagnosis, 681 epidemiology, 681 ethionamide, 614, 635, 645, 682 fluoroquinolones, 682 HIV–coinfected individuals, 681, 807 investigations, 681 isoniazid, 410, 447, 576, 610, 635, 642, 681, 682, 780, 782, 810 management, 681–682
996
antituberculous drug selection following resolution, 682 reintroduction of antituberculous drugs, 682 temporary drug regimens, 682 para-aminosalicylic acid, 645, 682 prevention, 682 prodromal symptoms, 680 prothionamide, 645 pyrazinamide, 410, 611, 612, 635, 642, 681, 682 rifampicin, 410, 578, 611, 635, 642, 681, 682 Herbal extract immunomodulators, 529, 752 High resolution computed tomography, 253, 254 lymphadenopathy children, 262 mediastinal, 380 miliary tuberculosis, 239 nontuberculous mycobacteria-induced hypersensitivitylike lung disease, 258 postprimary tuberculosis, 242, 243, 245, 298 tracheobronchial tuberculosis, 299 High-performance liquid chromatography, mycobacterial species identification, 63, 65, 173, 219 Highly active antiretroviral therapy (HAART) see Antiretroviral therapy Hilar lymphadenopathy, 120, 121, 130, 237, 377 children, 143, 262, 297, 361 expansile pneumonia, 370 imaging, 238, 297 ocular tuberculosis investigation, 482 Hip tuberculosis, case study, 841–842 Histamine-2 blockers, 680 Histopathology, 205–209 granulomas, 205–206 tuberculosis diagnosis, 205–206, 209 differential diagnosis, 206–209 Histoplasma capsulatum, 207 Historical aspects, 1–6, 44, 129, 377, 457, 978–979 antituberculous chemotherapy, 4–5, 926, 930–931 clinical trials, 917 developed countries, 932 developing countries, 931–932 Bacillus Calmette-Gue´rin (BCG) vaccines, 759–760 bovine tuberculosis, 146 eradication programmes, 151 breast tuberculosis, 469 cause of tuberculosis, 3–4, 44 childhood tuberculosis, pre-chemotherapy studies, 133–144 communicable disease theory, 786 control strategies, 5, 786, 938 cutaneous tuberculosis, 484 diagnosis, 4 DOTS strategy, 933 epidemiology, 3, 931 migration, 892 national TB control programmes, 795, 933 ocular tuberculosis, 476, 477 sociological theories of tuberculosis susceptibility, 925–926 spinal tuberculosis, 494, 519, 520 surgical management, 516 thyroid tuberculosis, 506 transmission (contagiousness), 8 treatment, 4–5, 516, 930 tuberculin skin test, 179 HIV infection, 1, 5, 18, 19 antiretroviral therapy see Antiretroviral therapy BCG vaccination contraindication, 113, 706–707, 708 breastfeeding, 577–578 children, 154, 363, 533, 632 BCG local reactions, 577 BCG vaccination risk, 113 causes of lung disease, 160 clinical examination, 157 clinical staging (WHO), 322 cotrimoxazole prophylaxis see Cotrimoxazole healthcare workers, 707–708 diagnosis before BCG vaccination, 706–707 host vulnerability factors, 13 injection-related iatrogenic transmission, 687 lymphadenopathy, 165 mother-to-child transmission, 160 nontuberculous mycobacteria coinfection, 66
disseminated disease, 66, 69, 72 imaging findings, 259–260 Mycobacterium avium complex, 72 pulmonary disease, 61 patient care/support, 809 testing and counselling, 221, 317, 344, 363, 533, 605, 632, 655, 674, 775, 784, 808 pregnanct patients, 576 prison inmates, 585–586 WHO ProTEST initiative, 804–805 tuberculosis coinfection see HIV–tuberculosis coinfection tuberculosis contact investigations, 773, 775 tuberculosis prevention, 529, 605 infection control strategies in congregate/healthcare settings, 808 tuberculosis risk, 75, 130, 132, 154, 156, 166, 167, 332, 524, 762–763, 771, 804 antiretroviral drug prophylactic effect, 780 control strategies, 790 vaccine clinical trials MVA85A vaccine, 110 Mycobacterium vaccae, 111 safety, 113 see also Collaborative tuberculosis/HIV activities HIV-1 cellular entry, 102 impact of tuberculosis on infection, 100–101 replication with tuberculosis coinfection, 101, 102–103 reverse transcription, 102 tuberculosis pathogenesis enhancement, 100, 101 HIV–tuberculosis coinfection, 96–97, 117, 131, 132, 332, 515, 727, 728, 788, 980 abdominal tuberculosis, 383, 525 adjunctive corticosteroids, 529 adjunctive immunotherapy, 104, 529, 718, 751 AIDS surveillance definitions, 524 extrapulmonary tuberculosis, 378 antiretroviral therapy see Antiretroviral therapy antituberculous chemotherapy, 526–528, 543, 627, 641, 652, 653 drug interactions, 618–625 empiric therapy, 528 prophylaxis, 347, 807–808 rifamycin dosage, 610 thiacetazone contraindication, 556 antituberculous drug adverse effects, 676, 679, 684 hepatotoxicity, 681, 682 skin reactions, 679–680 Bacillus Calmette-Gue´rin (BCG) adverse effects, 763–764 disseminated disease (BCG-osis), 767–768 immune reconstitution syndrome (BCG IRIS), 768 protective efficacy, 763 breast tuberculosis, 472 case studies, 816, 819, 821, 839–840, 852–853, 854–857, 867, 880–885 CD4 T cell effects, 97, 98–99, 103 central nervous system tuberculosis, 401, 402–403 chest radiographs, 328, 336, 337, 526, 655, 808 children see Childhood tuberculosis clinical aspects, 524–529 clinical presentation, 96–97, 165, 166, 334, 525, 655 clinical trials of new drugs, 917 collaborative activities see Collaborative tuberculosis/ HIV activities community involvement in healthcare/control programmes, 663, 666 diagnosis, 159, 160, 166, 729 laboratory services, 740 serological tests, 191 diagnostic algorithms, 316, 317–318, 319 disseminated tuberculosis, 386 DOTS programmes, 674 strategy adaptation, 933–934 drug interactions, 618–625 drugs used to treat opportunistic infections, 623–624 see also Antiretroviral therapy effusion fluid cytomorphology, 210 epidemiology, 22, 25, 96, 100–101, 160, 524, 756, 927, 940, 979 current status, 935 mortality, 19, 21, 100, 545
INDEX extensively drug-resistant tuberculosis, 541, 551, 553, 555 management, 557 extrapulmonary tuberculosis, 343, 377, 378–379, 525, 528 clinical presentation, 378 drug resistant disease, 555 female genital tuberculosis, 458 fine needle aspiration biopsy, 210 cytomorphology, 212–213 gastrointestinal tuberculosis, 424, 435 gender-related issues, 572, 886 Global Plan to Stop TB (2006-2015), 950 granulomatous host response, 97, 98, 99–100, 124, 125, 205 histopathology, 97–98, 205 HIV viral load, 101, 719 HIV virus genotypic diversification, 103 HIV virus replication impact, 101, 102–103 imaging, 96–97, 158, 159, 254, 526 following HAART, 254–256 immune restoration inflammatory syndrome see Immune restoration inflammatory syndrome immune system effects, 719 response to Mycobacterium tuberculosis, 98–99 inflammatory microenvironment, 103–104 International Standards for Tuberculosis Care, 651, 652 intracranial tuberculomas, 385 investigations, 525–526 latent infection diagnosis, 780, 781 prophylaxis, 781, 783, 784 long-term care facility outbreaks, 585 lung cavitation, 11 lymphadenitis, 380, 397, 398, 521, 525 male genital tuberculosis, 451 management algorithms, 321 drug resistant disease, 554 individuals on antiretroviral therapy, 318–319, 320 management approaches, 604–605 research priorities, 750, 751 mediastinal lymphadenopathy, 398 meningitis, 384, 409, 413, 416, 525 cerebrospinal fluid mycobacterial load, 404 mesenteric lymphadenopathy, 398 micronutrient supplements, 529 monocyte/macrophage impact, 98, 103 multidrug resistant tuberculosis, 524, 536, 545–546, 555, 583, 656 associated mortality, 545 management, 554, 645 musculoskeletal tuberculosis, 494, 525 Mycobacterium bovis tuberculosis, 150 myocarditis, 359 national TB control programmes, 800 monitoring, 799 nosocomial outbreaks, 583 ocular tuberculosis, 476, 481 opportunistic infections prevention, 605 otitis media, 463 pancreatic tuberculosis, 510, 511 pathogenesis, 96–104 pathophysiology, 124–125 pericardial tuberculosis, 359 effusions, 351, 357, 381, 525 treatment, 357 pleural effusions, 342, 343, 344, 345, 346, 381, 525 pregnant women, 320, 572, 574, 575, 577, 578–579, 810–811 vertical transmission prevention, 578 prison inmates, 585, 586–587, 606 prognosis, 338, 524–525 progression of tuberculosis, 525 prostate tuberculosis, 450, 451, 455 pulmonary tuberculosis, 160, 334, 525 reactive depression, 686 renal tuberculosis, 383, 525 research priorities, 752–753 shelter accommodation inmates, 588 specimens for diagnosis, 526, 527 spinal tuberculosis, 501 sputum smear microscopy, 171, 229, 317–318, 323, 332, 524, 526, 651 smear-negative cases, 317, 318, 332–333, 334
Stop TB Strategy implementation, 24, 943, 951 surveillance programmes, 799, 806 tuberculin skin test, 96, 97, 132, 181, 220, 525, 780 tuberculosis case finding, 807 tumour necrosis factor antagonist therapy, 723 workplace healthcare programmes, 904 zoonotic tuberculosis, 149, 150 HLA alleles, tuberculosis susceptibility, 88 HLA-B51, 88 HLA-B52, 88 HLA-DQ, 79, 88 HLA-DQB1*0503, 88 HLA-DR, 88 HLA-DRB1*15, 88 HLA-DRB1*16, 88 HLA-H2-DM, 79 Homeless people, 587, 588, 979 barriers on pathway to cure, 912 contact tracing, 776 latent disease prophylaxis, 781 Stop TB Strategy implementation, 944 see also Shelters, homelessness Hong Kong, 22, 540 Hospice care, 606 Hospital admission, 603 children, 635 meningitis management, 630 drug-resistant tuberculosis, 605 historical aspects, 931 Host mycobacterial killing, 84 Host–pathogen interactions, 13, 55, 75, 87–93, 787 central nervous system tuberculosis, 401 childhood tuberculosis, 142 early events, 56 late events, 57 latency/dormancy, 56–57 nontuberculous mycobacteria, 66 persistence, 56–57 postprimary disease, 56, 57 primary infection, 56, 75 risk of infection, 771 role of immunotherapy, 718, 751, 752 Hot tub hypersensitivity pneumonitis, 46, 256, 257–258 ‘Hotboxing’, 584, 590 HSP65DNA therapy, 752 Human resources laboratory services, 741 TB control strategies, 791, 798 Human rights, 661 of migrants, 896 Hydrocephalus, 127, 251, 271, 384, 402, 410, 413, 414, 416, 421, 506 communicating, 413, 414, 417, 418 imaging, 271, 273–274, 284, 285, 311, 404, 414, 417, 418 non-communicating, 413, 417, 418 outcome in children, 418, 421 pathogenesis, 406 treatment, 417–418, 419, 420, 422 medical, 418 neurosurgery, 410 ventriculoperitoneal shunting, 418, 422 Hypercalcaemia immune reconstitution inflammatory syndrome, 698 renal failure patients with tuberculosis, 441, 563 Hyperinflation, unilateral, 364–365 medical management, 366–367 Hyperprolactinaemia, 504 Hypersensitivity pneumonitis histopathology, 208 nontuberculous mycobacterial infection, 256, 257–258 Hypertension, drug-induced, 966 Hyperthyroidism, 507 Hypomethylated CpG DNA motifs, 77 Hyponatraemia, tuberculous meningitis, 402 Hypopituitarism, 504 Hypopyon, 481 Hypothalamic dysfunction, 504 Hypothalamo-pituitary-adrenal axis activation, tuberculosis susceptibility influence, 91, 92 Hypothyroidism, 507 drug-induced, 687 children, 535
Hysterosalpingogram, 458 endometrial tuberculosis, 459 fallopian tube tuberculosis, 460 infertility investigation, 460 ovarian tuberculosis, 512 Hysteroscopy endometrial tuberculosis, 459 fallopian tube tuberculosis, 460, 461 infertility investigation, 460
I Idiopathic pulmonary fibrosis, 566 IFNGR1 mutations, 87 IFNGR2 mutations, 87 IL12A, 87 IL12B, 87 IL12Rb1, 87 Ileocaecal tuberculosis, 424, 425, 520 children, 433 clinical presentation, 425 imaging, 426, 427 Iliac creat autograft, 501 Imaging, 223–224, 237–260, 297–314 active versus inactive disease, 253–253 childhood tuberculosis, 158, 159, 262–295, 362–363, 858–869 intrathoracic disease classification, 361, 362 complications of tuberculosis, 250–251 historical aspects, 4 HIV–tuberculosis coinfection, 96–97 manifestations of surgical therapy, 249–250 nontuberculous mycobacteria infection, 256–260 postprimary tuberculosis, 242–249 primary tuberculosis, 237–256 progressive, 241–242 unusual manifestations of tuberculosis, 250 Imbalance, antituberculous drug-induced, 685, 686 Imipenem Mycobacterium abscessus pulmonary disease, 71 Mycobacterium avium complex skin infections, 71 Mycobacterium chelonae pulmonary disease, 71 Mycobacterium fortuitum pulmonary disease, 71 nontuberculous mycobacteria susceptibility testing, 66 Immigrants, 515, 584–585, 800, 892 access to healthcare, 893, 894, 895, 898 border control practices, 896 contact tracing, 776 healthcare workers, 584 pre-employment screening, 706 migrant workers, 893, 895, 897 public hostility, 895 remitances, 892 screening, 896 Stop TB Strategy implementation, 944 tuberculosis case study, 896 central nervous system, 401 childhood abdominal, 432 control strategies, 733–735, 790 high-burden countries, 897 long-term care facility outbreaks, 585 low-burden countries, 167, 896–897 multidrug resistant, 655 prison setting outbreaks, 585 renal tuberculosis with renal failure, 440 shelter accommodation outbreaks, 588 workplace risk, 902 see also Migration Immune reconstitution inflammatory syndrome, 100, 255–256, 260, 320, 329, 339, 378, 379, 380, 398–399, 447, 528, 579, 633, 641, 676, 689–699, 752, 784, 809 aetiological agents, 689, 690 BCG lymphadenitis, 391, 394 case reports, 691–694, 852–853, 854–855, 884 children, 634, 695 clinical presentation, 339, 528, 690, 695 complications, 698 definition, 689 diagnosis, 689, 690, 697, 698 differential diagnosis, 697 epidemiology, 689–690
997
INDEX Immune reconstitution inflammatory syndrome (Continued) HIV viral load, 690, 696, 699 intracranial tuberculomas, 385 management, 697–698 mesenteric lymphadenopathy, 398 outcome, 698 pathology, 698–699 pregnant women, 579 prevention, 698, 699 timing of antiretroviral therapy initiation, 695, 699 renal failure, 447 research priorities, 753, 754 risk factors, 695, 696 CD4 cell counts, 696 extrapulmonary/diseminated tuberculosis, 695 tuberculin skin test response, 696 type of antiretroviral drugs, 696 tuberculin skin test, 698 tuberculous lymphadenitis, 398 unmasking previously asymptomatic tuberculosis, 378, 690, 695, 698 Immune response, 130, 333, 719, 761 children, 85, 143, 144 correlates of protection, 75 vaccine development applications, 111–113 research priorities, 747, 753–754 to Bacillus Calmette-Gue´rin (BCG), 112 Immune restoration disease see Immune reconstitution inflammatory syndrome Immune-based diagnostic tests, 179–192, 220–221, 326, 729, 730 childhood tuberculosis, 326 male genital tuberculosis, 452 new methods, 233–234 antibody response detection, 233 antigen detection, 233 tuberculosis-specific organic compounds, 233–234 terminology, 180 Immunohistochemistry, 209 Immunology, 75–85 Immunosuppressed patients, 560–570 latent disease prophylaxis, 781 risk of tuberculosis, 333, 771 see also HIV infection; HIV–tuberculosis coinfection Immunosuppressive acidic protein, pleural effusions, 381 Immunotherapy, 718–724 granulocyte-macrophage colony-stimulating factor, 721–722 HIV–tuberculosis coinfection, 104, 529 interferons, 720–721 interleukin, 2, 721 interleukin, 12, 722 multidrug resistant tuberculosis, 546 research priorities, 746, 751 thalidomide, 722–723 therapeutic vaccines, 723–724 treatment goals, 718 tumour necrosis factor blockade, 723 Implementation research, 747, 755, 981–982 In vitro fertilization, 461 Incubation period, 136 Independent data monitoring committee, 923 Index of suspicion, 166–167, 205, 316 adult patients, 164 extrapulmonary tuberculosis, 388 HIV infected individuals, 525 neonatal tuberculosis, 573 nosocomial outbreaks, 581, 582 nucleic acid amplification test sensitivity influence, 199 tuberculous meningitis, 384 India, 12, 19, 22, 23, 25, 150, 887, 888, 889, 940 breast tuberculosis, 469 Business Aliance to Stop TB, 906 childhood tuberculosis, 40 clinical trials of care delivery, 931–932 community involvement in tuberculosis control programmes, 663, 664 DOTS programme implementation, 668–675 internal migration, 897 multidrug resistant tuberculosis, 539, 551, 642 ocular tuberculosis, 476 pituitary tuberculosis, 504
998
private health facilities, 603, 604 tuberculosis incidence rate, 19 tuberculous lymphadenitis, 391 workplace tuberculosis, 901, 902 Indonesia, 19, 23, 25, 40, 940 Induced sputum, 216–217, 326, 526, 534, 563, 565, 581, 652 children, 216–217, 326, 362 multidrug resistant tuberculosis, 534 neonates, 574 infection control precautions, 706 Infants extrapulmonary tuberculosis, 377 HIV–tuberculosis cofinfection, 160–161 meningitis, tuberculous, 413 miliary tuberculosis, 362 pneumonia, 160–161 expansile, 369 pre-chemotherapy studies haematogenous spread, 142 mortality, 136 pulmonary disease, 139, 140 radiologic signs, 138 sputum specimen collection, 216–217 tuberculosis progression, 144 tuberculosis risk, 41, 154, 155, 324 Infecting dose, 142 Infection control, healthcare settings, 595–596, 598, 701–709, 790, 808, 903–904, 944 administrative measures, 703–708, 904 aerosol-generating procedures, 706 cough hygiene, 706, 904 diagnostic protocols, 704, 706 environmental measures (engineering controls), 708–709, 904 fast-tracking procedures, 705 general measures, 702 healthcare worker exposure prevention, 903 hierarchy of controls, 703 HIV–infected individuals, 583, 808 infection control plan, 703, 704, 944 goals, 703 isolation procedures, 704, 705–706 local policies/procedures development, 704–705 masking patients, 705, 904 personal respiratory protection, 709, 904 protocols for potentially infectious patients, 704–705 risk assessment, 701, 904 risk classification, 703 risk management, 701–702 staff education/training, 704, 706 staff screening, 704, 706–707 surgical staff, 521–522 tuberculosis-specific measures, 702, 703 ventilation, 708–709 see also Nosocomial transmission Infectiousness of patients, 11, 129, 133, 155, 339–340, 787 assessment for surgical staff safety, 521–522 index case assessment for contact tracing, 773 Infectivity, Mycobacterium tuberculosis strain differences, 12 Infertility, 127 female genital tuberculosis, 457 fallopian tube involvement, 460–461 management, 461 ovarian tuberculosis, 512, 513 male genital tuberculosis, 450, 451, 455, 521 epidydimal involvement, 512 management, 451 Infliximab, 333, 568 tuberculosis risk, 569 Informed consent clinical trial participants, 918 Good Clinical Practice, 920 vaccine trials, 114 fine needle aspiration biopsy, 211 HIV testing in older child, 161 Informed consent forms, clinical trial participation, 918 Inguinal hernia, 434 inhA, 610 mutations, 52, 53, 610, 614 Injecting drug use see Substance abuse Injection-related adverse effects, 687 Innate immune response, 75, 143, 718
central nervous system tuberculosis, 401 children, 85 INNO-LiPA Mycobacteria assay, 173 INNO-LiPA Mycobacteria v2, 201 INNO-LiPA Rif.TB, 176, 201–202, 233 Insertion sequences, 29 Institutional outbreaks, 585, 808 contact tracing, 773 Institutional Review Boards/Independent Ethics Committees, 920 Integrase inhibitors, rifamycin interactions, 618 Integrated Management of Adolescent and Adult Illness, 654 Integrated Management of Childhood Illness (IMCI) programme, 652 Integrated tuberculosis services, 661 Integrins, 83 Intention to treat (ITT) analysis, 918 Interferon-a immunotherapy, 720 multidrug resistant tuberculosis, 720 Interferon-a variants, tuberculosis susceptibility, 88 Interferon-b variants, tuberculosis susceptibility, 88 Interferon-g, 76, 80, 82, 98, 99, 752 Bacillus Calmette-Gue´rin (BCG) response, 112 functions, 79, 83, 84 immune response to mycobacteria, 718, 719, 761 production as marker of vaccine efficacy, 112, 113 receptor variants, genetic tuberculosis susceptibility, 87 Interferon-g Elispot assay, 113 MVA85A vaccine trial primary outcome, 108 Interferon-g immunotherapy, 720, 752 multidrug resistant tuberculosis, 546, 720–721 Mycobacterium avium complex pulmonary disease, 70 Interferon-g levels, 730 ascites fluid, 428 pleural effusions, 344, 345, 369, 381 tuberculous meningitis, 405 tuberculous pericarditis, 356, 382 Interferon-g release assay, 13, 25, 38, 179, 185–189, 221, 326 childhood tuberculosis, 362 contact tracing applications, 776–777, 778 development, 185–186 effusion fluid levels, 222 elderly people, 565 formats (commercial kits), 186 guidelines, 188, 221 latent infection detection, 780–781 HIV coinfected individuals, 525 nontuberculous mycobacterial infections, 362 performance, 186–188 unresolved issues, 188–189 pericarditis, tuberculous, 355 pleural effusions, 345 research priorities, 749–750 sensitivity/specificity, 186, 192 tuberculin skin test comparisons, 187, 188 advantages/disadvantages, 185–186, 221 Interferon-g inducible p47 GTPases, 84 Interleukin 1b (IL-1b), 82 polymorphism, tuberculosis susceptibility, 88 Interleukin 1 receptor antagonist (IL-1RA) polymorphism, tuberculosis susceptibility, 88 Interleukin 2 (IL-2), 80, 719 Bacillus Calmette-Gue´rin response, 112 HIV–tuberculosis coinfection, 99 immune response to mycobacteria, 718 immunotherapy, 721, 752 Interleukin 4 (IL-4), 57, 80, 82 gene variant, tuberculosis susceptibility, 89 HIV–tuberculosis coinfection, 99 Interleukin 4 (IL-4) inhibitor therapy, 752 Interleukin 5 (IL-5), 80 Interleukin 6 (IL-6), 82, 752 immune response to mycobacteria, 718 Interleukin 8 (IL-8), 98 Interleukin 10 (IL-10), 80, 82, 92, 719 gene variant, tuberculosis susceptibility, 89 granuloma resolution, 85 HIV–tuberculosis coinfection, 99 Interleukin 12 (IL-12), 82, 98, 752 HIV–tuberculosis coinfection, 99 immune response to mycobacteria, 718, 761 immunotherapy, 722
INDEX Interleukin 12 (IL-12) gene (IL12B), tuberculosis susceptibility, 87 Interleukin 12 receptor gene (IL12Rb1), tuberculosis susceptibility, 87 Interleukin 12p70 (IL-12p70), 80 Interleukin 13 (IL-13), 80, 82 granuloma resolution, 85 Interleukin 18 (IL-18), 80–81 immune response to mycobacteria, 718 Interleukin 23 (IL-23), 81 Interleukin 23 (IL-23) gene, tuberculosis susceptibility, 87 Interleukin 27 (IL-27), 81 Internally displaced persons, 893, 897 International Standards for Tuberculosis Care, 316, 649–657, 674, 797, 945 aherence, 653–654 contact investigation, 656 development, 649 diagnosis, 650–652 HIV coinfection, 651 smear-negative pulmonary tuberculosis, 651 drug resistance assessment/management, 655–656 HIV testing, 655 Implementation Guide, 657 multidrug resistant tuberculosis, 656 patient support, 653–654 potential uses, 657 public health responsibilities, 656–657 record-keeping, 654–655 reporting systems, 657 situational analysis applications, 657 standard 1, 650 standard 2, 650–651 standard 3, 651 standard 4, 651 standard 5, 651–652 standard 6, 652 standard 7, 652 standard 8, 652 standard 9, 653–654 standard 10, 654 standard 11, 654–655 standard 12, 655 standard 13, 655 standard 14, 655–656 standard 15, 656 standard 16, 656 treatment, 652–653 International Union against Tuberculosis and Lung Disease, 727, 786 Interstitial keratitis, 478 Interstitial nephritis, tuberculous, 439–440, 445 Intestinal obstruction, 127, 425, 426 children, 433, 434 Intestinal strictures, 425 children, 432, 433, 434, 435 treatment, 436 Intestinal tuberculosis, 121, 382, 424, 520 children, 432 pathology, 432–433 imaging, 303 double-balloon enteroscopy, 428 magnetic resonance enteroclysis, 428–429 malabsorption, 425 see also Gastrointestinal tuberculosis Intracranial tuberculomas, 311, 384, 385, 401 case studies, 832–834, 858–859 children, 413, 414, 421–422, 858–859 clinical presentation, 402, 421 diagnosis, 405–406, 421–422 differential diagnosis, 402 expansion, 410 IRIS-related, 698 imaging, 251–252, 416 management, 422 adjunctive corticosteroids, 410 neurosurgery, 410 optic/oculomotor nerve compression, 480–481 pathology/pathogenesis, 406–407 stereotactic biopsy, 405 Intracyctoplasmic sperm injection, 451 Intramedullary abscess, case study, 864 Intravenous immunoglobulins, 752
Intravenous pyelography, 223 children, 269, 277 Intravenous urography, 252, 441, 442, 443, 444, 452 Investigator’s Brochure, 921, 922 Involuntary detention, extensively drug-resistant tuberculosis, 557 Ipr1, tuberculosis resistance, 91 Iran, 886 Iridocyclitis, chronic granulomatous, 387 Iron supplementation, 395 IS6110 Bacillus Calmette-Gue´rin (BCG) daughter strains, 50 evolutionary lineage studies, 51, 55 genotyping mixed infections, 34 nucleic acid amplification tests, 197 PCR-based methods, 30 restriction fragment length polymorphism, 29, 31, 32, 35, 36, 51 IS (insertion sequnces), 51 Isolation criteria for discontinuing, 706 extensively drug-resistant tuberculosis patients, 557 infection prevention in healthcare settings, 583, 595, 704, 705–706, 904 problems, 585 patient consent, 583, 584 respiratory (airborne infection isolation), 708 Isoniazid, 543, 608, 609, 610, 638, 639, 640, 932, 961 acetylator status, effects on metabolism, 52, 610, 629, 677 adrenal tuberculosis, 509 adverse effects, 610, 677, 678, 807, 964, 965, 966, 967 children, 635 depression/psychosis, 686 encephalopathy, 447, 455 haematological, 683 hepatotoxicity, 410, 447, 576, 610, 635, 642, 681, 682, 780, 782, 810 neurotoxicity, 610, 633, 642, 676, 677, 684 ocular toxicity, 483, 683–684 seizures, 684, 685 skin rash, 679 bactericidal activity, 608, 610 biliary excretion, 447, 455 breast tuberculosis, 474 broncho-oesophageal fistula, 372 catalase metabolism, 12 central nervous system penetration, 417, 545, 557 childhood tuberculosis, 330, 331, 366, 417, 435, 628, 629, 631, 633 clinical efficacy, 610 congenital tuberculosis, 577 cutaneous tuberculosis, 491 disseminated BCG disease (BCG-osis), 768 drug interactions, 969–970 expansile pneumonia, 370 extrapulmonary tuberculosis, 379 female genital tuberculosis, 461 gastrointestinal tuberculosis, 430, 435 genitourinary tuberculosis, 447 historical aspects, 5, 133, 926, 930, 931 HIV–tuberculosis coinfection, 527, 633, 641, 807 International Standards for Tuberculosis Care, 652, 653 with liver function impairment, 642 lymphadenitis, tuberculous, 394, 398 male genital tract tuberculosis, 455 meningitis, tuberculous, 384, 407, 408, 417 mode of action, 52, 56, 610 Mycobacterium bovis tuberculosis infection, 151 Mycobacterium kansasii infection, 70, 71 ocular tuberculosis, 478, 482 organ transplant patients, 521, 567 pancreatic tuberculosis, 511 pericardial effusions, 357 pharmacokinetics, 610, 642 children, 629 pituitary tuberculosis, 506 pregnant women, 576, 641, 810 prophylaxis, 5, 19, 25, 230, 610, 754, 776, 783, 784 case study, 881 cerebral tuberculosis prevention, 411 children, 41, 330, 607, 636
clinical trials, 917 duration of therapy, 781–782 efficacy, 780 historical aspects, 780 HIV–infected individuals, 41, 318, 529, 605, 804, 807 monitoring, 782 multidrug resistant tuberculosis, 536, 636 neonates, 576, 577, 642 organ transplant patients, 567 pregnant women, 810 regimens, 781–782, 783 renal transplant patients, 441 tumour necrosis factor a antagonist use, 569 workplace healthcare programmes, 904 with renal function impairment, 447, 455, 564, 642 resistance, 19, 20, 35, 53, 535, 631, 638, 639, 640, 655, 730, 731, 740, 754, 757, 927 BCG strains, 764 cross resistance, 614 detection, 174, 175, 176 line probe assays, 201, 202 molecular beacons, 202 mutations, 52, 233, 542, 552, 610 nontuberculous mycobacteria, 65 prevention, 610 tuberculous meningitis, 408 see also Extensively drug-resistant tuberculosis; Multidrug resistant tuberculosis spinal tuberculosis, 500 standard treatment regimen, 608–609 precautions, 609 strain differences in susceptibility, 12 susceptibility testing, 232, 542, 730, 741 Israel, 539 Itraconazole, cytochrome P450 inhibition, 619, 620
J Japan, 22 Jarman poverty index, 910 Jaundice, 380, 382, 383, 426, 511 drug-induced hepatotoxicity, 681, 682, 687 children, 633–634 neonatal tuberculosis, 573, 577 Jejunoilial bypass surgery patients, 568 Johne’s disease, 52 Joint pain, antituberculous drug side effects, 680
K Kanamycin, 613, 961 adverse effects, 965 nephrotoxicity, 613, 682 ototoxicity, 613, 685 peripheral neuropathy, 684 central nervous system penetration, 545, 557 clinical efficacy, 613 cross resistance, 555, 556 amikacin, 613, 644 extensively drug-resistant tuberculosis, 20, 555, 556 see also Extensively drug-resistant tuberculosis multidrug resistant tuberculosis, 613 male genital tuberculosis, 455 in renal failure patients, 564 resistance, 539, 540, 551, 757 mutations, 552 susceptibility testing, 730 nontuberculous mycobacteria, 66 Kapsoi sarcoma, 161 katG, 610 mutations, 12, 35, 52, 53, 610 rapid drug resistance detection, 201 Kazakhstan, 21, 539 Keloids, complicating BCG vaccination, 484 Kenya, 19 Keratinizing squamous metaplasia (leukoplakia), genitourinary tuberculosis, 446 Ketoconazole, cytochrome P450 inhibition, 620 Kirchner medium, 355 Koch phenomenon (Koch-like reaction), 108, 723 vaccine clinical trials, 113 Koch, Robert, 3, 4, 44, 129, 146, 179, 786, 978 Koch’s bacillus, 727 Koch’s postulates, 484, 785
999
INDEX Koebner phenomenon, 488 Koeppe nodules, 478 Korea, 23 extensively drug-resistant tuberculosis, 552, 557 Kyphosis, 497, 499, 500, 519 Kyrgyzstan, 21 KZN strain, 553
L Laboratory result conversion units, 957 Laboratory safety, 742–743 Laboratory services, 738–744, 746 DOTS programme implementation, 668, 669, 739 human resources, 741 microbiological culture, 739, 742 networks, 741–742, 791 nucleic acid amplification tests, 739 quality assurance, 669, 739, 743 research role, 743–744 resource-constrained countries, 669 sputum smear microscopy, 739 improving diagnostic services for poor people, 913 on-spot delivery of results, 913 standards, 669 Stop TB strategy implementation, 943 TB control programme requirements, 740–741, 791 Lactate dehydrogenase ascites fluid, 461 effusion fluids, 221 pericardial effusions, 355 pleural effusions, 344, 369, 381 Lactic acidosis, drug-induced, 966 Lady Windermere syndrome, 257 Lamivudine, 624, 625 adverse effects, 578 pregnant patients, 578 LAMP (loop-mediated isothermal amplification)-based assays, 198, 224, 233 Langerhans’ giant cells, 98, 125, 205, 379, 453, 509 renal tuberculosis, 445 sarcoidosis, 206 Laparoscopy, 224 fallopian tube tuberculosis, 460–461 female genital tuberculosis, 458, 461 gastrointestinal tuberculosis, 428, 434 infertility investigation, 460 ovarian tuberculosis, 512 peritoneal tuberculosis, 461, 520 Laparotomy gastrointestinal tuberculosis, 430, 434 pancreatic tuberculosis, 511 peritoneal tuberculosis, 520 Large-sequence polymorphisms, 51 Mycobacterium tuberculosis complex lineage differentiation, 55 Laryngeal biopsy, 464 Laryngeal tuberculosis, 335, 378, 387, 463–464 children, 373 diabetic patients, 560 diagnosis, 464 pulmonary tuberculosis association, 463, 464 treatment, 464 Latent tuberculosis, 13, 17, 75, 121, 131, 771, 787 children, 144, 781 contacts investigation/management, 656, 776 diagnosis, 25, 230 research approaches, 749 vaccine development challenges, 113 differentiation from active disease, 323 gender-related differences, 887–888 granuloma formation, 75 HIV coinfection, 96, 525–526, 780, 781, 783, 784, 807 immigrants, 733, 734 immune-based tests, 179 interferon-g release assay, 186–188, 192, 776–777, 778, 780–781 mycobacterial persistence mechanisms, 56–57 progression, high-risk groups, 781 serological tests, 189, 192 treatment, 780, 783, 784, 807 ensuring completion, 777–778 pregnant women, 810
1000
regimens, 781–782 target groups, 780–781 TB control strategies, 783–784 tuberculin skin test, 179, 185, 187, 188, 192, 780, 781 unresolved issues, 728–729 Latin America, 951 community involvement in tuberculosis control programmes, 663 Latvia, 21 extensively drug-resistant tuberculosis, 540, 552, 557 LCx test, 198, 199, 200 LED lamp fluorescent systems, 171, 231, 739 Lehman, Jorgen, 4 Leprosy, 207, 440, 445, 512, 615, 735, 949 histopathology, 207 immune response, 98 immunotherapy, 720, 721, 722 lepromatous, 207 tuberculous, 207 Levofloxacin, 615, 961 clinical efficacy, 615 multidrug resistant tuberculosis, 545 meningitis, 408 prophylaxis, 536, 782 Lichen scrofulosorum, 488, 491 clinical presentation, 488 complicating BCG vaccination, 484 differential diagnosis, 492 Line probe assays (strip tests), drug resistance detection, 201–202, 219–220 Linezolid, 615, 961 adverse effects, 615, 678, 963, 965, 966 myelosuppression, 683 optic neuropathy, 683 peripheral neuropathy, 684 clinical efficacy, 615 Mycobacterium abscessus pulmonary disease, 71 Mycobacterium chelonae pulmonary disease, 71 nontuberculous mycobacteria susceptibility testing, 66 Lipid antigen presentation, 80 Lipoarabinomannan, 47, 49 antigen-based diagnosis, 326 immune-based assays, 174, 223, 233 macrophage CR3 interaction, 76 Lipopolysaccharide, 77 Lipoprotein antigens, 79 Liquefaction necrosis, 11, 268, 297, 298 see also Pneumonia, expansile Liquid culture media, 172, 219, 231–232 drug susceptibility testing, 175 Lithuania, 21, 539 Liver abscess, 378, 395 Liver biopsy, 395, 399 neonates, 574 Liver failure, drug-induced, 681, 682, 687 see also Hepatotoxicity, drug-induced Liver failure patients, antituberculous chemotherapy, 642 drug-induced hepatotoxicity risk, 681 multidrug resistant tuberculosis, 645 second-line drugs, 645 Liver transplant patients, 567 Liver tuberculosis see Hepatobiliary tuberculosis Local exhaust ventilation (LEV), 708 Long bone tuberculosis, case studies, 865 Long-term care facility outbreaks, 585 Loop-mediated isothermal amplification (LAMP)-based assays, 198, 224, 233 Lopinavir rifampicin interaction, 633 ritonavir interaction, 620, 622 Lo¨wenstein-Jensen (LJ) medium, 47, 62, 172, 219, 231, 458, 730 LRG–47, 84 Lubeck disaster, 759 Lung auscultation, ‘amphoric’ sound, 334 Lung biopsy, 515 Lung fibrosis, 121, 122 children, pre-chemotherapy studies, 141 imaging, 297, 298 Lung nodules, imaging, 253, 254 branching configuration (‘tree-in-bud’ opacities), 242, 243, 253, 298, 299 chest radiographs, 237
childhood tuberculosis, 268, 269 miliary tuberculosis, 239–240 postprimary tuberculosis, 242, 245 Lung parenchymal cells, mycobacterial persistence, 729, 787 Lung resection extensively drug-resistant tuberculosis, 557 historical aspects, 516–517 indications, 517 children, 368 multidrug resistant tuberculosis, 546–547 preoperative evaluation, 517 surgical goals, 517 surgical procedure, 517, 518 thoracic complications, 517 Lung tissue destruction, 126 imaging, 242, 244, 297, 298, 299 see also Cavitating lung disease Lung transplant patients, 256, 260, 567 Lupus, drug-induced, 966 Lupus vulgaris, 387, 484 clinical presentation, 486–487 complicating BCG vaccination, 484, 768 differential diagnosis, 492 eyelid lesions, 477 histopathology, 487 Mycobacterium bovis tuberculosis, 149 Mycobacterium tuberculosis detection, 485 vulval tuberculosis, 459 see also Scrofuloderma Lymph node biopsy bronchoscopic, 521 cervical lymphadenopathy, 465 HIV–tuberculosis coinfection, 526 lymphadenitis, 393, 397 neonates, 574 Lymph node enucleation endoscopic, 567 expansile pneumonia, 371 transthoracic, 367–368 Lymph node rupture, 120 bronchogenic dissemination, 262, 297, 298 childhood airway disease, 364, 367–368 empyema thoracis, 343 lymphobronchial tuberculosis (expansile pneumonia), 369, 370 zoonotic tuberculosis, 149 Lymph node tissue samples, 205 Lymphadenitis, tuberculous, 131, 165, 238–239, 253, 333, 377, 380–381, 397 abdominal tuberculosis, 269, 275, 276, 278, 303–304, 382 aetiological agents, 391 BCG adenitis, 765–766 case presentations, 820, 821 chest radiographs, 336, 361, 364 children, 154, 155, 210, 262, 269, 275, 276, 278, 361, 364, 365, 391–395, 433, 434 airway compression/infiltration, 364 clinical examination, 157, 392–393 complications, 144 differential diagnosis, 393 epidemiology, 391, 392 imaging, 239, 262, 264, 265, 266, 268, 269, 270, 275, 276, 278, 362–363 oesophageal perforation, case study, 869 pathogenesis, 391–392 pre-chemotherapy studies, 138, 140–141 treatment, 394, 630–631 clinical presentation, 380, 392–393, 397 computed tomography, 365 diagnosis, 393, 394, 397 DOTS programme implementation, 671 diagnostic algorithms, 317, 319 expansile pneumonia, 369 fine needle aspiration biopsy, 210, 526 gastrointestinal tuberculosis, 301, 427, 433, 434, 520–521 granulomatous, 120 HIV coinfection, 165, 166, 254, 380, 397, 398, 521, 525, 526 differential diagnosis, 380 immune reconstitution inflammatory syndrome, 528, 690, 697
INDEX miliary tuberculosis, 240 neonatal tuberculosis, 573 nontuberculous mycobacteria, 67–68, 69, 71 ocular tuberculosis, 482 organ transplant patients, 567 ovarian tuberculosis, 512 pericarditis, tuberculous, 352 peripheral lymph nodes, 397 primary tuberculosis, 297, 298 cutaneous, 486 renal failure patients, 563 resolution of radiographic abnornalities, 241 treatment, 262, 398–399 paradoxival reaction, 398 surgical, 521 ultrasonography, 223 zoonotic tuberculosis, 148–149 see also Cervical lymphadenopathy; Hilar lymphadenopathy; Mediastnal lymphadenopathy; Mesenteric lymphadenopathy Lymphangiectasia, intestinal, 433, 434 Lymphatic spread see Dissemination Lymphobronchial tuberculosis see Pneumonia, expansile Lymphocytic interstitial pneumonia, 566 Lymphogranuloma venereum, 426, 512 Lymphoid interstitial pneumonitis, HIV–infected children, 161 Lymphoma, 239, 301, 303 Lymphotoxin-a, 80, 82 granuloma formation, 84 Lysogeny, 53 Lysosomes, 77 phagosome fusion, 79 Lysozyme, 223 pleural fluid, 344, 345, 369 tuberculous pericarditis diagnosis, 356
M M72 vaccine see Mtb72F/M72 vaccine M cells, 424, 432 Macrolides, nontuberculous mycobacteria pulmonary disease, 70, 71 Macromolecular structure, mycobacteria, 48–49 Macrophages, 9, 13, 49, 75, 378, 379 activation, 117, 119, 718 role of adjuvant immunomodulatory therapy, 752 adenosine deaminase activity, 222 antigen processing, 77–78 CD1-restricted T-lymphocyte lysis, 82–83 CD8 T cell cytolysis/apoptosis induction, 82 cytokine production, 80–81, 718 functional variants, tuberculosis susceptibility, 90–91 granuloma formation, 117–118, 119, 130 HIV infection, 124 HIV–tuberculosis coinfection impact, 98, 103 mycobacterial killing, 84 mycobacterial phagocytosis, 56, 75–76, 333 receptors, 75, 76 mycobacterial survival/persistence, 49, 56, 84, 333, 718 P2X7 receptor polymorphism, extrapulmonary tuberculosis susceptibility, 401 phagosomal maturation, 77–78 Toll-like receptor signalling, 77 Macular oedema, 481 Magnetic resonance imaging, 224, 251 abdominal lymphadenopathy, 303, 304 adrenal tuberculosis, 509 arthritis, tuberculous, 294, 308–309, 502 breast tuberculosis, 473 bursitis, tuberculous, 309 central nervous system tuberculosis, 251, 310 cerebral infarction, 311 childhood tuberculosis, 271, 273, 274, 286, 287, 288, 289, 290, 416, 421 abdominal, 269 lymphadenopathy, 268 osteoarticular, 291, 292, 293, 294 extrapulmonary tuberculosis, 671 gastrointestinal tuberculosis, 301, 303 magnetic resonance enteroclysis, 428–429 hepatosplenic tuberculosis, 304, 305 HIV–tuberculosis coinfection, 526 hydrocephalus, 311, 414, 417
intrathoracic lesions, 300 male genital tuberculosis, 452 mediastinal lymphadenopathy, 398 meningitis, tuberculous, 271, 273, 274, 286, 287, 288, 289, 290, 310–311, 384, 404–405, 416 cerebrospinal fluid flow assessment, 271 mesenteric lymphadenopathy, 398 myocarditis, tuberculous, 359 osteomyelitis, tuberculous, 310 extra-axial, 309 ovarian tuberculosis, 512 pancreatic tuberculosis, 305, 511 pericarditis, tuberculous, 356 constriction, 353, 354 effusions, 352 peritoneal tuberculosis, 303 pituitary tuberculosis, 506 pleural tuberculous, 344 effusions, 299, 300 primary tuberculous lymphadenopathy, 238 prostate tuberculosis, 306 radiculomyelitis, tuberculous, 313, 402 renal tuberculosis, 252 spinal tuberculosis, 291, 292, 293, 307, 308, 385, 497, 498, 519 syringomyelia, 313 tenosynovitis, tuberculous, 309, 310 tuberculomas, 271, 304 intracranial, 312–313, 406, 416, 421 myelitic, 313 Magnetic resonance spectroscopy, cerebral tuberculomas, 405–406 Major histocompatibility complex (MHC) Class I molecules, 75, 77 antigen presentation, 78, 79–80 segregated antigens, 80 tuberculosis susceptibility alleles, 88 Major histocompatibility complex (MHC) Class II molecules, 75, 77 antigen presentation, 78, 79 dendritic cells, 77 HIV infection effects, 99 macrophages, 117 tuberculosis susceptibility alleles, 88 Malabsorption, intestinal tuberculosis, 425 Malawi, 42, 229, 524 Male breast tuberculosis, 470 Male genital tuberculosis, 383, 441, 450–456, 521 complications, 455 diagnosis concurrent renal tuberculosis, 452 immune-based tests, 452 polymerase chain reaction-based methods, 451 differential diagnosis, 451 epidemiology, 450 HIV coinfection, 451 imaging, 252, 306, 452 infertility, 450, 451, 455 investigations, 451–452 management, 453–455 with renal function impairment, 455 surgical treatment, 455 multidrug resistant tuberculosis, 454–455 pathology, 452–453 prevention, 455–456 symptoms/signs, 450–451 transmission, 450, 455 sexual, 455–456 Malignant disease with tuberculosis, 564–565 clinical presentation, 564–565 diagnosis, 564–565 epidemiology, 564 prognosis, 565 treatment, 565 Malnutrition, 18, 92, 333, 605, 771 antituberculous drug adverse effects, 676 childhood tuberculosis, 154, 155 gastrointestinal disease, 433, 435 multidrug resistant disease, 535 extrapulmonary tuberculosis, 377 food supplements, 435, 605–606 pyridoxine deficiency, 684 tuberculin skin test false-negative result, 181
tuberculous gumma (metastatic tuberculous abscess), 488 Mammography, breast tuberculosis, 473 Management algorithms BCG adverse events, 766 childhood tuberculosis, 323–331 HIV–tuberculosis coinfection, 321 individuals on antiretroviral therapy, 318–319, 320 multidrug resistant tuberculosis, 554 where there are few of no diagnostic facilities, 316–322 Management research priorities, 750–751 Mannan, 77 Mannose receptors, 76 Mannose-binding lectin variants, tuberculosis susceptibility, 89 Mannose-capped lipoarabinomannan, 49, 56 dendritic cell mycobacterial uptake, 76 Toll-like receptor signalling, 77 Mantoux test see Tuberculin skin test Maraviroc rifampicin interaction, 623 rifamycin interaction, 621 Marfan’s law, 148 Mastectomy, 474 Mastitis, bovine tuberculosis, 146, 148 Mastitis, tuberculous, 387 acute miliary, 469, 470 disseminated/confluent, 469, 470 granulomatous, 474 histopathology, 474 nodular, 469–470 obliterans type, 469, 470 radiological features, 473 sclerosing, 469, 470, 473 Mastoiditis, tuberculous, 463 Mathematical modelling control strategies, 790 tuberculosis transmission, 13–14 MB/BacT system, 172, 175, 473 Measles, 9, 166 Media publicity/promotion, 791, 979 DOTS strategy, 934 Mediastinal lymphadenopathy, 377, 380, 397–398, 521 childhood tuberculosis, 297, 361, 362 airway compression, 364–365 primary, 262 diagnosis, 515 expansile pneumonia, 369 HIV coinfection, 398 imaging, 238, 297 immune reconstitution inflammatory syndrome, 690, 695 lymph node biopsy, 521 pericarditis, 352 Mediastinitis, tuberculous, 241, 251 Medical at risk conditions, 166 Memory T cells, 119 Meningitis, tuberculous, 121, 127, 131, 165–166, 333, 384, 401 adjunctive corticosteroids, 409–410, 418, 529, 628, 630 antituberculous chemotherapy, 407–408, 628, 630 Bacillus Calmette-Gue´rin (BCG) in prevention, 762 ‘border zone encephalitis’, 311 case studies, 826–830, 831–834 cerebral infarctions, 311 cerebrospinal fluid examination, 402, 404, 415 adenosine deaminase levels, 404 Mycobacterium tuberculosis nucleic acid detection, 404 children, 154, 155, 328, 384, 413–414, 416, 533, 627, 628, 630, 787, 826–830, 861 congenital tuberculosis, 577 differential diagnosis, 416–417 epidemiology, 413 management, 379, 416–417, 628, 630 multidrug resistant tuberculosis, 533 natural history, 787 neuroimaging, 271, 273–274, 280, 281, 282, 310–311 pre-chemotherapy studies, 136, 139, 141, 142 prognosis, 418, 420 signs/symptoms, 413–415 stages of progression, 414 thalidomide trials, 722–723
1001
INDEX Meningitis, tuberculous (Continued) clinical presentation, 384, 401–402, 413–415 consciousness level depression, 414 hyponatraemia, 402 meningeal irritation, 414 motor paralyses, 402, 414–415 movement disorders, 415 cranial nerve involvement, 311, 480 diagnosis, 384, 403–404, 414, 415–416 clinical, 328, 403–404, 414, 415, 480 delayed, 415 direct cerebrospinal fluid examination/culture, 404 microbiological, 415 neuroimaging, 251–252, 404–405, 416 new strategies, 405 nucleic acid amplification techniques, 200–201, 416 diffuse disease, 273 drug adverse effects management, 410 focal presentation, 271 HIV coinfection, 166, 384, 409, 416, 525, 861 mycobacterial load, 404 hydrocephalus see Hydrocephalus hyponatraemia, 410 intracranial pressure elevation, 413, 414 management, 417–418 monitoring, 414 multidrug resistant tuberculosis, 545 neuro-ophthalmological findings, 480, 481 choroidal tubercles, 481 optic atrophy, 480 pathology/pathogenesis, 406–407, 413 pituitary involvement, 504, 506 pregnant women, 574 prognosis, 410, 414 spinal involvement, 385, 402 treatment, 379, 384–375 surgical, 410 tuberculoma formation, 311 Menstrual fluid specimen, acid-fast bacilli detection, 458 Mental health facility outbreaks, 584 Mesenteric lymphadenopathy, 380, 398, 425, 520 children, 433 imaging, 269 clinical presentation, 380 HIV–tuberculosis coinfection, 398, 525, 526 imaging, 427, 526 zoonotic tuberculosis, 148, 149 Methadone, rifampicin interaction, 782 Methylprednisolone, high-dose therapy, 723 Mexico, 61, 150 MGIT system, 170, 172, 173, 212, 219, 473 MGIT 960 system, 175, 542, 543 MIBI scintigraphy, parathyroid tuberculosis, 508 Microbiological culture, 169–177, 216–217, 219, 227, 326, 729, 787 ascites fluid, 428, 434, 461 breast tuberculosis, 473 childhood tuberculosis, 326, 362, 534, 652 diagnosis confirmation, 159 re-treatment cases, 631 clinical trial endpoints, 113 cutaneous tuberculosis, 489 disseminated BCG disease (BCG-osis), 768 drug susceptibility testing see Drug susceptibility testing empyema fluid, 343 extensively drug-resistant tuberculosis, 554 extrapulmonary tuberculosis, 651 female genital tuberculosis, 458 genitourinary tuberculosis, 383, 441 HIV–tuberculosis coinfection, 526 International Standards for Tuberculosis Care, 649, 650, 651, 652 laboratory services, 739, 742 lymphadenitis, tuberculous, 393 meningitis, tuberculous, 384, 404, 415 methods, 172–173 liquid media systems, 231–232 multidrug resistant tuberculosis, 534 contact tracing, 536 mycobacterial identification see Mycobacterial identification ocular tuberculosis, 482 organ transplant TB patients, 567
1002
pericardial fluid, 355 pleural effusion fluid, 343, 344, 345–346, 369, 381 pregnant patients, 575 prostate tuberculosis, 451, 452 pulmonary tuberculosis, 336 smear-negative, 651 spinal tuberculosis, 498 Stop TB strategy implementation, 942 Microbiological specimens, 217 cerebrospinal fluid, 384, 404, 415 collection/handling, 169–170, 216–218 contamination levels, 169, 170 cytology, 209 fine needle aspiration material, 212 health facility procedures, 603 liquefication, 171 neonates, 574 preparation for culture, 171–172, 650, 739 storage, 170, 218 tissue samples, 205 transport, 170, 603 urine, 441 Microcolony diagnostic method, 730 Micronutrient supplements, 529 Microsatellites, 51 Microscopic observation of drug susceptibility (MODS) assay, 174, 176–177, 219, 232, 326, 408, 558 Microscopy mycobacteria detection, 170–171 new diagnostic methods, 231 see also Sputum smear microscopy MicroSeq 500 system, 173 Middlebrook 7H9 medium, 172, 176 Middlebrook 7H10 medium, 219 Middlebrook 7H11 medium, 219 Middlebrook 7H12 medium, 219 Migration, 892–899, 927 acute, 893 anticipatory, 893 disease dissemination, 896 historical aspects, 892 internal to seek healthcare, 898 international, 894–895 regular versus unofficial, 895 see also Immigrants Miliary tuberculosis, 131 children, 154, 155, 240, 262, 268, 269, 361, 362 antituberculous chemotherapy, 628, 630 congenital tuberculosis, 577 pre-chemotherapy studies, 136, 139, 142 symptom-based diagnosis, 328 treatment guidelines, 330, 331 clinical presentation, 166 definition, 386 HIV–tuberculosis coinfection, 97, 334 imaging, 239–240, 253, 262, 268, 269, 299 brain infection, 251, 252 postprimary tuberculosis, 247 pathophysiology, 120, 121 perinatal transmission, 572 pleural effusions, 381 pregnant patients, 574 skin lesions, 488 differential diagnosis, 492 Military installation outbreaks, 587 Milk Mycobacterium bovis transmission, 148, 150 pasteurization, 151 Millar asthma, 495 Millenium Development Goals, 23–24, 25, 772, 804, 901, 936, 940, 942, 946, 949, 951, 979, 982 tuberculosis/HIV targets, 942 Mine workers, 902 environmental protection, 905 Mini-laparoscopy, 224 Minimal inhibitory concentration (MIC) cycloserine, 614 determination methods, 175 ethionamide, 614 fluoroquinolones, 615 isoniazid, 610 nontuberculous mycobacteria susceptibility testing, 65 Minocycline
Mycobacterium fortuitum pulmonary disease, 71 Mycobacterium marinum infection, 72 Mitogen-associated protein kinase (MAPK) p38, 79 mmaA3, 761 Mobile populations/individuals, 800 collaborative tuberculosis/HIV care, 810 health care management, 606 Stop TB Strategy implementation, 944 tuberculosis control strategies, 790 see also Immigrants; Migration Modified Vaccinia Ankara (MVA), 108 Molecular beacons, drug resistance detection, 202, 233 Molecular epidemiology, 28–36 applications, 33–35 data interpretation, 33 methods clustering analysis, 33 evolutionary/phylogenetic studies, 35 genotyping, 29–33 outbreaks in congregate settings, 584, 585, 586, 588, 591 terminology, 35 Molecular methods, 209, 212 diagnosis, 232–233, 729 drug susceptibility testing, 175–176, 219, 233, 542 epidemiology see Molecular epidemiology laboratory error detection, 36 nontuberculous mycobacteria identification, 62–65 terminology, 35 virulence studies, 35–36 Monocytes adenosine deaminase activity, 222 HIV–tuberculosis coinfection, 98, 103 Morocco, 23 Mortality, 19, 21, 132, 332 childhood tuberculosis, 41–42 pre-chemotherapy studies, 136, 140, 142 epidemiological reporting criteria, 38 ethnic factors, 136, 925 extensively drug-resistant tuberculosis, 545, 551, 553 HIV–tuberculosis coinfection, 19, 21, 96, 97, 100, 229, 332, 545 multidrug resistant tuberculosis, 41–42, 545, 551 Mycobacterium bovis tuberculosis, 151 perinatal, 575 pregnant patients, 575 socioeconomic factors, 925 tuberculous pericarditis, 351 Moxifloxacin, 615, 961 clinical efficacy, 615 clinical trials, 917 duration of treatment, 751 multidrug resistant tuberculosis, 408, 545 Mycobacterium kansasii pulmonary disease, 71 nontuberculous mycobacteria susceptibility testing, 66 tuberculous meningitis, 410 Mozambique, 19 MPB64 skin (transdermal) patch test, 224 MPT32, 233 MPT63/64, 232, 405 Mtb72f, 753 Mtb72F/M72 vaccine, 107, 110–112 clinical studies, 111 preclinical studies, 110 MTD (Mycobacterium tuberculosis Direct) test, 63, 64, 197, 198, 200 MTT assay, 232 Much’s granules, 57 Mucormycosis, 207 Multidrug resistant tuberculosis, 5, 11, 12, 174, 219, 229, 515, 539–547, 980 adherence, 535, 643, 646 antituberculous chemotherapy, 19, 35, 534–535, 613, 640–641, 642–643 aminoglycosides, 467 children, 534–535, 628, 631–632 duration of treatment, 645 empirical treatment, 543, 644, 656 individualized regimens, 543, 644–645, 656, 733 regimen design, 643–644 second-line drugs, 535, 632, 641, 642, 643, 656 standardized regimens, 543, 644, 645–646, 656, 733 treatment principles/guidelines, 545, 642–643
INDEX Beijing lineage, 55 breast tuberculosis, 474 breastfeeding women, 645 children, 41, 42, 532–537, 753 acquisition, 532–533 case detection, 533, 534 clinical presentation, 533 confirmation, 534 contact tracting/management, 536, 607 diagnosis, 532, 533 new (primary) resistance, 532 nutrition influences, 535–536 ‘presumed’ MDR-TB, 534 previosly treated (acquired) resistance, 532–533 risk factors, 533–534 socioeconomic factors, 535 treatment, 534–535, 628, 631–632 control strategies, 547, 799, 800, 934, 944 cutaneous tuberculosis, 492 definitions, 532, 533 diagnosis, 739, 740 laboratory system requirements, 738 DOTS strategy, 944 DOTS-Plus strategy, 934 drug susceptibility testing, 641, 642, 644, 730, 740 follow-up, 741 elderly people, 565 epidemiology, 21–22, 41–42, 539–542, 642, 927, 943 current status, 935, 940 incidence, 19–20 molecular studies, 34–35 extrapulmonary tuberculosis, 545 health facility management, 605 hepatic failure patients, 645 HIV coinfection, 524, 536, 545–546, 555, 656 associated mortality, 545 treatment, 554, 645 imaging, 249 immunotherapy, 546, 718, 751 interferon therapy, 720–721 interleukin 2 therapy, 721 International Standards for Tuberculosis Care, 655, 656 isolation of infectious cases, 705, 706 laboratory diagnosis, 542–543 conventional methods, 542 first line drug susceptibility detection, 542 molecular assays, 542 rapid methods, 542 second line drug susceptibility detection, 542–543 latent disease treatment, 782 resource-constrained countries, 783 male genital tuberculosis, 454 management, 554, 642–643, 645, 732, 944 length of parenteral drug administration, 731 number of drugs, 730–731 optimal regimen, 732, 733 pulmonary tuberculosis, 408 surgical, 517, 546–547, 731, 733 tuberculous meningitis, 408–409 unresolved issues, 730–731 Mycobacterium bovis tuberculosis, 150 national TB control programmes, 800 surveillance/monitoring activities, 799 outbreaks, 808 air-travel-related, 590, 591 confined locations, 583, 584 healthcare settings, 583, 645 management, 790 prison, 585, 587 patient support, 656 pregnant women, 576, 645 prevention, 645, 740 prognosis, 545 prophylaxis in contacts, 536, 636 renal failure patients, 645 research priorities, 751, 753, 757 risk factors, 655 Stop TB Strategy implementation, 24, 943–944, 951 transmission prevention, personal respiratory protection, 709 workplace healthcare, 904 see also Extensively drug-resistant tuberculosis
Murein, 48 Muscle involvement, 495, 496 Musculoskeletal tuberculosis, 494–502 children, 494 case studies, 841, 864–867 imaging, 274, 291, 292, 293, 294, 295 clinical presentation, 495 diagnostic delay, 495 epidemiology, 494–495 HIV coinfection, 494, 525 pathogenesis, 495 see also Osteoarticular tuberculosis Mutations, drug resistance, 34, 552–553 cross-resistance/class-resistance, 553 isoniazid, 610 rapid detection, 554 rifampicin, 610 MVA85A vaccine, 107, 108–109, 753 clinical studies Gambia, 110 HIV–infected individuals, 110 South Africa, 110 UK, 108–110 local side effects, 109 preclinical studies, 108 safety, 109–110 My D88, 77, 79 Myanmar, 19, 23, 25 Myco/F Lytic, 172 Mycobacteria other that TB (MOTT) see Nontuberculous mycobacteria Mycobacterial identification, 65, 173–174, 219, 232 antigen detection methods, 174 culture-based methods, 173–174, 219, 232 genotypic analysis, 173 high-performance liquid chromatography, 63, 65 mycolic acid analysis, 173 nucleic acid probes (AccuProbe), 63, 65 phage assays, 174, 232 phenotypic methods, 173 rapid methods, 232 Mycobacterial interspersed repetitive units (MIRUs), 32 Mycobacterial-enhanced infection loci (mel 1 and 2), 56 Mycobacteriophages, 53 Mycobacterium, 5, 44–57 antigenic structure, 47–48 classification, 45–46, 61 molecular methods, 45 Runyoun’s groups, 44–45 ecology, 45–46 evolutionary aspects, 1, 54 genetic typing, 5 growth characterisitics, 46–47 historical aspects, 44 macromolecular structure, 48–49 metabolism, 46–47 morphology, 46 rapid growers, 45, 47 slow growers, 47 Mycobacterium abscessus, 45, 46, 173, 256 epidemiology, 60 fibrocavitary disease, 257 nodular bronchiectasis, 257 pulmonary disease treatment, 71 Mycobacterium africanum, 50, 219 evolutionary aspects, 54 regions of difference, 54 Type I/II, 50 see also Mycobacterium tuberculosis complex Mycobacterium aquae see Mycobacterium gordonae Mycobacterium asiaticum, 63 Mycobacterium avium, 45, 46, 173 BCG response effects, 762 historical aspects, 44 Mycobacterium avium brunense, 47 Mycobacterium avium complex, 49, 256, 485 agglutination typing, 48 antigens, 47, 48 breast lesions, 472 cervical lymphadenitis, 67 cultivation medium, 47 disseminated infection, 69, 72, 378 drug susceptibility testing, 65
limitations, 70 epidemiology, 60, 61 fibrocavitary disease, 257 gastrointestinal infection, 435 HIV coinfection, 69, 259, 378 identification high-performance liquid chromatography, 63, 65 nucleic acid probes (AccuProbe), 63, 65 immune reconstitution inflammatory syndrome, 689, 695 immunotherapy, 722 lymphadenitis, 71, 391, 397, 398 nodular bronchiectasis, 257 plasmids, 54 pulmonary disease, 66, 70, 71 clinical presentation, 66 renal tuberculosis, 445 skin infections, 71 susceptibility genes, 88 treatment, 70, 71, 72 Mycobacterium avium intracellulare, 47 fine needle aspiration biopsy cytomorphology, 213, 214 musculoskeletal tuberculosis, 495 nucleic acid probes (AccuProbe), 63, 65 Mycobacterium avium lepraemurium, 47, 61 Mycobacterium avium paratuberculosis, 47, 49, 61, 173, 432 genome, 52 Mycobacterium avium sylvaticum, 49 Mycobacterium bovis, 146–152, 377, 787, 793 animal hosts, 147 Bacillus Calmette-Gue´rin (BCG) development, 5, 759, 760 bovine disease see Bovine tuberculosis cultivation medium, 47 drug susceptibility, 151, 612 testing, 542 eradication programmes, tuberculosis epidemiology following, 149 evolutuonary/phylogenetic studies, 1, 29, 35, 54 fine needle aspiration biopsy cytomorphology, 213, 214 genome, 51 historical aspects, 44 human tuberculosis see Zoonotic tuberculosis identification, 65, 219 intestinal tuberculosis in children, 432 lymphadenitis, 391, 397 treatment, 394 natural immunization effect, 148 ocular tuberculosis, 476, 477 pyrazinamide resistance, 612 regions of difference, 54, 55 variants, 50 virulence, 148 see also Mycobacterium tuberculosis complex Mycobacterium canetti, 35, 50 Mycobacterium caprae, 50 zoonotic importance, 146, 147, 148 Mycobacterium celatum, 173 Mycobacterium chelonae, 45, 46, 173, 256 eyelid lesions, 477 fibrocavitary disease, 257 historical aspects, 44 nodular bronchiectasis, 257 ocular tuberculosis, 478 pulmonary disease treatment, 71 Mycobacterium chelonae-abscessus group, 63 Mycobacterium fortuitum, 45, 256, 257 eyelid lesions, 477 historical aspects, 44 pulmonary disease, 71 skin infections, 71 treatment, 71 Mycobacterium fortuitum-smegmatis group, 63 Mycobacterium gastri, 61 Mycobacterium gordonae, 46, 61, 173 identification high-performance liquid chromatography, 63 nucleic acid probes (AccuProbe), 63, 65 Mycobacterium haemophilum, 47 cervical lymphadenitis, 68 Mycobacterium hiberniae, 61 Mycobacterium intracellulare, 173 Mycobacterium kansasii, 46, 173, 256
1003
INDEX Mycobacterium kansasii (Continued) disseminated infection, 69, 72 drug susceptibility testing, 65–66 limitations, 70 epidemiology, 60, 61 fibrocavitary disease, 257 HIV coinfection, 69, 260 nucleic acid probes (AccuProbe), 63, 65 pulmonary disease, 65, 70–71 chest radiographs, 336 clinical presentation, 66, 68 treatment, 70–71, 72 Mycobacterium leprae, 44, 46, 98, 485 cell wall phenolic glycolipids, 49 genome, 52 heat shock protein 65 (hsp65) therapeutic vaccine, 724 Mycobacterium malmoense, 256 cervical lymphadenitis, 68 epidemiology, 60 identification, 63 Mycobacterium marinum, 46, 56 clinical presentation, 46, 56, 67, 69 diagnosis, 69 drug susceptibility testing, 70 epidemiology, 61 identification, 63 transmission, 66 treatment, 72 Mycobacterium microti, 50, 61 evolutionary aspects, 54 regions of difference, 54, 55 see also Mycobacterium tuberculosis complex Mycobacterium nonchromogenicum, 61 Mycobacterium peregrinum, 45 Mycobacterium pinnipedii, 50 zoonotic importance, 147 Mycobacterium protuberculosis, 54 Mycobacterium ranae see Mycobacterium fortuitum Mycobacterium scrofulaceum, 391 identification, 63 lymphadenitis, 67 treatment, 71 Mycobacterium simiae, 173 drug susceptibility testing, 70 fibrocavitary disease, 257 identification, 63 Mycobacterium terrae, 46, 61 Mycobacterium triviale, 61 Mycobacterium tuberculosis, 787 antituberculous drug bactericidal activity, 608 Asian/South Indian type, 50 attenuation for vaccine development, 753 bacteriophages, 53 clades, 1 cultivation medium, 47 cutaneous tuberculosis, 485 dose required to cause infection, 9 drug resistance mutations, 552–553 drug susceptibility testing, 542 evolutionary aspects, 1, 2, 29, 35 fine needle aspiration biopsy cytomorphology, 214 genetic mutation during infection, 12 genome, 28–29, 51 historical discovery, 3–4 host killing mechanisms, 84 identification, 65, 219 lymphadenitis, 68, 391, 397, 398 M cell transport, 432 microbiological testing, 169–177 musculoskeletal tuberculosis pathogenesis, 495 strains, 50 drug-resistant, 169 host–pathogen compatibility variation, 35–36 mixed infections, 34 molecular epidemiology, 28 propagation differences, 12 virulence variability, 787 Toll-like receptor interactions/signalling, 77 transmission see TransmissionMycobacterium tuberculosis complex Mycobacterium tuberculosis complex, 28, 44–57, 377, 476, 477 definition, 49–50 evolution, 54–55
1004
genetic markers, 29 genotyping methods, 29–33 identification, 65 high-performance liquid chromatography, 63, 65 nucleic acid probes (AccuProbe), 63 lineages (clades), 55 nomenclature, 55 Spreading Index (SI), 55 molecular genotyping, 45 phage typing, 53 phylogenetic tree, 29 species names, 50 virulence determinants, 55–56 Mycobacterium tuberculosis H37Rv genome, 51 regions of difference, 54 Mycobacterium tuberculosis specific deletion 1 (TbD1), 32, 54, 55 Mycobacterium ulcerans, 1, 46, 485 clinical presentation, 67 diagnosis, 69 epidemiology, 61 mycolactone, 55 skin disease see Buruli ulcer transmission, 66 treatment, 72 Mycobacterium vaccae immunotherapy, 111, 724, 752 HIV–tuberculosis coinfection, 111, 529 multidrug resistant tuberculosis, 546 regulatory T cell effects, 93 Th1 T cell (protective) response, 57 as vaccine candidate, 107, 111 Mycobacterium xenopi, 46, 256 drug susceptibility testing, 70 epidemiology, 60 identification, 63 pulmonary disease clinical presentation, 67 treatment, 71 Mycobactins, 49 Mycolactone, 55 Mycolic acid, 48, 53 cultured mycobacteria identification, 173 Mycolyl transferases, 79 Mycophenolate mofetil, antituberculous drug interactions, 563 Mycosides, 49 Myelitic tuberculoma, 313 Myelitis, 406 Myocardial scintigraphy, 359–360 Myocarditis, tuberculous, 351–360 Myometrial tuberculosis, 458 Myositis, tuberculous, 501, 502
N N-acetyl-L-cysteine–sodium hydroxide, culture specimen preparation, 172, 650 N-acetyltransferase polymorphism, isoniazid metabolism, 53, 610 Nasal tissue biopsy, 465 Nasopharyngeal aspirates, 209, 217 cytomorphology, 210 processing, 209 Nasopharyngeal tuberculosis, 387, 465 treatment, 465 National reference laboratories, 742, 744, 791 National TB control programmes, 795–802 adherence promotion, 652, 934 advocacy, communication and social mobilization (ACSM), 799 child treatment records/follow-up, 635 collaborative tuberculosis/HIV activities, 804, 805 coordination of activities, 798 developed countries, 795 developing countries, 795–798 drug resistance detection, 944 drug supplies, 797, 799 employment sector partnerships, 904 evaluation of performance, 727–728, 799 functions, 797 funding, 786, 797, 800 future development, 801–802
historical aspects, 795, 933 human resources, 798 laboratory system requirements, 738 operational research, 800 organization, 796–797 planning activities, 797 policy formulation, 797 programme review, 799 recording systems, 799 research activities, 790 Stop TB Strategy implementation, 940, 942, 946 supervision, 798 surveillance/monitoring activities, 799 technical challenges, 800–801 technical standards, 797 technical support, 798 Natural history of tuberculosis, 17–19, 129–132, 787–788 childhood tuberculosis in pre-chemotherapy era, 39, 133–144, 323 new vaccine approaches, 107 untreated tuberculosis, 132 Natural killer cells, 718 CD1 molecule regulation, 80 function, 83 granuloma formation, 75 Navy ships, contact tracing, 773 Neck deep spaces tuberculosis, 466 see also Cervical lymphadenopathy Negative pressure respiratory isolation rooms, 705, 708 Nelfinavir, rifabutin interaction, 623 Neomycin, ear tuberculosis, 463 Neonates, 572–579 investigations, 573–574 isoniazid prophylaxis, 642 management following maternal tuberculosis exposure, 576 asymptomatic infants, 576–577 symptomatic infants, 577 specimen collection, 574 tuberculosis presentation, 573 see also Congenital tuberculosis; Perinatal tuberculosis Nephrotoxicity aminoglycosides, 467, 677 capreomycin, 613 kanamycin, 613, 682 Netherlands, 34, 167, 888, 932 Neutrophils, granuloma formation, 75 Nevirapine adverse effects, 578, 621, 697 skin rash in children, 633 antituberculous drug interactions, 557, 624 clarithromycin, 645 rifampicin, 578, 619, 633, 752, 810 rifamycins, 620, 621, 624 pregnant patients, 578 New Zealand, 540 Niacin test, 173, 219 Nicotine, 92 Nigeria, 19, 150 Night sweats, 142, 156–157, 164, 316, 333, 335, 352, 381, 383, 426, 466, 495, 511, 650 childhood tuberculosis, 156–157 Nitrate reduction assay, 219, 232, 730 Nitric oxide, 84, 718, 752 Nitric oxide synthetase 2, 84 Nocardia, 46, 47, 48, 63 drug susceptibility testing, 65 identification, 63 pulmonary infection, 336 NOD2, 90 Nodular granulomatous phlebitis (phelbitic tuberculid), 488 Nodular tuberculid, 488 clinical presentation, 488, 491 differential diagnosis, 492 Non-nucleoside reverse transcriptase inhibitors, 810 antituberculous drug interactions, 528, 557 rifampicin, 619, 641, 782, 810 rifamycins, 618, 620–621, 633 cytochrome P450s induction, 619 immune reconstitution inflammatory syndrome, 696 pregnant patients, 578 see also Antiretroviral therapy
INDEX Non-steroidal antiinflammatory drugs, 680, 684, 697 Nonchromogens, 44 Nontuberculous mycobacteria, 44, 45–46, 60–72 bacteriology, 61–62 BCG response influence, 762 bone/joint infection, 68–69, 71–72 clinical presentation, 66–67 cutaneous infection, 66, 68–69, 72, 485 diagnosis, 207, 362 disseminated infections, 69, 72 drug susceptibility testing, 65–66, 542 limitations, 69 epidemiology, 60–61 geographic differences, 60 histopathology, 207 identification, 62–65 in culture, 173 genotypic analysis, 173, 174 imaging findings immunocompromised patients, 259–260 intrathoracic infection, 256–260 thoracic patterns, 256 interferon-g release assays, 362 investigations, 69 isolation, 61–62 liquid media, 232 lymphadenitis, 67–68, 69, 71, 391, 397 cervical, 327 differential diagnosis with HIV coinfection, 380 management, 394 lysogenic strains, 53 musculoskeletal infection, 495 ocular infection, 477, 478 pathogenesis, 66 pericarditis, 357–358, 382 plasmids, 54 prevention of infection, 72 pulmonary disease, 60, 61 clinical presentation, 66–67 diagnostic criteria, 69 investigations, 69 management, 70 prevention, 72 risk factors, 66 rapid-growing, 61, 63, 71 risk factors, 61 sensitization, 46 slow-growing, 61, 62 soft-tissue infection, 68–69, 71–72 transmission, 66 treatment, 69–70, 71 tuberculin skin test false-positive result, 181–182, 183 tuberculosis susceptibility influence, 92 Norway, 35, 886 Nose tuberculosis, 387, 465 orificial tuberculosis, 487 treatment, 465 Nosocomial transmission, 581–583, 595 extensively drug-resistant tuberculosis, 553–554, 557 key features of outbreaks, 582 prevention, 547, 553–554, 557, 581, 645 healthcare workers, 903 isolation, 583 program inadequacies, 582, 583 see also Infection control, healthcare settings Notification systems see Reporting systems Nramp1 see Slc11a1 Nucleic acid amplification tests, 197–202, 223, 232–233, 652, 729, 742 clinical uses, 198 commerical assays, 223 FDA-approved, 197–198 not FDA-approaved, 198 performance, 198 cost-effectiveness, 201 diagnosis, 197–202, 223 cerebral tuberculomas, 405 extrapulmonary tuberculosis, 199–200 meningitis, 200–201, 404, 416 pleuritis, 200–201, 345 drug resistance detection, 201–202 guidelines for use, 199 in-house assays, 198–199, 223
laboratory service requirements, 739 mechanism of action, 197 mycobacterial identification, 219 sensitivity/specificity, 197, 198, 199, 200, 223, 232 Nucleic acid probes nontuberculous mycobacteria identification, 62, 63, 65 nucleic acid amplification tests, 197 Nucleic acid-based assays, 169 cultured mycobacteria identification, 173 Nucleoside analogues, rifampicin interactions, 623 Nucleoside reverse transcriptase inhibitors, 810 adverse effects, 684 immune reconstitution inflammatory syndrome, 696 Nurse-run clinics, 596, 598, 711 nurse support, 598 patient education, 598 Nursing care, 711–717 core features (definition), 711, 712 documentation, 713 person-centred approach, 711–712 Nursing Intervention Classification, 713 Nursing process, 711–712 assessment, 711, 712 care plans, 712–713 case study, 713–717 diagnosis, 711–712 categories, 713 NANDA-International system, 712 problem–aetiology–symptoms (PES) system, 712 interventions, 713 outcomes, 713 Nutrition supplementation, 19, 605–606 children with multidrug resistant tuberculosis, 536 gastrointestinal tuberculosis patients, 435 Nutritonal status assessment, children, 157 Nystagmus, antituberculous drug-induced, 685, 686
O Obliterative fibrous pleuritis, 124 Occupational transmission, 10–11 healthcare workers see Healthcare workers high-risk settings, 902 military personnel, 587 prison staff, 586 tuberculosis control strategies, 790 see also Workplace tuberculosis Ocular BCG adverse effects, 768 Ocular toxicity, antituberculous therapy, 483 see also Optic neuritis Ocular tuberculosis, 387, 476–483 case resport, 837–838 children, 477 clinical presentation, 477–478 corticosteroid therapy-related, 481 diagnosis, 481–482 epidemiology, 476, 477 historical aspects, 476, 477 HIV coinfection, 476, 481 hypopyon, 481 investigations ocular, 481–482 systemic, 482 neuro-ophthalmological findings with neurotuberculosis, 480–481 pathogenesis, 476–477 treatment, 478, 479, 482–483 without detectable systemic tuberculosis, 481 Oculomotor nerve involvement, 480–481 pituitary tuberculosis, 504 Oedema, drug-induced, 966 Oesophageal perforation case study, 869 childhood tuberculosis, 372–373 clinical presentation, 372 management, 373 Oesophageal tuberculosis, 372, 382, 425, 520 clinical presentation, 425 Oesophago-mediastinal fistula, 250, 251 Oesophago-pericardial fistula, 520 Ofloxacin, 615, 962 adverse effects, 678 childhood tuberculosis, 634
clinical efficacy, 615 cross resistance, 555 disseminated BCG disease (BCG-osis), 768 hepatitis patient treatment, 682 multidrug resistant tuberculosis, 545 prophylaxis, 536, 782 susceptibility testing, 730 Ogawa medium, 231 Omental involvement, 303 OPC–67683, 616 Operational research, 743, 747, 755, 791, 800, 981–982 Stop TB Strategy implementation, 945 Optic atrophy, 480, 481 Optic nerve lesions, 480–481, 504 Optic neuritis, 480, 483, 676, 683–684, 965 children, 535 Oral cavity tuberculosis, 387, 466, 487 differential diagnosis, 466 treatment, 466 Oral fusion inhibitors, rifamycin interactions, 618 Oral hypoglycaemic agents, rifamycin interactions, 561 Orbital tuberculosis, 479 Organ transplant patients, 256, 259, 260, 521, 560 antituberculous drug prophylaxis, 781 isoniazid, 567 tuberculosis clinical presentation, 567 differential diagnosis, 567 epidemiology, 566–567 renal, 440 Orificial tuberculosis (tuberculosis cutis orificialis), 487 differential diagnosis, 492 Origins of tuberculosis, 1, 896 Oropharyngeal tuberculosis, 466 Orphanage outbreaks, 585 Oscillopsia, antituberculous drug-induced, 685, 686 Osteitis cystica tuberculosa multiplex, 309 Osteitis, tuberculous, 293, 295 Osteoarticular tuberculosis, 385, 501–502 chest wall, 374 children, 374, 466 antituberculous chemotherapy, 631 case studies, 865, 866, 867 disseminated skeletal disease, 494 HIV coinfection, 867 pre-chemotherapy studies, 137 epidemiology, 494 hip involvement, 841–842 Phemister’s triad, 252, 308, 501 radiography, 223 skull/facial bones, 466 Osteomyelitis, tuberculous, 501, 502 children, 293, 502 clinical presentation, 293, 495 closed multiple diaphysitis, 502 cystic lesions, 252, 293 closed, 502 multifocal (osteitis cystica tuberculosa multiplex), 309 dactylitis see Dactylitis differential diagnosis, 309 disseminated skeletal disease, 502 imaging, 252, 293, 310, 502 extra-axial disease, 309 Otitis media, tuberculous, 387, 463 HIV coinfected children, 463 Ototoxicity, drug-induced, 677, 685, 965 amikacin, 685 aminoglycosides, 467, 576, 645, 677, 685, 686 capreomycin, 685 kanamycin, 613, 685 streptomycin, 613, 641, 685, 686 risk to foetus, 576 Outbreaks in confined locations, 581–592 management, 790 molecular epidemiological studies, 34 multidrug resistant tuberculosis, 808 Outcome measures, clinical trials, 918 Ovarian tuberculosis, 505, 512–513 clinical presentation, 512 complications, 513 differential diagnosis, 512 epidemiology, 512
1005
INDEX Ovarian tuberculosis (Continued) investigations, 512–513 management, 513 pathology, 513 oxyR-ahpC mutations, 52
P P2X7 receptor polymorphism, tuberculosis susceptibility, 91, 401 P-glycoprotein, role in drug interactions, 619 PA–824, 616 Paediatric patient-wise drug boxes, 670 Pakistan, 19, 40 community involvement in control programmes, 663 Pancreatic tuberculosis, 382, 383, 426, 505, 510–511, 521 clinical presentation, 426, 511 differential diagnosis, 511 epidemiology, 510–511 HIV coinfection, 510, 511 imaging, 305 investigations, 511 endoscopic ultrasound-guided fine needle aspiration, 429 management, 511 pathology, 511 Panniculitis, 501 Panophthalmitis, tuberculous, 480 HIV coinfected patients, 481 Papua New Guinea, Buruli ulcer distribution, 61 Papular tuberculid, 484 Papulonecrotic tuberculid, 387, 485, 488 clinical presentation, 488, 489 differential diagnosis, 492 Para-aminosalicylic acid, 52, 614, 638, 932, 962 adverse effects, 557, 678, 963, 964, 965, 966, 967 children, 535 hepatotoxicity, 645, 682 hypothyroidism, 687 central nervous system penetration, 545 dosage, 614 drug interactions, 970–971 extensively drug-resistant tuberculosis, 555, 556 historical aspects, 4, 5, 930, 931 meningitis, tuberculous, 407, 417 multidrug resistant tuberculosis, 534, 643 male genital tuberculosis, 455 pericardial effusions, 357 resistance, 638, 731 mutations, 552 nontuberculous mycobacteria, 65 prevention, 608 teratogenicity risk, 576 Paracetamol, 684 Paradoxical reactions, 339, 379, 689 Parameningeal tuberculosis, 311 Paranasal sinus tuberculosis, 387, 465 case report, 837–838 treatment, 465 Paraspinal abscess, 495, 496 Parathyroid tuberculosis, 505, 507–508 clinical presentation, 507, 508 differential diagnosis, 507–508 epidemiology, 507 investigations, 508 management, 508 pathology, 508 Paravertebral abscess, 307 imaging, 291 neonatal tuberculosis, 573 surgical drainage, 520 parC, 615 parD, 615 Parotid abscess, 387 Participatory poverty assessments, 910 Particulate filter respirators, 709 EN149, 709 face-seal fit, 709 FFP3, 709 N-series/N95, 553, 583, 603, 709 sputum collection safety, 603 see also Personal respiratory protection Partnership approach, community healthcare programmes, 662–663, 666
1006
Pasteurization of milk, 151 Pathogen-associated molecular patterns (PAMPs), 75, 77 Pathogenesis of tuberculosis, 119–120, 130–132 PATHOZYME assay, 191 Patient empowerment, stop TB Strategy, 945 Patient information leaflets, clinical trial participation, 918, 920 Patient support, 598, 754 adherence improvement, 640, 643, 654, 671, 672, 930, 934 antituberculous chemotherapy, 639 extensively drug-resistant tuberculosis, 555 HIV–infected individuals, 808, 809 individualization, 654 International Standards for Tuberculosis Care, 653–654 multidrug resistant tuberculosis, 643, 656 reactive depression management, 686 Stop TB strategy implementation, 943 see also DOTS supporters Patient TB card, 599 child treatment records, 635 Patient-wise drug boxes, 673 Patients’ Charter for Tuberculosis Care, 650, 654, 799, 945 Pattern recognition receptors (PRRs), 75 pathogen-associated molecular pattern (PAMP) interactions, 77 see also Toll-like receptors PE proteins, 51 Penis tuberculosis, 450, 451 Pentoxifylline, HIV–tuberculosis coinfection treatment, 104 Peptide vaccines, 753 Peptidoglycan, 77 Perforins, 82, 83 Perfusion imaging, childhood meningitis, 271 Perianal fistula, 426 Perianal tuberculosis, 426, 487 Pericardial biopsy, 355, 382 Pericardial calcification, 241 Pericardial effusions, 165 adenosine deaminase assay, 222 childhood tuberculosis, 361, 382 imaging, 274 diagnosis, 352–353 HIV–tuberculosis coinfection, 166, 351, 357, 381, 525 interferon-g release assays, 222 lysozyme, 223 management, 357–358, 382 pathology, 351 symptoms/signs, 352 ultrasonography, 223 Pericardial fluid, 209, 221 cytomorphology, 210 processing, 209 specimen collection, 217 Pericardial tuberculosis, 377 adjunctive corticosteroids, 529, 628 children, 155, 628 clinical examination, 157–158 see also Pericardial effusions; Pericarditis, constrictive; Pericarditis, effusive-constrictive; Pericarditis, tuberculous Pericardiectomy, 358, 382 Pericardiocentesis, 354–355, 382 Pericarditis, constrictive, 127, 241, 351, 381 clinical presentation, 382 diagnosis, 353–354 imaging, 300 management, 358 pathology, 351–352 symptoms/signs, 352 Pericarditis, effusive-constrictive diagnosis, 354, 355 management, 358 symptoms/signs, 352 Pericarditis, tuberculous, 131, 250, 351–360, 381–382 adjunctive corticosteroids, 379 clinical presentation, 352, 381 constrictive scarring, 351 diagnostic criteria, 356 differential diagnosis of congestive disease, 356–357
epidemiology, 351 fibrinous exudation, 351 granulomatous caseation/fibrosis, 351 HIV–tuberculosis coinfection, 359 investigations, 352–354, 382 direct diagnostic methods, 354–355 imaging, 382 indirect diagnostic methods, 356 integrated approach, 356, 357 lymphadenopathy, 352 management, 357–358, 382 pathology, 351–352 prognosis, 359 serosanguinous effusions, 351 see also Pericarditis, constrictive; Pericarditis, effusive-constrictive Perinatal death, 575 Perinatal tuberculosis, 572–579, 810 clinical presentation, 573 pathogenesis, 572, 573 Perineal fistula, 455 Peripheral neuropathy, drug-induced, 676, 965 amikacin, 684 antiretroviral drugs, 684 capreomycin, 684 cycloserine, 684 differential diagnosis, 684 ethambutol, 684 ethionamide, 614, 684 fluoroquinolones, 615, 684 kanamycin, 684 linezolid, 684 management, 684 pathogenesis, 684 prevention, 684 Peritoneal tuberculosis, 383, 424, 425, 520 ascites, 301–303 children, 155, 432 pathology, 433 diagnosis, 461 biopsy, 461 dry type, 253, 301, 433 female genital tuberculosis presentation, 461 fibrotic type, 253, 301, 425 imaging, 253, 301, 303, 461 ultrasonography, 427 renal failure patients, 563 wet type, 301, 425, 433 Peritoneum imaging, 303 Perlsucht (pearl disease), 146 Persistence, mycobacterial, 143, 787, 927 mechanisms, 56–57 role of adjuvant immunomodulatory therapy, 751, 752 Persistent generalized lymphadenopathy, 165 Personal respiratory protection, 553, 583, 595, 709, 902, 904 see also Particulate filter respirators Peru, 23, 25, 164 community involvement in control programmes, 663 extensively drug-resistant tuberculosis, 552, 557 multidrug resistant tuberculosis, 642 Peyer’s patches, 424, 432 Phage typing, 53 Phage-based assays, 326 diagnosis, 730 drug susceptibility testing, 176, 219, 220 mycobacterial identification, 174, 232 Phagocytosis, 75–76 endocytic pathway, 77, 78 Phagolysosome, 79, 130 Phagosome, 56 maturation, 77–79 LRG–47, 84 Pharmaceutical company marketing, 674 Pharmacovigilance, 916 Pharyngeal tuberculosis, 387 Phase I trials, 916 Phase II trials, 916 Phase III trials, 916 Phase IV trials, 916 Phemister triad, 252, 308, 501 Phenolic glycolipid, 47, 49, 401 PhilCAT, 604
INDEX Philippines, 19 extensively drug-resistant tuberculosis, 552 Phlyctenular conjunctivitis, 333, 387, 478, 491 clinical presentation, 478 treatment, 482 tuberculin skin test contraindication, 489 Photochromogens, 44 Phrenic nerve crush procedure, 249 Phrenic nerve lesions, 373 Phthisis, 1 see also Postprimary tuberculosis Phylogenetic studies, molecular methods, 35 Pituitary tuberculosis, 504–505 clinical presentation, 504 complications, 506 differential diagnosis, 504 epidemiology, 504 investigations, 506 management, 506 pathology, 506 Plasmids, 54 Pleural biopsy, 346 Pleural complications, 131 Pleural effusions, 124, 131, 165, 342–348, 377, 381 case studies, 819 childhood tuberculosis, 154, 155, 274, 361, 362, 368–369, 381, 533 clinical examination, 157, 368 complications, 368 investigations, 368 multidrug resistant tuberculosis, 533 pre-chemotherapy studies, 137, 140, 141 clinical presentation, 165, 343, 368, 381 diagnosis, 343–344, 368, 381 adenosine deaminase assay, 222 biochemical tests, 344–345 cytology, 345 direct tests on pleural fluid, 369 DOTS programme implementation, 671 fluid differential white blood cell count, 345 guidelines in resource-constrained settings, 346 microbiological examination, 345–346 nucleic acid amplification techniques, 345 tuberculin skin test, 345 differential diagnosis, 345 HIV–tuberculosis coinfection, 166, 254, 342, 343, 344, 345, 346, 381, 525, 526 management, 347 pregnant patients, 574 imaging, 240, 254, 274, 299 chest radiographs, 344, 526 postprimary tuberculosis, 246 ultrasonography, 223 immune reconstitution inflammatory syndrome, 690, 697 pathogenesis, 124, 342–343 primary tuberculosis, 124 renal failure patients, 563 treatment, 347, 369, 381 Pleural fibrosis, 141 Pleural fluid, 209 cytomorphology, 210 neonatal specimens, 574 processing, 209 specimen collection, 217 Pleural tuberculosis, 124, 342–248, 377 children, 368–369 clinical presentation, 343 diagnosis, 344, 369 guidelines in resource-constrained settings, 346 epidemiology, 342 pathogenesis, 342–343 pleural biopsy, 346 renal failure patients, 563 treatment, 347 see also Pleural effusions; Pleurisy, tuberculous; Pleuritis, tuberculous Pleurisy, tuberculous, 378 imaging, 299 Pleuritic chest pain, 333, 334, 343 pleural effusions, 381 Pleuritis, tuberculous, 124 effusion fluid cytomorphology, 210
nucleic acid amplification tests, 199–200 Pleurocutaneous fistula, 247 Plombage, 249, 516 radiographic manifestations following, 249, 250 Pneumoconiosis fibrosis, 61 Pneumocystis jiroveci penumonitis, 605 prophylaxis/treatment, rifampicin interactions, 624 Pneumolith, 139, 141 Pneumonectomy, 517 Pneumonia, expansile (lymphobronchial tuberculosis), 364, 369–371 bronchoscopy, 370, 371 clinical presentation, 369 management, 370–371 pathology, 369 radiographic features, 369–370 Pneumonia, tuberculous, 131, 333 children, 155, 297 HIV coinfection, 160–161 imaging, 268 multidrug resistant tuberculosis, 533 neonates, 573 Pneumoperitoneum therapy, 4 Pneumothorax, 250, 339 artificial, 516 historical aspects, 4 imaging, 247, 300 Polymerase chain reaction-based methods, 169 Bacillus Calmette-Gue´rin (BCG) adverse events diagnosis, 764, 765, 767 drug resistance detection, 176, 201 line probe assays, 201–202 molecular beacons, 202, 233 HIV diagnosis, 221 IS6110 genotyping, 30 mixed infection genotyping, 34 mycobacterial identification, 173, 219 nontuberculous mycobacteria, 62–63 mycobacterial interspersed repetitive units (MIRUs), 32 Mycobacterium tuberculosis detection, 326 adrenal tuberculosis, 509 breast tuberculosis, 473 cutaneous tuberculosis, 488, 489 Eales’ disease, 479 female genital tuberculosis, 458 gastrointestinal tuberculosis, 428, 434 genitourinary tuberculosis, 441 male genital tuberculosis, 452 meningitis, 384 ocular tuberculosis, 482 ovarian tuberculosis, 512 pancreatic tuberculosis, 511 parathyroid tuberculosis, 508 pericardial fluid, 355 pituitary tuberculosis, 506 pleural fluid, 344, 345, 369, 381 spinal tuberculosis, 498 tuberculids, 485, 488 nucleic acid amplification tests see Nucleic acid amplification tests real-time assay, 223, 233, 404 regions of difference detection, 54 single nucleotide polymorphisms (SNPs) detection, 33 Polymorphic GC-rich repetitive sequence (PGRS), 51 restriction fragment length polymorphism, 32 Polyserositis, tuberculous, 343 Ponset’s disease (chronic tuberculous rheumatism), 502 Population attributable fractions, 18–19 Porins, 49 Portugal, 167 Positron emission tomography see 18F-fluoro–2-deoxyD-glucose positron emission tomography (FDG-PET) Post-marketing surveillance, 916 Postmenopausal bleeding, 457, 459, 512 Postprimary tuberculosis, 131, 242, 332 children, 362 pre-chemotherapy era studies, 137, 141–142 course, 121 dissemination of Mycobacterium tuberculosis, 121–122 forms, 131 imaging, 242–243, 297–298 chest radiographs, 336
HIV coinfection, 254 local complications, 123–124 lung cavitation, 122–123 pathogenesis, 121–122 pulmonary symptoms/signs, 333–334 unresolved issues, 728, 729 Pott’s disease see Spinal tuberculosis Poverty, 92, 166, 167, 535–526, 585, 605, 660, 668, 727, 756, 908–914, 925, 926, 927, 979 access to healthcare, 981 associated depression, 686 associated gender issues, 886 barriers to accessing tuberculosis services, 908, 912–913 case studies, 912 diagnostic services, 912–913 service delivery reforms, 913–914 conceptual analyses, 909–911 due to global social changes, 927–928 food supplements, 605–606 health care cost-recovery scheme impact, 801 impoverishing effects of pathway to cure, 912 measurement methods, 910 Millenium Development Goals, 936 relevance to tuberculosis control strategies, 792, 908, 909, 940 research approaches, 756 social disadvantage, 909 Poverty line/indicators, 910, 911 ppcA mutations, 53 PPE proteins, 51 Practical Approach to Lung Health (PAL), 944 Prednisolone HIV–tuberculosis coinfection, 104 immune reconstitution inflammatory syndrome, 697 pericardial effusions, 357 tuberculous meningitis, 409 tuberculous pericarditis, 529 Prednisone childhood tuberculosis, 628, 630 airway disease, 366 expansile pneumonia, 370 immune reconstitution inflammatory syndrome, 697 meningitis, tuberculous, 418, 630 pericarditis, tuberculous, 382 pleural tuberculosis, 347 Pregnant women, 572–579 antiretroviral therapy, 578, 810–811 efavirenz contraindication, 578, 634, 641, 810–811 antituberculous chemotherapy, 576, 578, 641 adverse effects, 677 second-line drugs, 645 HIV–tuberculosis coinfection, 575, 577, 578–579 collaborative management activities, 810–811 management algorithms, 320–321 immune reconstitution inflammatory syndrome, 579 perinatal mortality, 575 tuberculosis, 810 clinical presentation, 574 genital, 459 investigations, 575 management, 575–576 multidrug resistant, 576, 645 obstetric outcome, 575 perinatal/neonatal outcome, 575 progression, 574–575 see also Perinatal tuberculosis Premature birth, 575, 810 Primary complex see Ghon complex Primary drug resistance, 552 Primary tuberculosis, 56, 143, 237–238, 332, 627, 728 children, 136, 239, 240, 262, 297, 361–363 pre-chemotherapy era studies, 137, 138 clinical presentation, 238, 333–334, 361–363 complications, 120–121, 262 cutaneous manifestations, 486–487 HIV–tuberculosis coinfection, 96 imaging, 238–241, 297 chest radiographs, 138, 336 resolution of radiographic abnornalities, 240–241 lymphadenitis, 391, 392 outcome, 130–131 pathogenesis, 119–120, 130
1007
INDEX Primary tuberculosis (Continued) pleural effusions, 124 progression, 120–121, 130, 131, 137, 241, 627 age-related risk, 144, 324, 362 Prison inmates, 790, 800, 979 contact tracing, 773, 776 health care management, 606 HIV coinfection, 585, 586–587, 606 collaborative management activities, 810 multidrug resistant tuberculosis, 655 Stop TB Strategy implementation, 944 Prison TB outbreaks, 585–587, 808 key features, 583 Private sector healthcare, 603–604, 663, 756, 800, 889, 914 DOTS programme involvement, 668, 674, 942 laboratory services access, 741, 742 public sector colaboration, 649 see also Public–private mix Stop TB Strategy implementation, 944–945 tuberculosis care standards, 649, 650, 657 Programmatic research, 981–982 Proportion method, drug susceptibility testing, 175, 219, 542, 543 Prostate biopsy, 452, 456 Prostate tuberculosis, 383, 450, 511 clinical presentation, 450–451 diagnosis, 451, 452 differential diagnosis, 451 HIV coinfection, 450, 451, 455 imaging, 306, 452 pathology, 452 space-occupying lesions, 127 surgical treatment, 455 transrectal ultrasonographic biopsy guidance, 452 Prostate-specific antigen, 452 Prostatic abscess, 451 Protease inhibitors ‘boosted therapy’, 622 cytochrome P450 inhibition, 619, 620 drug interactions, 528, 557, 623 rifampicin, 619, 641, 782 rifamycins, 618, 620, 621–622, 633, 655 immune reconstitution inflammatory syndrome risk, 696 ‘superboosted therapy’, 622, 624 see also Antiretroviral therapy Protein ascites fluid, 428, 434, 461 cerebrospinal fluid, 221 tuberculous meningitis, 402, 415 effusion fluid (exudate), 221 pericardial effusions, 355 pleural effusions, 344, 346, 369, 381 Protein losing enteropathy, 433 Protein microarrays, 233 Protein S deficiency, acquired, 521 ProTEST, 804–805, 808 Prothionamide, 613, 614, 960 adverse effects, 678 hepatotoxicity, 645 biliary excretion, 447, 455 central nervous system penetration, 545, 557 extensively drug-resistant tuberculosis, 556 mode of action, 52, 53 multidrug resistant tuberculosis, 643 children, 534 male genital tuberculosis, 455 meningitis, 408 with renal function impairment, 455 resistance-determining gene mutations, 52 Proton pump inhibitors, 680 Psoas abscess, 307, 495, 496, 520, 521 surgical drainage, 520 Psychosis, antituberculous drug-induced, 686 Public awareness, 791 Public health legislation, 789 Public health services DOTS programme implementation, 668–669 responsibilities extensively drug-resistant tuberculosis, 557 International Standards for Tuberculosis Care, 656–657
1008
Public–private mix, 604, 800, 942 DOTS programme implementation, 668, 674, 945 improving services for poor people, 914 laboratory services, 741 Stop TB Strategy implementation, 944 Public–private sector collaboration, 649 Pulmonary artery pseudoaneurysm, 521 Pulmonary artery rupture, 121 Pulmonary BCG disease, 767, 768 Pulmonary collapse therapy, surgical interventions, 249–250 Pulmonary complications, 131 Pulmonary tuberculosis, 515 active case finding, 338, 339 antituberculous chemotherapy, 338, 526–528, 628–630, 639 case histories, 814–818 children, 154, 155, 160–161, 262–269 adult-type disease (with fibrocavitory changes), 262 clinical examination, 157 imaging, 262–269, 270 multidrug resistant disease, 535 primary, 262 progressive disease, 262 signs/symptoms, 361–363 treatment, 628–630 see also Childhood tuberculosis classification, 332 clinical presentation, 165, 332–340, 361–363, 650 elderly patients, 335 postprimary disease, 333–334 primary disease, 333–334 complications, 262, 338–339 computed tomography, 297–300 culture-/smear-negative, 334, 651 diagnosis, 335–336, 651 biopsy, 515 serological tests, 180–192 see also Diagnosis diagnostic algorithms, 316–317, 669 differential diagnosis, 335 empiric antibiotic therapy, 337–338 epidemiology, 332–333 see also Epidemiology HIV–tuberculosis coinfection, 160–161 clinical features, 335, 525 treatment, 526–528 see also HIV–tuberculosis coinfection laryngeal tuberculosis association, 463, 464 magnetic resonance imaging, 300 Mycobacterium bovis infection, 148 paradoxical reactions, 339 pathology, 338 pathophysiology, 333 physical examination, 157, 334 pregnant patients, 574 prevention, 339–340 prognosis, 338 recurrent disease, 335 surgical treatment, 515–516 indications, 517 thoracic complications, 517 zoonotic tuberculosis, 149 Pulmonary veins rupture, 122 Purified protein derivative (PPD) testing see Tuberculin skin test Putty (cement/mortar) kidney, 252, 253, 445 Pyelonephritis, tuberculous, 445 Pyrazinamide, 608, 609, 611–612, 638, 639, 640, 962 adrenal tuberculosis, 509 adverse effects, 612, 678, 688, 963, 964, 965, 966, 967 children, 635 hepatotoxicity, 410, 611, 612, 635, 642, 681, 682 HIV–coinfected individuals, 807 joint pains, 680 skin rash, 679 bactericidal activity, 608 biliary excretion, 447, 455 breast tuberculosis, 474 broncho-oesophageal fistula, 372 central nervous system penetration, 417, 545, 557, 628
childhood tuberculosis, 330, 331, 417, 435, 535, 628, 629, 630, 631 airway disease, 366 clinical efficacy, 612 contraindication with liver failure, 645 disseminated BCG disease (BCG-osis), 768 drug interactions, 969–970 duration of treatment, 608 expansile pneumonia, 370 extensively drug-resistant tuberculosis, 555, 556 extrapulmonary tuberculosis, 379 female genital tuberculosis, 461 gastrointestinal tuberculosis, 430, 436 genitourinary tuberculosis, 447 International Standards for Tuberculosis Care, 652, 653 lymphadenitis, tuberculous, 394, 398 meningitis, tuberculous, 408, 417, 630 mode of action, 52, 53, 612 multidrug resistant tuberculosis, 408, 535, 536, 545, 643, 644, 782 ocular tuberculosis, 482 pancreatic tuberculosis, 510 pericardial effusions, 357 pharmacokinetics, 612 children, 629 pituitary tuberculosis, 506 pregnanct women, 576, 641 prophylaxis, 536, 780, 782, 807 with renal failure, 455, 564, 642 resistance, 49, 50, 612, 927 BCG strains, 764 gene mutations, 52, 53 Mycobacterium bovis, 151 spinal tuberculosis, 500 standard treatment regimen, 543, 608–609 precautions, 609 susceptibility testing, 175, 219, 730 Pyridoxine, 447, 455, 610, 614, 633, 676 deficiency, 684 HIV–tuberculosis coinfection, 347 renal failure patients, 642 supplementation, 684 children, 635 drug-induced seizure management, 685 Pyuria, sterile, 438, 439 male genital tuberculosis, 451, 452 renal tuberculosis, 521
Q Quality assurance clinical trial design, 920 community healthcare programmes, 666 Good Clinical Practice/Good Laboratory Practice, 919 laboratory services, 739, 743 sputum smear microscopy, 669, 743, 789 QuantiFERON-TB, 113, 730 QuantiFERON-TB Gold, 113, 186, 187, 221, 326, 345, 777, 780, 781 Quinolones clinical trials, 917 male genital tuberculosis, 455 neonates, prophylaxis, 576 teratogenicity risk, 576
R Rab proteins, 79 Radiculomyelitis, tuberculous, 313, 402 imaging, 313 syringomyelia complicating, 313 Raltegravir (MK-0518), drug interactions, 619 rifampicin, 623 rifamycins, 621 Randomization, clinical trial design, 916 Randomized controlled trials, 916, 930 cluster design, 917 group design, 917 Ranke complex, 237, 333, 361 imaging, 238, 297 Rasmussen aneurysm, 121, 242, 250, 338 case study, 817–818 imaging, 250–251, 300
INDEX rBCG, 753 rBCG30, 753 rBCG30 vaccine, 107, 110 clinical studies, 110 RD1 segment genes, 54, 55, 56, 186 RDmic, 54 Reactivation, 13, 17, 56, 75, 121, 131, 332, 333, 515, 771, 787 elimination goals, 24–25 environmental factors, 92 epidemiology, 20 molecular studies, 33 HIV–tuberculosis coinfection, 96, 99, 804 Mycobacterium bovis tuberculosis, 149 tuberculosis in immigrants, 733 unresolved issues, 729 Reactivation tuberculosis see Postprimary tuberculosis Real-time assay polymerase chain reaction, 223, 233 tuberculous meningitis diagnosis, 403 Reazurin assay, 232 Record-keeping adherence improvement, 934 clinic cards, 599, 602 clinical trial management, 922, 923 clinics, 599 collaborative tuberculosis/HIV activities, 807 confidentiality, 655 Good Clinical Practice/Good Laboratory Practice, 919 investigators’ responsibilities, 920 sponsors’ responsibilities, 921 International Standards for Tuberculosis Care, 654–655 national TB control programmes, 799 notification, 599 patient cards, 599 Stop TB Strategy implementation, 943 TB registers, 599, 600–601 workplace tuberculosis, 906 Recrudescent tuberculosis see Postprimary tuberculosis Rectal fistula, 434 Rectal tuberculosis, 382, 426 children, 434 clinical presentation, 426 Recurrent laryngeal nerve palsy, 521 Recurrent tuberculosis, 131 see also Reactivation Referral form, 597 Referral pathways, 595, 596, 603 DOTS programme implementation, 670, 672, 673 HIV–tuberculosis coinfection, 674, 804 migrant patients, 898 private facilities, 604 public–private mix, 604 Refugees, 800, 893, 894, 895, 897 collaborative tuberculosis/HIV activities, 810 cost effectiveness of tuberculosis control strategies, 733–735 Stop TB Strategy implementation, 944 Regions of difference, 54–55 Registers, tuberculosis, 603 HIV infected patients, 605 collaborative activities, 807 treatment outcome definition, 603 tuberculosis clinic records, 599, 600–601 workplace tuberculosis, 906 Regulatory T cells, 82, 719 tuberculosis susceptibility influence, 93 Rehabilitation centres, contact tracing, 773 Reinfection, 75, 131, 333, 728, 729, 771, 787 Renaissance, 2 Renal biopsy, 439–440 Renal colic, 438, 446 Renal failure, 439, 440 antituberculous chemotherapy precautions, 447, 563, 642 ethambutol, 483, 535 male genital tuberculosis, 455 multidrug resistant tuberculosis, 645 second-line drugs, 645, 646 streptomycin contraindication, 613 antituberculous drug-induced, 677, 964–965 acute, 682–683 diabetic patients, 676
caused by tuberculosis, 521 clinical presentation, 563 epidemiology, 562 investigations, 563 management, 563–564 sample collection, 563 chronic, 440 dialysis patients, 440 immune reconstitution inflammatory syndrome, 447 Renal transplant patients, 440–441, 563 antituberculous chemotherapy, 447 contraindications, 455 isoniazid prophylaxis, 441 tuberculosis, 562–563 Renal transplant units, contact tracing, 773 Renal tuberculosis, 126, 383, 438, 521 case report, 845–847 children, 269, 277 chronic renal failure patients, 440 clinical presentation, 438–440 diagnosis, 441–442 concurrent male genital tuberculosis, 452 delay, 438 renal biopsy, 439–440 disseminated disease, 445 glomerular disease, 440 HIV coinfection, 383, 525 imaging, 252, 253, 269, 277, 305–306, 441–444 intravenous pyelography, 223 interstitial nephritis, 439–440, 445 localized disease, 445 pathogenesis, 438 pathology, 444–445 renal transplant patients, 440–441 sterile pyuria, 438, 439, 521 surgical treatment, 448 zoonotic, 149 Reporting systems, 39, 599 collaborative tuberculosis/HIV activities, 807 International Standards for Tuberculosis Care, 657 Stop TB Strategy implementation, 943 Research, 746–757, 955 antituberculous drugs, 753 biomarkers of disease, 752 childhood tuberculosis, 753 clinical management improvement, 750 control strategies, 790–791 diagnostic tests, 746, 747, 748–750, 753 epidemiology, 756–757 ethical issues, 757 extensively drug-resistant tuberculosis, 757 funding, 974–977, 981 HIV–tuberculosis coinfection, 752–753 immune reconstitution inflammatory syndrome, 754 immunopathogenesis, 747, 753–754 immunotherapy, 746, 751 implementation research, 747, 755 multidrug resistant tuberculosis, 757 preventive strategies, 754–755 role of TB laboratories, 743–744 Stop TB Strategy implementation, 945–946 vaccines, 746, 747, 753–754 Residential institutions, 585 tuberculosis control strategies, 790 Resistance see Drug resistance Resistant ratio method, 175, 542, 543 Respiratory failure broncho-oesophageal fistula, 372 corticosteroids treatment, 379 Respiratory procedures infection transmission risk, 581, 702, 706 personal respiratory protection, 603, 709 Respiratory protection, 709 see also Particulate filter respirators; Personal respiratory protection Respiratory and shock syndrome, antituberculous druginduced, 687 Restaurant outbreaks, 589 Restriction fragment length polymorphism (RFLP), 11, 52, 584, 585, 586, 588, 589, 733 IS6110 analysis, 29, 31, 32, 35, 36, 51 polymorphic GC-rich repetitive sequence (PGRS), 32 Reticuloendothelial system tuberculosis, 399
children, 394–395 clinical presentation, 394–395 epidemiology, 394 pathogenesis, 394 treatment, 395, 399 Retinal tuberculosis, 479 vascular disease, 479–480 Retinal vasculitis, 480, 481 adjuvant corticosteroids, 482 Retropharyngeal abscess, 466 children, 374 diagnosis, 466 treatment, 466 surgical drainage, 520 Revised National Tuberculosis Control Programme (India), 669, 670, 898 Rheumatism, chronic tuberculous (Ponset’s disease), 502 Rhodococcus identification, 63 Rib graft, 501 Rib resection, 516 Ribotyping, 45 Rich focus, 251, 384, 406, 413 rupture, 251 Rifabutin, 608, 609, 610, 611, 962 adverse effects, 963, 964, 965, 966, 967 childhood tuberculosis, 633 clinical efficacy, 611 cytochrome P450s induction, 528, 620, 623 drug interactions, 623, 969 antiretroviral agents, 528, 633 azole antifungal agents, 624 clarithromycin, 624 nelfinavir, 623 protease inhibitors, 623, 624 ritonavir, 619, 623 HIV–tuberculosis coinfection, 481, 527 male genital tract tuberculosis, 455 Mycobacterium avium complex disseminated infection, 72 Mycobacterium kansasii infection, 70 Mycobacterium marinum infection, 72 ocular tuberculosis, 481 pharmacokinetics, 611 prophylaxis, 782 susceptibility testing, 543 Rifalazil, 610 Rifampicin, 608, 609, 610–611, 638, 639, 640, 684, 933, 962–963 adrenal tuberculosis, 509 adverse effects, 611, 678, 697, 963, 964, 965, 966, 967 acute haemolytic anaemia, 687 acute renal failure, 682 body fluids discolouration, 686–687, 967 children, 635 hepatotoxicity, 410, 578, 611, 635, 642, 681, 682 HIV–coinfected individuals, 807 influenza-like syndrome, 687 respiratory and shock syndrome, 687 skin rash, 679 thrombocytopenia, 683 thyroiditis/hypothyroidism, 467 bactericidal activity, 608, 611 biliary excretion, 447, 455 breast tuberculosis, 474 broncho-oesophageal fistula, 372 Buruli ulcer (Mycobacterium ulcerans infection), 72 central nervous system penetration, 408, 417, 545, 557, 630 childhood tuberculosis, 330, 331, 417, 435, 628, 630, 631, 632, 633 airway disease, 366 congenital, 577 clinical efficacy, 611 clinical trials, 917 cutaneous tuberculosis, 491 cytochrome P450s induction, 528, 619, 620, 630, 633 diabetic patients, dosage, 562 disseminated BCG disease (BCG-osis), 768 drug interactions, 967–968 abacavir, 623 antacids, 680, 687 antiretroviral drugs, 455, 481, 528, 641, 676, 687, 809 atovaquone, 624
1009
INDEX Rifampicin (Continued) azole antifungal agents, 623 clarithromycin, 624 contraceptive pills, 687 corticosteroids, 455, 630 cotrimoxazole, 624 cyclosporin, 455 dapsone, 624 efavirenz, 620–621, 624, 633, 752, 810 etravirine, 621 lopinavir, 633 maraviroc, 621, 623 methadone, 782 nevirapine, 578, 621, 624, 633, 752, 810 non-nucleoside reverse transcriptase inhibitors, 641 protease inhibitors, 621–622, 641 raltegravir, 621, 623 ritonavir, 622 tacrolimus, 455 TMC–125, 623 warfarin, 687 zidovudine, 619, 623 duration of treatment, 608 expansile pneumonia, 370 extrapulmonary tuberculosis, 379, 630 female genital tuberculosis, 461 gastrointestinal tuberculosis, 430, 436 genitourinary tuberculosis, 447 historical aspects, 5, 931 HIV–tuberculosis coinfection, 526–527, 632, 633, 641, 807 International Standards for Tuberculosis Care, 652, 653 with liver function impairment, 642 lymphadenitis, tuberculous, 394, 398 male genital tract tuberculosis, 455 meningitis, tuberculous, 385, 408, 417, 630 mode of action, 52, 610 Mycobacterium bovis tuberculosis, 151 Mycobacterium kansasii infection, 70, 71 Mycobacterium marinum infection, 72 Mycobacterium xenopi pulmonary disease, 71 nontuberculous mycobacterial susceptibility, 65 ocular tuberculosis, 478, 482 organ transplant patient management, 521 P-glycoprotein induction, 619 pancreatic tuberculosis, 511 pericardial effusions, 357 pharmacokinetics, 610–611 children, 629 with liver function impairment, 642 pituitary tuberculosis, 506 pregnant women, 576, 641 prophylaxis, 780, 782, 807 in isoniazid-resistant cases, 636 neonates, 576, 577 with tumour necrosis factor a antagonist use, 569 in renal failure patients, 455, 564, 642 resistance, 19, 20, 35, 527, 535, 611, 631, 639, 640, 655, 730, 731, 740, 757, 927 cross resistance, 611, 644 detection, 174, 175, 176, 326, 542 line probe assays, 201, 202, 220 molecular beacons, 202, 233 molecular determinants, 53 mutations, 52, 219, 233, 542, 552, 554, 610 rapid detection, 554 tuberculous meningitis, 408 see also Extensively drug-resistant tuberculosis; Multidrug resistant tuberculosis spinal tuberculosis, 500, 631 standard treatment regimen, 543, 608–609 precautions, 609 susceptibility testing, 174, 175, 176, 232, 326, 408, 542, 730, 741 Rifamycins, 610–611 antiretroviral drug interactions, 618, 620, 676 management recommendations, 624–625 mechanisms, 618, 620 non-nucleoside reverse transcriptase inhibitors, 620–621, 633 protease inhibitors, 621–622, 633, 655 research approaches, 625 cross resistance, 555, 644
1010
cytochrome P450s induction, 528, 633 drug interactions with agents for opportunistic infection management, 623–624 oral hypoglycaemic agent interactions, 562 pharmacokinetics in children, 629 prophylaxis, 782 Rifapentine, 608, 609, 610, 611 clinical efficacy, 611 cytochrome P450 induction, 620 HIV–tuberculosis coinfection, 527 pharmacokinetics, 611 children, 629 prophylaxis, 25, 782 rifampicin cross resistance, 611 Right middle lobe syndrome, 339 Riley, Richard, 8, 9, 10, 11, 12 Risk assessment, healthcare settings, 701 infectious case isolation, 705 Risk classification of healthcare settings, 703 Risk management, healthcare settings, 701–702 Risk of tuberculosis, 17–18, 129–130, 142–143, 332–333, 787 associated disorders, 561 burden of disease relationship, 728 children, 133–134, 136, 323 at-risk age periods, 41, 136, 154, 155, 324 seasonal variation, 134 contacts, 771 corticosteroids use, 566–567 determinant factors, 771 elderly people, 565 epidemiological studies, 727–728 gender differences, 887–888 HIV–infected individuals, 332, 762–763 HIV–tuberculosis coinfected household contacts, 328 index case assessment for contact tracing, 773 infecting dose, 142 pathogen virulence, 143 population attributable fractions, 18–19 sputum smear negative cases, 133, 155 Ritonavir cytochrome P450 effects, 619, 620 drug interactions clarithromycin, 645 rifabutin, 619, 623 rifampicin, 622, 633 rifamycins, 633 voriconazole, 620 P-glycoprotein inhibition, 619 Romania, 21 Rome, ancient, 1 rpoB mutations, 35, 53, 219, 610 drug susceptibility testing, 201, 408 rrs mutations, 613 Russia, 19, 21, 227, 553 extensively drug-resistant tuberculosis, 557 gender disparities in tuberculosis, 887 multidrug resistant tuberculosis, 539, 540, 547, 551, 927, 943 nosocomial outbreaks, 583 prison setting TB outbreaks, 587, 606 Rv3676, 761
S 16S ribosomal DNA amplification, 197 mycobacterial identification, 173 nontuberculous mycobacteria, 63–64, 65 Salivary gland tuberculosis, 387, 466 diagnosis, 466 treatment, 466 Sanitorium care, 19, 795, 930, 931 child patients, 133 historical aspects, 4 Sarcoidosis, 426, 444, 512, 874–878 case studies, 877–878 causes, 874–875 corticosteroids use, risk of tuberculosis, 566 definition, 874 diagnosis, 875–876 epidemiology, 874 granulomatous mastitis, 474 histopathology, 206–207
immune reconstitution inflammatory syndrome, 689 ocular lesions, 479 pituitary involvement, 504 treatment, 876–878 Scandinavia, 40, 60, 148 Scavenger receptors, 76 Schatz, Albert, 4 Schistosomiasis, 207, 512 School outbreaks, 584, 588, 808 boarding schools, 589 Scleral tuberculosis, 478 Scoliosis, 141, 499 Scotochromogens, 44 Scrofula, 2, 484 see also Cervical lymphadenopathy; Lymphadenitis, tuberculous Scrofuloderma, 387 clinical presentation, 487–488 complicating BCG vaccination, 484 diagnosis, 485 differential diagnosis, 492 vulval tuberculosis, 459 see also Lupus vulgaris Scrotal abscess, 512 Scrotal fistula, 450, 455, 512 SDA (strand displacement amplification) test, 198 Seals, tuberculosis transmission, 147 Secondary (adult-type) tuberculosis see Postprimary tuberculosis Segmental tuberculosis, 120–121 Seibert, Florence, 4, 179 Seizures, 127, 271, 328, 384 adult patients, 402 antituberculous drug-induced, 684–685 clinical presentation, 684 differential diagnosis, 684 investigations, 685 management, 685 intracranial tuberculomas, 402, 421 neonatal tuberculosis, 573 tuberculous meningitis, 413 Self-administered drug therapy, 654, 917 Semen analysis, male infertility investigation, 452 Semen samples, male genital tuberculosis diagnosis, 451, 452, 456 Seminal vesicle tuberculosis, 450, 451, 511 Septi-chek, 473 Serological tests, 179, 189–192, 223, 326, 730 antigens, 189 commercial tests, 190 extrapulmonary tuberculosis, 191–192 latent tuberculosis, 192 meningitis, tuberculous, 405 pulmonary tuberculosis smear-negative, 191 smear-positive, 189–190 sensitivity/specificity, 189, 190, 191 Serous effusions, 165 Serpiginous choroiditis, 479 SEVA TB test, 191 Sexual transmission, 455–456, 457, 511 prevention, 455, 457 Sexually transmitted disease screening, 808 Shelters, homelessness, 655 contact tracing, 773, 777 TB outbreaks, 587–588 key features, 583 Sialitis, tuberculous, 387 sigK, 761 Sigma factors, 13 Silica exposure, 13, 901, 902 prevention, 902 Silicosis, 13, 18, 130, 143, 166, 333, 336, 512, 562, 773, 902 tuberculosis clinical presentation, 562 latent disease treatment, 781, 782 prognosis, 562 Simon’s focus, 237, 333 Singapore, 22 Single nucleotide polymorphisms (SNPs), 33, 35, 51 Mycobacterium tuberculosis complex lineage differentiation, 55
INDEX Sixth nerve palsy, 480 pituitary tuberculosis, 504 Skeletal X-ray, 223 childhood tuberculosis, 274, 294 parathyroid tuberculosis, 508 spinal tuberculosis, 519 tuberculous arthritis, 294, 501 tuberculous osteitis, 294 Skin biopsy, 489 Skin infection, nontuberculous mycobacteria, 68–69 treatment, 71–72 Skin itching, differential diagnosis, 679 Skin rash differential diagnosis, 679 drug challenge/reintroduction, 679, 680 drug-induced, 679, 697, 964 children, 633 see also Cutaneous drug reactions Skin, tuberculosis see Dermatological tuberculosis Skull, bone tuberculosis, 466–467 children, 466 case study, 867 Skull X-ray hydrocephalus, 417, 418 pituitary tuberculosis, 506 Slc11a1/SLC11A1 polymorphism, tuberculosis susceptibility, 89, 90–91 Slovenia, 150 Small bowel involvement see Intestinal tuberculosis Smoking, 18, 19, 130, 143, 166, 333, 888, 944 tuberculosis susceptibility influence, 92 Smoth, Theobald, 146 Social justice, 925–928, 981 community healthcare programmes, 664 patient-centred health service provision, 662 Social mobilization, community healthcare programmes, 665 Social network-linked outbreaks (bars/pubs), 589–590 Social science research, 755 Social welfare benefits, 905 Socioeconomic factors, 605–606, 660, 668 childhood tuberculosis mortality, pre-chemotherapy era studies, 136 multidrug resistant disease, 535 global control strategies, 980 positive tuberculin skin test, 182 research priorities, 747, 755 tuberculosis risk, 10, 788, 925 workplace tuberculosis impact, 901–902 Sodium hydroxide mucolytic agent, 172 Soft tissue nontuberculous mycobacterial infection, 68–69 diagnosis, 69 treatment, 71–72 Soft tissue tuberculosis, 502 imaging, 309 Solid culture media, 172, 174, 219 Soluble interleukin–2 receptor (sIL–2R), pleural effusions, 381 Somalia, 35 South Africa, 19, 157, 227, 231, 351, 391, 413, 524, 528, 595, 596 extensively drug-resistant tuberculosis, 540, 551, 557 multidrug resistant tuberculosis, nosocomial outbreaks, 583 perinatal tuberculosis, 572 prison setting TB outbreaks, 606 South African Tuberculosis Vaccine Initiative (SATVI), 110, 114 South America, 3, 150 multidrug resistant tuberculosis, nosocomial outbreaks, 583 South Korea, extensively drug-resistant tuberculosis, 540 South-East Asian Region, 951 SP110, tuberculosis resistance, 91 Space-occupying lesions, 127 Spain, 149, 150, 167, 553 Sparfloxacin, 615 Spina ventosa, 252, 293 case study, 864 Spinal arachnoiditis, 384 Spinal cord compression, 496, 519 cervical spine, 520 Spinal cord decompression, 501, 520
Spinal meningitis, 402 Spinal osteomyelitis, 250 Spinal radiographs, 291, 497 Spinal tuberculosis, 126, 377, 385, 402, 494–502 antituberculous chemotherapy, 385, 467, 500, 519, 631 bracing and bed rest, 500, 519 cervical spine, 466–467, 495, 496, 497, 520 children, 154, 155, 291, 292, 293, 385, 499, 519, 520, 631 airway compression, 374, 868 case studies, 862, 863, 868, 871–873 clinical examination, 157 clinical presentation, 166, 385, 495, 519 diagnosis, 496–499, 519 biopsy, 497–498 haematology, 497 Mycobacterium tuberculosis detection, 497–498 tuberculin skin test, 497 differential diagnosis, 307–308, 497 DOTS programme implementation, 671 epidemiology, 494, 519 gibbus deformity, 252, 291, 307, 402, 495 historical aspects, 1, 494, 519, 520 HIV coinfection, 501 imaging, 252, 291, 292, 293, 307–308, 497, 519 intraspinal involvement, 313 kyphosis, 495, 496, 497, 499, 500, 519 localized types, 496 anterior, 496, 519 central, 496, 519 peridiscal, 496, 519 posterior, 496 meningitis, 402 neurological compromise, 496, 499, 500, 519, 520 Frakel/Tuli grading system, 499 osteitis, 291 progression, 500 scoliosis, 499 spinal cord involvement, 385, 496 spondylodiscitis/spondylitis without disk involvement, 307 surgical treatment, 500–501, 519–520 anterior radical debridement plus strut graft fusion (Hong Kong operation), 520 cervical disease, 520 indications, 519 posterior approach (laminectomy), 520 thoracic disease, 520 Spleen abscess, 395, 399 HIV–tuberculosis coinfection, 378, 526 Spleen tuberculosis, 382, 399, 521 children, 394 imaging, 304–305 ultrasonography, 223 nodules, 253 Splenomegaly, 394–395 see also Hepatomegaly/hepatosplenomegaly Spoligotyping (spacer oligonucleotide typing), 30, 32, 35, 50, 52, 149 evolutionary studies, 55 Mycobacterium tuberculosis complex lineage differentiation, 55 Spreading Index (SI), 55 Sputum production, pulmonary tuberculosis clinical presentation, 165 Sputum samples, 170 collection see Sputum specimen collection culture see Microbiological culture direct drug resistance testing, 175, 176 microscopy see Sputum smear microscopy Mycobacterium tuberculosis transmission, 8, 11–12, 706 processing, 171–172, 209–210, 650–651, 739, 746 decontamination, 232 liquification/bleach treatment, 171, 172, 218, 231, 650 see also Microbiological specimens Sputum smear microscopy, 164, 316, 739, 740 audit of healthcare setting protocols, 704 childhood tuberculosis, 159, 326, 362, 652 epidemiological studies, 41 multidrug resistant disease, 534 treatment guidelines, 330, 331 contact tracing, 536, 773 cytomorphology, 210
diabetic patients, 561 diagnosis, 209, 216, 227, 326 healthcare services, 931 limitations, 219, 227, 228, 229 new methods, 231 nucleic acid amplification test combination, 199 sensitivity, 229, 316, 651, 746 diagnostic algorithms, 316, 317, 651 DOTS programme evaluation, 673 implementation, 669–670 examination procedure, 170–171, 218–219 grading, 219 extensively drug-resistant tuberculosis, 554 extrapulmonary tuberculosis, 651 follow-up algorithms, 317 gender-related differences, 572, 888 HIV–tuberculosis coinfection, 97, 166, 171, 229, 317–318, 323, 332, 524, 526, 651 smear-negative cases, 317, 318, 332–333, 334 International Standards for Tuberculosis Care, 649, 650–651, 652 laboratory safety, 742 laboratory services, 738, 739, 741, 742, 746 availability in resource-constrained settings, 317 improving diagnostic services for poor people, 913 on-spot delivery of results, 913 laryngeal tuberculosis, 464 national TB control programmes, 795, 797 organ transplant patients, 567 patient infectiousness relationship, 11, 129, 133, 787 patient monitoring, 599, 603 end of treatment, 603 response to treatment, 608, 654, 672 at two months, 599 pericarditis, tuberculous, 355 postprimary tuberculosis, 131 pregnant women, 575 pulmonary tuberculosis, 336 quality assurance, 669, 743, 789 renal failure patients, 563 staining, 218–219 fluorescence, 651 Stop TB strategy implementation, 942 transmission risk relationship, 36, 143, 156, 808 vertical, 573 see also Acid-fast bacilli Sputum specimen collection, 169–170, 216, 650, 740 audit of protocols in healthcare setting, 704 children, 326, 328, 362, 650, 652 bronchoscopy, 365 difficulties, 154–155, 159, 209 neonates, 574 DOTS programme implementation, 669 elderly people, 565 gastric aspirates see Gastric aspirates health facility procedures, 603 induction see Induced sputum infection control precautions, 216, 595, 706 staff safety, 603 procedure, 216 Sri Lanka, 23, 25 SRL172 see Mycobacterium vaccae Staining, mycobacterial, 46–47, 171 sputum smears, 218–219 Standard infection prevention and control principles, 702 Standard Operating Procedures (SOPs), 922 conduct of clinical trials, 921 Standards of tuberculosis care, 789 see also International Standards for Tuberculosis Care STAT–1, 84 mutations, tuberculosis susceptibility, 88 Statistical analysis, clinical trial data, 918, 921, 923 Stavudine adverse effects, 557, 578 neurotoxicity, 633, 684 pregnant patients, 578 Stevens-Johnson syndrome, 679 Stop TB Partnership, 744, 746, 790, 791, 801, 804, 909, 936, 940, 946, 949 advocacy, communication and social mobilization (ACSM) working group, 799 TB Research Movement, 981–982
1011
INDEX Stop TB Partnership (Continued) TB/HIV Working Group, 805 website, 955 Working Groups, 950 Stop TB plan, 742 Stop TB Strategy, 22, 23–24, 25, 42, 164, 189, 338, 558, 639, 668, 669, 674, 738, 772, 796, 930, 935–936, 940–948, 949, 951 advocacy, communication and social mobilization (ACSM), 949 care provider engagement, 944–945 childhood tuberculosis, 627 community involvement, 660, 661, 664 components, 796, 942–943 development, 935–936 DOTS expansion, 942–943, 946, 949 drug availability, 599 goals, 942 health system strengthening, 944 implementation, 796, 936–937, 950 progress, 946–948 monitoring, 946 patient/community empowerment, 945 principles, 936, 941 reseach approaches, 945–946 tuberculosis–HIV coinfection, 943–944 Working Group on New TB Vaccines, 114 workplace healthcare programmes, 905 Storekeepers, tuberculosis control programme involvement, 914 Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), 757 Streptokinase, empyema management, 347 Streptomycin, 609, 612–613, 638, 639, 640, 684, 963 adverse effects, 455, 613, 678, 964, 965, 966 acute renal failure, 682, 683 injection-related, 687 nephrotoxicity, 613 ototoxicity, 576, 613, 641, 685, 686 peripheral neuropathy, 684 risk to foetus, 576 breast tuberculosis, 474 Buruli ulcer (Mycobacterium ulcerans infection), 72 cerebrospinal fluid penetration, 417, 613, 630 childhood tuberculosis, 330, 417, 630 clinical efficacy, 613 contraindications pregnant women, 641 with renal function impairment, 447, 455, 564 cross resistance, 555 cyclosporin interaction, 447 extensively drug-resistant tuberculosis, 555, 556 historical aspects, 4, 5, 516, 638, 751, 795, 926, 930, 931 clinical trial design, 917, 930 with liver function impairment, 642, 682 lymphadenitis, tuberculous, 394 meningitis, tuberculous, 407, 408, 410, 417, 630 mode of action, 52, 613 Mycobacterium avium complex pulmonary disease, 70 Mycobacterium kansasii pulmonary disease, 71 Mycobacterium marinum infection, 72 ocular tuberculosis, 478 ovarian tuberculosis, 513 pancreatic tuberculosis, 511 pericardial effusions, 357 pharmacokinetics, 613 pituitary tuberculosis, 506 renal excretion, 447, 455, 613, 682–683 resistance, 638, 640, 731, 927, 930 mutations, 52, 552 prevention, 608 susceptibility testing, 542, 730, 741 Stress, psychological, tuberculosis susceptibility influence, 91–92 Stressed populations, tuberculosis epidemiology, 895 Stricturoplasty, 430, 436 Stridor cervical spinal tuberculosis, 495 childhood airway disease, 364 laryngeal tuberculosis, 463–464 String test, 218, 326 Submarine outbreaks, 130, 788
1012
Subsidiarity principle, 665 Substance abuse, 166, 944, 979 antituberculous chemotherapy adverse effects, 676 with liver disease, 642 HIV infection collaborative tuberculosis/HIV activities, 810 prevention, 809 testing and counselling, 655 latent disease prophylaxis, 781 positive tuberculin skin test, 182 prison populations, 585, 586, 587 social network-linked outbreaks, 589, 590 Sulfamethoxazole, Mycobacterium kansasii pulmonary disease, 71 Sulfolipids, 49 Sulphonamides Mycobacterium fortuitum pulmonary disease, 71 Mycobacterium kansasii infection, 70 Mycobacterium marinum infection, 72 Superoxide dismutase, 48 Suppurative lymphadenitis, BCG adverse events, 765, 766 Surfactant protein A receptors, 76 Surfactant protein A variants, tuberculosis susceptibility, 89 Surfactant protein D variants, tuberculosis susceptibility, 89 Surgical site infections, 521 Surgical treatment, 515–522 abdominal tuberculosis, 520–521 airway disease (children), 367–368 BCG adenitis, 766 breast tuberculosis, 474 cardiovascular disorders, 521 cerebral tuberculomas, 410 empyema, 517–519 extensively drug-resistant tuberculosis, 557 gastrointestinal tuberculosis, 430, 436 genitourinary tuberculosis, 448, 521 historical aspects, 516 lymphadenitis, 521 male gential tract tuberculosis, 455 multidrug resistant tuberculosis, 546–547, 731, 733 pituitary tuberculosis, 506 precautions for staff, 521–522 pulmonary tuberculosis, 515–516 indications, 517 thoracic complications, 517 radiographic manifestations following, 249–250 spinal tuberculosis, 500–501, 519–520 anterior procedures, 501 posterior fusion, 501 spinal deformity, 501 thyroid tuberculosis, 507 tuberculous meningitis/hydrocephalus, 410 Surveillance, 19, 789–790 drug resistance, 739 HIV infection among tuberculosis patients, 806 Susceptibility to tuberculosis environmental factors, 91–93, 130, 136 genetic factors, 87–91, 130, 136, 401, 787 host vulnerability factors, 13 Sweden, 167 Swimming pool granuloma, 46, 56, 69 clinical presentation, 69 diagnosis, 69 Switzerland, 150, 167 Sympatric hosts, 55 Synovitis, tuberculous, 501 Syphilis, 512 ocular lesions, 479 tertiary, histopathology, 207–208 Syringomyelia, 313 Systemic lupus erythematosus, 560, 563 corticosteroids use, risk of tuberculosis, 566
T T cells, 75 activation, 82, 119 co-stimulatory pathways, 82 Bacillus Calmette-Gue´rin (BCG) response, 112 dendritic cell interactions, 76, 77
granuloma formation, 118 subset functions, 82–83 tuberculosis immune response, 56, 378, 718, 719 see also Th1 cells; Th1 response; Th2 cells; Th2 response; Th17 response T-cell receptor (TCR), 82 T-SPOT.TB, 113, 186, 187, 221, 326, 345, 730, 777, 781 Tacrolimus, rifampicin interaction, 455 Tanzania, 19, 150, 727 TB7.7, interferon-g release assay, 185 TB10.4 , AERAS–402 vaccine, 111 TB Alert, 981 TB Research Movement, 981 TbD1, 32, 54, 55 TBNet, 898 Tendon/tendon sheath involvement, 495, 496 Tendonitis, drug-induced, 965 Tenofovir, 641 adverse effects, 557 rifamycin interaction, 624, 625 Tenosynovitis, tuberculous, 309, 501, 502 imaging, 309, 310 Terhalose dimycolates, 49 Terizidone, 614, 960 adverse effects, 535 neurotoxicity, 614 extensively drug-resistant tuberculosis, 556 mode of action, 614 multidrug resistant tuberculosis, 534 teratogenicity risk, 576 Testicular sperm extraction, 451 Testicular tuberculosis, 450, 505, 511–512 clinical presentation, 512 complications, 512 differential diagnosis, 512 epidemiology, 511 imaging, 306 pathology, 512 treatment, 512 Th1 cells, cytokine production, 80, 82 Th1 response, 57, 76, 77, 80, 82, 719 Bacillus Calmette-Gue´rin (BCG), 112 HIV–tuberculosis coinfection, 99 immune reconstitution inflammatory syndrome, 698 immunotherapy enhancement, 720 Mycobacterium vaccae, 111 nontuberculous mycobacteria, 92 pericardial effusions, 351 pleural effusions, 342, 381 therapeutic enhancement, 752 tuberculosis susceptibility genes, 87–88 Th2 cells, cytokine production, 80 Th2 response, 57, 82 deterimental effect on tuberculosis, 92–93 HIV infection, 99 pregnant patients, 575 Th17 response, 82 Thailand, 19, 40 Thalidomide adverse effects, 722 brain abscess, 422 central nervous system tuberculosis, 406, 546 clinical trials, 722–723 HIV–tuberculosis coinfection, 104 meningitis, tuberculous, 418 mode of action, 722 Thiacetazone, 4, 614, 684, 740 adverse effects, 614, 630, 676, 678, 679 blood dyscrasias, 683 contraindications, 679–680 HIV–infected patients, 556 historical aspects, 931 multidrug resistant male genital tuberculosis, 455 resistance mutations, 552 Thoracoplasty, 249, 250, 516 radiographic manifestations following, 250 Thoracotomy, 357, 367 Thrombocytopenia, antituberculous drug-induced, 683 Thrombocytopenic purpura, 395 Thromboembolic events, immune reconstitution inflammatory syndrome, 698 Thyroid scan, 467 Thyroid tuberculosis, 467, 505, 506–507
INDEX case report, 843–844 clinical presentation, 507 complications, 507 differential diagnosis, 507 epidemiology, 506–507 historical aspects, 506 investigations, 507 management, 467, 507 pathology, 507 Thyroxin therapy, 687 Tierra del Fuego, 3 Tigecycline, Mycobacterium abscessus pulmonary disease, 71 Tinnitus, antituberculous drug-induced, 685 TIRAP polymorphism, extrapulmonary tuberculosis susceptibility, 401 Tissue destruction, 126, 131 childhood tuberculosis, 144 immunotherapy, 718, 751 musculoskeletal tuberculosis, 495 Tissue fibrosis, 127 Tissue samples, 205 TK medium, 174, 219, 326 TLR2, 77, 79, 84 polymorphism, tuberculosis susceptibility, 90 TLR4, 77, 79 macrophage Mycobacterium tuberculosis uptake, 76 polymorphism, tuberculosis susceptibility, 90 TLR6, 77 TMC125, rifampicin interaction, 623 TMC207, 616 Tobramycin Mycobacterium chelonae pulmonary disease, 71 nontuberculous mycobacteria susceptibility testing, 66 Toll-like receptors, 77, 84 antigen processing/presentation, 79 CD1 molecule upregulation, 80 lipoarabinomannan interactions, 49 Mycobacterium tuberculosis-specific ligand-receptor interactions, 77 phagosomal maturation, 79 signalling pathways, 77 variants, tuberculosis susceptibility, 90 Torticollis, 388, 495 Townsend poverty index, 910 Toxic epidermal necrolysis, 679 Toxoplasmosis, 207 Tracheal aspirates, 209, 217 cytomorphology, 210 neonatal specimens, 574 processing, 209 Tracheal deviation, 364 Tracheobronchial tuberculosis, 299 Tracheo-oesophageal fistula, 250, 251, 371, 382, 434 Traditional healers, 756, 889 Trafficking, human, 893 Transbronchial biopsy, 217 Transciption-mediated amplification time, 197 Transforming growth factor b (TGF-b), 82, 719 gene variant, tuberculosis susceptibility, 89 granuloma resolution, 85 Transforming growth factor b (TGF-b) inhibitor therapy, 752 Transient Mycobacterium tuberculosis infection, 13 Transmission, 8–15, 17, 123, 129, 323, 333, 484, 788 congregate settings, 10–11, 581 cycle, 132 environmental factors, 788 epidemiological data, 10–11 extensively drug-resistant tuberculosis, 553 host vulnerability factors, 13 human source factors, 11–12 male genital tuberculosis, 450, 455 mathematical modeling, 13–14 molecular epidemiological studies, 33 mycobacterial factors, 12–13 strain differences, 12 nontuberculous mycobacteria, 66 patient treatment status, 12 prevention in healthcare settings see Infection control, healthcare settings risk factors, 10, 17–18, 129–130 population attributable fractions, 18–19 sexual, 455–456, 457, 511
smear-negative cases, 36, 129 tuberculosis control strategies, 789, 792–793 vertical, 572–573 zoonotic, 147–148, 150 see also Nosocomical transmission; Occupational transmission Transmission-based infection precautions, 702 Transport, microbiological specimens, 170, 603 Transthoracic lymph node enucleation, 367–368, 371 Transudates, 344 Travel-related tuberculosis, 892–893 control strategies, 790 Trehalose dimycolate, 47 Trial management committee, 923 Trial steering committee, 923 Trimethoprim/sulfamethoxazole see Cotrimoxazole Tsukamurella identification, 63 Tube thoracostomy, empyema management, 517 Tuberculids, 386–387, 484 clinical presentation, 488 clinicopathological variants, 488 Mycobacterium tuberculosis detection, 485 Tuberculin skin test, 4, 13, 25, 38, 130, 131, 179–185, 220–221, 323, 333 administration, 179–180, 220 adrenal tuberculosis, 509 adverse reactions, 180 arthritis, tuberculous, 502 Bacillus Calmette-Gue´rin (BCG) vaccination effects, 181, 761 breast tuberculosis, 472 childhood tuberculosis, 39–40, 133, 158, 324, 326, 327, 363, 393 multidrug resistant disease, 533 clinical reaction, 179, 180 conversion, 185, 325 clinical trial endpoints, 113 contact tracing, 325, 536, 537, 775, 776 outbreaks in social settings, 589 contraindication with phlyctenular conjunctivitis, 489 control programme impact assessment, 727 cutaneous tuberculosis, 489–490 elderly people, 565 false negative, 181, 220, 336, 482, 525, 569, 780 false positive, 181, 220, 336, 458, 569 female genital tuberculosis, 458 gender-related differences, 572 guidelines, 221 healthcare workers, 10–11 pre-employment screening, 706 historical aspects, 179 HIV–infected children, 160, 328 HIV–tuberculosis coinfection, 96, 97, 132, 181, 220, 525, 780 immune reconstitution inflammatory syndrome, 696, 697, 698 immune response, 719 immunosuppressed children, 155 interferon-g release assay comparisons, 187, 188, 221 interpretation, 180, 181, 182, 183, 185 positive test, 182, 220 risk of development of disease, 182 size of reaction, 182, 220, 728 latent infection detection, 729, 780, 781 target groups, 780 vaccine development challenges, 113 limitations, 112, 113, 148, 155, 158, 160, 181, 220–221, 328, 336, 363, 525 studies of prevalence, 727, 728 long-term care facility staff screening, 585 lymphadenitis, tuberculous, 393, 397 materials, 179, 180 meningitis, tuberculous, 415 neonates, following maternal tuberculosis exposure, 576 nontuberculous mycobacteria, 60 cross-reactivity, 181–182, 183 ocular tuberculosis, 482 pancreatic tuberculosis, 511 pericarditis, tuberculous, 355, 382 pleural effusions, 345 primary tuberculosis, 332 prison inmate screening, 586
pulmonary tuberculosis, 336 reading result, 180, 220 sensitivity/specificity, 158, 185, 192 serial testing, 182, 186 boosting (from 2-step testing), 182, 184 conversion detection, 185 reversion detection, 185 shelter accommodation inmates, 588 spinal tuberculosis, 497 terminology, 180 tumour necrosis factor a antagonist pretreatment assessment, 569 Tuberculization theory, 925 Tuberculomas, 241, 242 biopsy, 516 cavitation, 241 hepatosplenic, 304 imaging, 247, 248, 251–252, 300, 304, 305, 311–313 children, 271, 280, 286, 287, 288, 289 intracranial see Intracranial tuberculomas myelitic, 313 myocarditis, 359 ocular tuberculosis, 478 parenchymal of central nervous system, 311–313 target sign, 313 postprimary tuberculosis, 247, 248 renal, 305 thrombotic complications, 521 Tuberculosteric acid, 405 Tubo-ovarian abscess, 306, 384 Tumour necrosis factor a, 82, 84, 92, 98, 752, 761 Bacillus Calmette-Gue´rin (BCG) response, 112 dendritic cell production, 81–82 gene, tuberculosis susceptibility alleles, 87 granuloma formation, 81, 84 macrophage production, 81–82 tuberculosis–HIV coinfection, 719 Tumour necrosis factor a antagonists, 568–569 granuloma formation inhibition, 723 HIV–tuberculosis coinfection treatment, 104 nontuberculous mycobacteria pulmonary infection risk, 61 pretreatment patient assessment, 569 tuberculosis chemoprophylaxis, 569–570 latent disease progression risk, 781 management, 570 risk, 333, 377, 569 Twin studies, 87
U Uganda, 19 Ultrasound, 223 abdominal tuberculosis children, 269, 275, 276 HIV–tuberculosis coinfection, 526 lymphadenopathy, 382, 398 arthritis, tuberculous, 308, 502 ascites, 269, 301–302, 303 breast tuberculosis, 473 empyema, 347 endometrial tuberculosis, 459 fine needle aspiration guidance, 429, 473 gastrointestinal tuberculosis, 427, 429, 434 genitourinary tuberculosis, 441 hepatic tuberculosis, 395 immune reconstitution inflammatory syndrome, 697 male genital tuberculosis, 451, 452 biopsy guidance, 452 organ transplant TB patients, 567 ovarian tuberculosis, 512 pancreatic tuberculosis, 511 parathyroid tuberculosis, 508 peritoneal tuberculosis, 303, 461 pleural tuberculous, 344 renal failure TB patients, 563 tenosynovitis, tuberculous, 309 testicular tuberculosis, 512 thyroid tuberculosis, 467, 507 Ultraviolet germicidal irradiation, 9, 10, 708, 709 Ultraviolet light, 553 healthcare facility infection control, 904
1013
INDEX UNITAID, 798 United Kingdom, 22, 167, 886 bovine tuberculosis, 147 childhood tuberculosis, 40 multidrug resistant tuberculosis, 540 United States, 20, 22, 494, 515, 951, 979 childhood tuberculosis, 40 extensively drug-resistant tuberculosis, 540, 553 extrapulmonary tuberculosis, 377, 378 historical aspects, 2, 3, 4 HIV–tuberculosis coinfection, 524 multidrug resistant tuberculosis, 539, 540, 583, 584, 587, 927 musculoskeletal tuberculosis, 494, 495 nontuberculous mycobacteria, 60, 61 prison setting TB outbreaks, 585–587, 606 recent resurgence in tuberculosis, 11, 12, 927 Ureteric fibrosis, 441 Ureteric strictures, 441, 444, 521 Ureteric tuberculosis, 445–446, 521 children, 269 imaging, 252, 269, 441 surgical treatment, 448 Urine, human-to-animal TB transmission, 150 Urine specimens acid-fast bacilli staining, 441 collection, 218 cytology samples, 209, 210 genitourinary tuberculosis, 441, 451, 452 molecular diagnostic methods, 441, 452 mycobacterial culture, 383 processing, 210 Uruguay, 23 Uterine tuberculosis, 306 Uveitis, 387 adjuvant corticosteroids, 482 drug-induced, 965 tuberculous, 476 anterior, 478 posterior (choroidal tuberculosis), 478–479 Uzbekistan, 539
V Vaccines, 5, 25, 107–114, 789, 792 candidate designs, 107–108, 109, 735 clinical trials, 108 development challenges, 111–113 economic considerations, 114 ethical issues, 114 latent infection identification, 113 morbidity/mortality surveillance, 114 phase III trial sites, 113–114 safety issues, 113 trial clinical endpoints, 113 vaccine-induced immune correlates of protection, 111–113 ideal properties, 107, 108 post-infection strategies, 107 pre-infection strategies, 107 product development partnerships (PDP), 229–230 research approaches, 746, 747, 753–754 Stop TB Strategy implementation, 945–946 therapeutic, 107 types, 107, 108 Vacuolar-proton ATPase, 79 Vaginal involvement, 458 Vaginal tuberculous ulcer, 455 Vaginitis, drug-induced, 967 Variable nucleotide tandem repeats (VNTRs), 32, 52 Vas deferens tuberculosis, 450, 451 Vasodilation/flushing, drug-induced, 966 Ventilation, 130, 134, 553, 581, 585 aircraft cabins, 590 healthcare facilities, 583, 595, 705, 706, 708–709, 904 district clinics, 598 laboratory safety, 742–743 long-term care facilities, 585 prisons, 586 shelter accommodation, 588 silica exposure protection, 902 sputum collection areas, 603 workplace transmission prevention, 905
1014
Ventriculoperitoneal shunting, 418, 422 Verrucosa cutis, 387, 486 differential diagnosis, 492 vulval tuberculosis, 459 VersaTREK, 172, 175 Vertical transmission, 572–573 prevention, 578 Vertigo, antituberculous drug-induced, 685 see also Ototoxicity Vesicoperineal fistula, 452 Vestibulo-cochlear toxicity, antituberculous druginduced, 685–686 clinical presentation, 685 differential diagnosis, 685 investigations, 685–686 management, 686 pathogenesis, 685 prevention, 686 see also Ototoxicity Video-assisted thoracoscopic surgery, 516 empyema, 519 thoracic spinal tuberculosis, 520 tuberculous lymphadenitis, 521 Vietnam, 19, 23, 25, 887, 888, 889 internal migration, 897–898 Villemin, Jean Antoine, 146, 147 Viomycin, 613 adverse effects, 678 extensively drug-resistant tuberculosis, 613 multidrug resistant male genital tuberculosis, 455 resistance cross resistance, 613 mutations, 552 Viral hepatitis, 681 Virulence, 55–56 Mycobacterium tuberculosis strain differences, 12, 35, 401 phenolic glycolipids, 49, 401 regions of difference (RDs), 55 terhalose dimycolates, 49 Visual field disturbances, 504 Visual impairment, drug-induced, 683–684 differential diagnosis, 683 investigations, 683 management, 683–684 see also Optic neuritis Vitamin D receptor polymorphisms, tuberculosis susceptibility, 90 Voluntary Testing and Counselling services, 808 von Pirquet, Clement Freiherr, 4 Voriconazole, ritonavir interaction, 620 Vulval tuberculosis, 458, 459
W W strain, 553 W-Beijing strain, 35, 169 genotyping, 30, 32 Waksman, Selman, 4, 930, 931 Warfarin, rifampicin interactions, 687 Water chlorination, 391 Web information sources, 972–973 Wedge resection of lung, 517 Wegener’s granulomatosis, 444 histopathology, 207 Weight loss, 164, 165, 316, 333, 335, 352, 381, 382, 383, 386, 425, 426, 466, 495, 511, 650 childhood tuberculosis, 156, 157 gastrointestinal, 433, 434 multidrug resistant disease, 533 HIV–tuberculosis coinfection, 525, 807 Well–Riley equation, 14 Wells, William Firth, 8, 9 West Pacific Region, 951 Western Europe, 20, 21, 22, 167, 951, 979 historical aspects, 2, 3, 13 multidrug resistant tuberculosis, 539, 583 musculoskeletal tuberculosis, 494, 495 nontuberculous mycobacteria, 60 recent resurgence in tuberculosis, 11, 12 Wheezing childhood airway disease, 364 expansile pneumonia, 369 Whipple’s disease, 239
WHO essential drugs, 609 WHO reserve drugs, 609 WHO Special Programme for Research and Training in Tropical Diseasees, 749 WHO Stop TB Strategy see Stop TB Strategy WHO treatment regimens, 639–640 children, 628, 629 new cases, 639–640 previously treated cases, 640–641 Women, 572, 788, 886 access to healthcare, 756, 757, 887, 913, 981 barriers on pathway to cure, 912 tuberculosis–HIV coinfection, 572, 886 collaborative activities, 810–811 workplace tuberculosis, 902 see also Gender-related differences Workplace definition, 901 environmental safety, 905 tuberculosis policy, 905 tuberculosis transmission risk, 808 Workplace healthcare programmes, 904 collaborative activities, 905, 906 guiding principles, 905–906 monitoring performance, 905, 907 rewarding success, 906 situational analysis, 905 tuberculosis services establishment, 905 Workplace tuberculosis, 901–907 adherence facilitation, 906 antituberculous chemotherapy, 906 case detection, 906 control strategies, 904–905 high-risk settings, 902–903 protective measures, 904 outbreaks, 584, 588 record-keeping, 906 socioeconomic impact, 901–902 see also Occupational transmssion
Z Zambia, 150 Zidovudine, 624, 625 adverse effects, 557 drug interactions, 619 rifampicin, 623 Ziehl–Neelsen staining, 36, 46–47, 171, 173, 651 cutaneous tuberculosis lupus vulgaris, 487 miliary tuberculosis, 488 orificial tuberculosis, 487 primary chancre, 486 scrofuloderma, 488 tuberculids, 488 verrucosa cutis, 486 fine needle aspiration biopsy material, 212 lung tissue, 123 pleural effusion fluid, 381 quality assessment, 743 sensitivity, 739 smears, 218 spinal tuberculosis biopsy specimens, 498 tuberculosis diagnosis, 205 see also Acid-fast bacilli Zimbabwe, 19 Zoo animals, tuberculosis transmission, 147, 148 Zoonotic tuberculosis, 146, 147 animal reservoirs, 787 clinical presentation, 148–149 developed countries, 149 developing countries, 150 epidemiology, 149, 150 multidrug resistant tuberculosis, 150 pathogenesis, 148–149 prevention, 151 transmission, 147, 150 human-to-animal, 150 human-to-human, 150 ingestion of derivative products, 148 inhalation, 147–148 traumatic inoculation, 148 treatment, 151
